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      P3.09-01 - PDL1 Profile of Filipino Lung Adenocarcinoma Patients Show Moderate Positivity and Low EGFR Correlation

      12:00 - 13:30  |  Presenting Author(s): Francisco III Maramara Heralde  |  Author(s): Maria Teresa Alhambra Barzaga, Nelia Tan-Liu, Mary Suzette Angeles, Samuel Bernal

      • Abstract

      Background

      The recent approval of anti-PD1 or PDL1 immunotherapy based on promising clinical trial results ushers in the accelerated adoption of pertinent companion diagnostics to make available the relevant therapy to cancer patients. The Lung Center of the Philippines established a routine immunohistochemistry-based diagnostic for PDL1 in collaboration with pharmaceutical companies to address the existing gap in diagnostic information that may have therapeutic implications in terms of who and to what extent, this subset of population may benefit from this new targeted therapy. This study aims to report the PDL1 profile of Filipino lung adenocarcinoma patients and evaluate its possible correlation with EGFR mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tumor block samples from 345 Filipino lung adenocarcinoma patients were processed for PDL1 testing using the Ventana PDL1 Assay. Samples with positive results were subjected to Cobas EGFR mutation testing.

      4c3880bb027f159e801041b1021e88e8 Result

      One hundred forty-two samples (i.e., 41.2%) were positive for the PDL1 markers. Majority of samples tested were males (i.e., 62-65% males vs. 35-38% females) with ages ranging from 64-66 years for both males and females. From a subset of eleven PDL1 positive samples, only three showed positive EGFR mutations (i.e., 27.3%) with two, showing L858R mutation and one T790M mutation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Moderate presence of the PDL1 markers were shown by Filipino lung adenocarcinoma patients suggesting that a moderate population could potentially benefit from anti-PD1 or PDL1 immunotherapy. Meanwhile, the low presence of EGFR mutation detected from the subset of PDL1 positive samples suggest a possibly mutually exclusive pattern for these biomarkers consistent with those reported in other studies. Albeit preliminary, co-EGFR testing could provide rationalization of clinical response and an alternative therapeutic targeting for this subset of patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-02 - Utilization of Laboratory Developed Tests for PD-L1 Evaluation is Dependent on Tumor Type

      12:00 - 13:30  |  Presenting Author(s): Jingxin Qiu  |  Author(s): Ankush Chander, Boulos Beshai, Kristopher Attwood, Angela R. Omilian

      • Abstract

      Background

      PD-L1 expression level evaluated by immunohistochemistry plays an important role in immunotherapy for many malignancies including non-small cell carcinoma of the lung (NSCLC), adenocarcinoma of the gastroesophageal junction/stomach (GEJ-G), melanoma and etc. With the growing number of indications for the use of PD-L1 immunotherapy, it has become impracticable for laboratories to adopt and maintain the various FDA approved assays for different tumor types. Harmonization to a standard assay would alleviate the current challenges and allow testing to be uniform among laboratories. The primary objective of this study was to determine if laboratory developed tests (LDTs) utilizing available antibodies are concordant with the FDA approved assays in NSCLC, melanoma and GEJ-G, and can therefore serve as alternatives for FDA approved assays.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiple tissue microarray slides containing NSCLC (714 cases), melanoma (87 cases) and GEJ-G (194 cases) were stained for PD-L1 with the 22C3 pharmDx Kit, the 28-8 pharmDx Kit, and/or three LDTs (clones 22C3, 28-8 and E1L3N). PD-L1 expression on tumor cells was scored for NSCLC and malignant melanoma, whereas expression on tumor cells and immune cells was scored for GEJ-G. All TMA slides were digitally scanned and independently evaluated by three board certified pathologists (JQ, AC, and BB) who were blinded to staining conditions. Raw scores were converted to a composite score based on the range of raw scores. Composite scores were compared for level of agreement utilizing a Kappa score and interclass correlation coefficients displayed on Bland-Altman plots.

      4c3880bb027f159e801041b1021e88e8 Result

      For NSCLC, the two FDA approved assays have a high level of concordance (Kappa 0.88, 95% CI 0.85-0.90) and the two LDTs (22C3 and E1L3N) also have high level of concordance (Kappa 0.82, 95% CI 0.78-0.85); however, concordance between two FDA approved assays and the two LDTs was low. For gastric adenocarcinoma, the 22C3 FDA approved assay and 22C3 LDT has a high level of concordance (Kappa 0.90, 95% CI 0.86-0.94), but the E1L3N LDT has a low level of concordance with both the 22C3 FDA approved assay and the 22C3 LDT. For malignant melanoma, there was low concordance among two FDA approved assays and two LDTs (28-8 and E1L3N).

      8eea62084ca7e541d918e823422bd82e Conclusion

      These results suggest that although LDTs can be used for evaluating PD-L1 in tumor, the utilization of LDT is tumor type dependent. One single LDT may not be sufficient to serve as appropriate alternative for the FDA approved assays on different types of tumor.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-03 - Alteration of Gut Microbiome in Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Jun Chen  |  Author(s): Ming Li, Jieli Yuan, Shu Wen

      • Abstract

      Background

      Lung cancer is the leading cause of cancer death. Better understanding of factors and pathways involved in lung cancer is needed to improve diagnose and treatment strategies. Recent studies have provided insights into the possible correlation between intestinal dysbiosis and cancer development. Although the immunological relationship between gut and lung had been suggested by many researches, however, to date, no study had investigated the characterization of gut microbiome in treatment naïve lung cancer patients, whether it is distinct from that of health individuals and contribute to the onset and development of lung cancer remain unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this study, we investigated whether gut microbiome of lung cancer patients (LC, n=28) is altered compare with that of matched healthy individuals (HC, n=19) by high throughout sequencing of the V3-V4 regions of 16S rDNA in their fecal samples. We also identified microbiota signatures specific for different histological types of lung cancer, including SSC, ADC, and SCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      The gut microbiome of lung cancer patients is characterized by decreased relative abundance of Prevotella, and increased bacteria groups such as Actinomyces, and Streptococcus, etc. We also detected an mild structural shift in gut microbiome between ADC and SCLC patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results showed that the gut microbiome of lung cancer patients altered significantly compared with healthy individuals. However, the association between microbial dysbiosis and lung cancer is not clearly understood, future studies involving larger cohorts and metagenomics, or metabolomics, may elucidate the correlations between gut microbiota and lung cancer development.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-04 - Assessment of PD-L1 Expression in Cytology Samples: An Anlaysis of 263 Consecutive NSCLC Biopsies.

      12:00 - 13:30  |  Presenting Author(s): Peter B Illei  |  Author(s): Ankit Rajgariah

      • Abstract

      Background

      FDA approved anti-PD1 therapy can be considered for first-line use in advanced NSCLC with high (≥50%) PD-L1 expression. FDA approval was based on resection and core biopsy specimens, thus excluding most cytology samples. Since the majority of lung cancer patients are diagnosed with advanced stage disease and therefore are not candidates for surgical resection, bronchoscopic biopsies targeting N1 or N2 lymph nodes and/or the primary tumor are often the first biopsies these patients are subjected to. There is a great clinical need to determine the suitability of cytology specimen in the assessment of PD-L1 expression of NSCLC since often these are the only tissue samples available in advanced stage lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PD-L1 immunohistochemistry was performed using the 22C3 antibody (Dako) on a Ventana automated platform on 263 consecutive clinical cytology samples in a 14 month period. The assay was cross validated with the FDA approved companion diagnostic test. The samples included 216 cell blocks of fine needle aspirates of various sites, as well as cell blocks of body cavity effusions, and 42 core biopsies of various organs (20 gauge cores). Tissue clots (majority) or cell blocks were made from the aspirates followed by fixation in 10% buffered formalin. After fixation the tissue clots, cell blocks, core biopsies and lung biopsies were subjected to routine tissue processing.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 246 (93.5%) samples with adequate tumor cellularity and 17 (6.5%) samples with no or less than 100 viable tumor cells (all cell blocks). The majority of samples (n216) were tissue clots/cell blocks, followed by core biopsies (n42) and other biopsy types (n5). No (<1%) PD-L1 expression was seen in 93 (35%), low (1-49%) expression in 57 (22%) and high (≥50%) expression in 96 (36.5%) cases. High PD-L1 expression was detected in 42 of 94 (44.7%) N2, 9 of 21 (42.8%) N1 lymph nodes and in 15 of 37 (40.5%) pleural/pericardial fluids. The cohort included 37 biopsies of distant metastases with high expression detected in 12 (32.4%) samples. Interestingly, all 12 liver metastases showed no (n6) or only low (≤10%, n6) PD-L1 expression. The rest of the specimens included lung mass aspirates, as well as core biopsies and FNA of N3 lymph nodes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tissue blocks of cytology specimens appear to be an adequate source of non-small cell carcinoma tissue for PD-L1 testing. Additional analysis is pending to determine response rates to immunotherapy in order to confirm the validity of testing results of cytology samples.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-05 - Significance of the Expression of PD-L1/PD-1 by Tumoral and Immune Cells in Non-Small Cell Lung Cancer. 

      12:00 - 13:30  |  Presenting Author(s): Cristian Ortiz -Villalón  |  Author(s): Luigi De Petris, Lorand Kis, Akira Yoshikawa, Hoa Ngoc, Anja C Roden, Junya Fukuoka, Angeles Montero

      • Abstract

      Background

      Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer, including adenocarcinoma, squamous cell carcinoma and large cell carcinoma. There is solid evidence that demonstrates the existence of anti-tumor adaptive T-cell mediated immunity activation in lung tumors, indicating that lung cancers are immunogenic. PD-L1and PD-1 expression level in lung cancer may be a predictive biomarker for the use of PD1/PD-L1 inhibitors. However, the reproducibility of PD-L1 staining using different antibodies and platforms is still a matter of debate. We assessed whether PD-L1 expression in non-small cell lung cancer is associated with specific clinical features or survival using four different antibodies and if the expression of PD-1 in TILs correlates with the expression of PD-L1 in same group of cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PD-L1 and PD-1 status was assessed with IHC (AB clone SP142 and SP263 - Ventana, 22C3, 28-8 – Dako and PD-1) on archival FFPE surgical tumor specimens, arrayed on tissue microarrays (TMAs) with duplicate 1 mm cores, from Karolinska University Hospital. All patients (n = 598) underwent curative surgery between 1987 and 2015. The following cases were excluded from survival analysis (n = 89): R1 resection, early post-operative mortality, adjuvant chemo- or radiotherapy. PD-L1 staining was scored as positive if present in > 1% of tumor cells, independently of staining intensity.

      4c3880bb027f159e801041b1021e88e8 Result

      Patient and tumor characteristics were as follows. Median age (IQR): 68 years (27-89); gender: male/female 54%/46%; histology: squamous-cell carcinoma (SCC)/Non-squamous (N-Sq)-NSCLC/carcinoid 219 (32%)/394 (58%)/45(7%); p-stage: IA/IB/IIA/IIB/IIIA/IIIB 50%/26%/10%/10%/2%/0.2%. PD-L1 28-8 was positive in 11% of cases, Pearson Chi-square p<0.0001). PD-L1 positivity 22C3/SP263/SP142 was 10%/13%/3%. All carcinoids were negative for PD-L1. In NSCLC, PD-L1 positivity for each antibody was associated with tumor size (T1/T2-4; Fisher’s exact test, p<0.001) and grade of differentiation (G1, G2 and G3; p<0.0002). Statistically significant association between PD-L1 expression and OS was only observed using the clone SP263 (log-rank p=0.013). PD-1 expression in TILs correlates with those of PD-L1 (clone 28-8).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this surgical series, the clone SP142 showed less PD-L1 expression in the tumor cells. PD-L1 status was associated with tumor size, grading and only the clone SP263 showed association between its expression and survival ratio. PD-1 expression in TILs correlates with those of PD-L1.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-06 - The Link Between Tumor Promoting Fibrous Microenvironment and Immunosuppressive Microenvironment in Stage I Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Takashi Sakai  |  Author(s): Keiju Aokage, Shinya Neri, Hiroshi Nakamura, Satoshi Okada, Tomohiro Miyoshi, Kenta Tane, Masato Sugano, Motohiro Kojima, Satoshi Fujii, Takeshi Kuwata, Atsushi Ochiai, Masahiro Tsuboi, Genichiro Ishii

      • Abstract

      Background

      Podoplanin-positive cancer-associated fibroblasts (PDPN (+)CAFs) play an important role in cancer progression in non-small-cell lung cancer (NSCLC). The aim of this study is to clarify the correlation between fibrous microenvironment containing PDPN (+) CAFs and immune microenvironment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      174 cases with stage I primary lung adenocarcinoma were analyzed in this study. We evaluated PDPN (+) CAFs and immune-related cells; CD 204-positive tumor-associated macrophages (CD204 (+) TAMs); CD8-positive T cells; and FOXP3-positive T cells in cancer stroma by immunohistochemical staining method. By analyzing the gene expression profiles of lung adenocarcinoma (n=442), we compared the expression level of immune-regulatory cytokines between PDPN expression-high group and PDPN expression-low group.

      4c3880bb027f159e801041b1021e88e8 Result

      Presence of PDPN (+) CAFs was a risk factor for recurrence (P = 0.012). The number of CD204 (+) TAMs was significantly higher in PDPN (+) CAFs cases than in PDPN (+) CAFs cases (P < 0.001). Furthermore, CD8 (+)/FOXP3 (+) T cell ratio was significantly lower in PDPN (+) CAFs cases (P = 0.027). Within the same tumor, the number of CD 204 (+) TAMs was significantly higher in PDPN (+) CAFs area than in PDPN (-) CAFs area (P < 0.001). Moreover, CD8 (+)/FOXP3 (+) T cell ratio tend to be lower in PDPN (+) CAFs area than in PDPN (+) CAFs area (P = 0.062). Microarray analysis revealed PDPN expression-high group had significant higher levels of M-CSF; a cytokine inducing M2 macrophage polarization, and TGFβ1, IDO, VEGFA and galectin 1; immunosuppressive cytokines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current results revealed that lung adenocarcinoma with PDPN (+) CAFs is typified by an immunosuppressive microenvironment, suggesting the close link between tumor promoting fibrous microenvironment and immune microenvironment.

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      P3.09-07 - Immunohistochemical Expression of Programmed Death-Ligand 1 in Diabetic Patients vs Non-Diabetics with Non-Small Cell Lung Cancer 

      12:00 - 13:30  |  Presenting Author(s): Negar Rassaei  |  Author(s): Michael Phillip Zaleski, Setareh Sharzehi, Rickie P Voland, John Michael Varlotto, Yongjun Liu

      • Abstract

      Background

      Immunohistochemical (IHC) expression of programmed death-ligand 1 (PD-L1) serves as a predictive biomarker to select a subgroup of patients who may benefit from immunotherapy. Diabetes mellitus type 2 (DM2) has been shown to be present in approximately 20-25% of lung cancer patients and adversely affects lung cancer outcome. Yet, there are no established studies which investigate potential differences in PD-L1 expression in this group of patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To investigate expression of PD-L1 in DM2 patients compared to non-DM2 patients, we assembled a retrospective cohort of 79 surgically-resected NSCLC cases (39-adenocarcinoma, 40-squamous cell carcinoma) without previous malignancies or pre-operative radiation. Clinical data were obtained by chart review. Patients with DM2 had Hb1Ac levels of 7.5-7.7. Histologic slides were methodically reviewed. PD-L1 (DAKO 22C3) immunohistochemistry was performed on slides with the maximum amount of viable tumor. Tumor positive score (TPS) was evaluated based on IASLC guidelines as follows: 0: no staining; 1: <1%; 2: 1-49%; and 3: >50%. Immunoreactivity was compared using Chi-square and Fisher’s exact tests.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 79 cases of NSCLC, 40 (50.6%) were patients with DM2, and consisted of 20 (50%) adenocarcinoma, and 20 (50%) squamous cell carcinoma. Non-DM2 patients showed a relatively equal TPS distribution from 0 to more than 50%; however, DM2 group largely showed TPS of less than 50% (P=0.0319 Chi-square test); (P=0.0347 Fisher's Exact test); (Table 1). No significant difference was observed between the two groups in terms of overall survival, local recurrence, metastasis, peritumoral inflammation, and necrosis.

      pd-l1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      DM2 patients were less likely to have PD-L1 >50%, and therefore they may be less likely to respond to PD-L1 inhibition alone in the adjuvant setting. These findings are in accordance with the literature that supports a worse prognosis, tendency for co-morbidities, and known immunologic defects for DM2 patients with NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-08 - Tumor Heterogeneity and Molecular Profile of NSCLC in Thai Population

      12:00 - 13:30  |  Presenting Author(s): Thanyanan Reungwetwattana  |  Author(s): Supoj Detarkom, Pimpin Incharoen, Artit Jinawat, Narumol Trachu, Kaettipong Kamprerasart, Naiyarat Prasongsook, Piyawan Tienchainaanda, Nareenart Iemwimangsa, Krarun Sararat, Wasun Chantratita

      • Abstract

      Background

      Oncogenic driven mutation is the key to develop targeted therapy in lung cancer. Different ethnicity and tumor heterogeneity affect the prevalence of molecular alteration. This study aimed to explore the unique molecular profile of lung adenocarcinoma in Thai population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We studied 166 lung adenocarcinoma patients’ molecular profile using Next Generation Sequencing (NGS) on 45 genes lung cancer panel (Ion Torrent system). Variants from NGS with coverage of higher than 1000X and cut off at 2% alternate variant frequency were considered positive. We validated the positive mutation of EGFR, BRAF, and KRAS by Real- Time PCR using the Amoy DX kit.

      4c3880bb027f159e801041b1021e88e8 Result

      This study found 68%(113/166) of EGFR mutation, 9.6%(16/166) of BRAF V600E, 32.5% (54/166) of KRAS mutation, 9%(15/166) of MET exon14 splice site, 4.8% (8/166) AKT mutation (E17K), 2.4% (4/166) of ROS1 mutation, 0.6% (1/166) of PIK3CA mutation (H1047R), and 0.6% (1/166) of PTEN mutation. Furthermore, we also found 40 patients (24.1%) who had more than one mutation in each person. We further validated the positive results by Real-Time PCR. Thirteen patients were obtained tissue from different organs and some with different period of time. T790M usually develop later in EGFR-positive patients who failed 1st or 2nd generation EGFR-TKI. Two patients (patient 5&9) who had lung surgery different lobe in same operation, had different mutation in tissues and one patient (patient 13) who obtained tissue from lung and pleural effusion cell block in different period of time had totally different mutation (Table1).

      Table1 Tumor heterogeneity profile in lung cancer patients

      case

      Hetrogenety in different organ

      date obtained tissue

      Gene mutation

      EGFR

      KRAS

      ROS

      PTEN

      AKT

      MET

      BRAF

      1

      RLL lobectomy

      12-Jun-2012

      Exon 19 Deletion

      negative

      negative

      negative

      negative

      negative

      negative

      Right lung

      4-May-2016

      Exon 19 Deletion T790M

      negative

      negative

      negative

      negative

      negative

      negative

      2

      lymph node

      16-Mar-2017

      negative

      negative

      negative

      negative

      negative

      negative

      negative

      Bone

      9-Apr-2017

      negative

      negative

      negative

      negative

      negative

      negative

      negative

      3

      Right upper lung biopsy

      20-Jan-2016

      Exon 19 Deletion

      negative

      negative

      negative

      negative

      negative

      negative

      Lung biopsy

      31-Mar-2017

      T790M

      negative

      negative

      negative

      E17K

      negative

      negative

      4

      lymph node

      13-Jan-2016

      negative

      G12A

      negative

      negative

      negative

      negative

      negative

      skin

      17-Jan-2016

      negative

      G12V G12D

      negative

      negative

      negative

      negative

      negative

      left humerous

      30-Jun-2016

      negative

      G12V

      negative

      negative

      negative

      negative

      negative

      5

      RML lobectomy

      13-Nov-2013

      Exon 19 Deletion

      G13D

      negative

      negative

      negative

      negative

      negative

      LUL lobectomy

      14-May-2014

      negative

      G12D G13D

      negative

      R233*

      negative

      negative

      negative

      LUL lobectomy

      14-May-2014

      negative

      G12V G12D

      D2033N

      negative

      negative

      negative

      negative

      6

      Right pleura biopsy

      11-Jan-2016

      Exon 19 Deletion

      negative

      negative

      negative

      negative

      negative

      negative

      RUL biopsy

      1-Mar-2017

      Exon 19 Deletion

      negative

      negative

      negative

      negative

      negative

      negative

      7

      RUL biopsy

      28-Sep-2015

      L858R

      negative

      negative

      negative

      negative

      negative

      negative

      Left pleural fluid cell block

      27-Jun-2016

      negative

      negative

      negative

      negative

      negative

      negative

      negative

      8

      Right pleural fluid cell block

      25-Mar-2016

      Exon 19 Deletion

      negative

      negative

      negative

      negative

      negative

      negative

      Left pleural fluid cell block

      9-Dec-2016

      T790M

      negative

      negative

      negative

      negative

      negative

      negative

      9

      RML lobectomy

      14-Mar-2013

      negative

      G13S

      negative

      negative

      E17K

      negative

      negative

      RLL wedge resectionRLL lo

      30-Mar-2017

      G719A L861Q

      negative

      negative

      negative

      negative

      negative

      negative

      10

      RLL lobectomy

      26-Aug-2013

      negative

      G12C G12D

      negative

      negative

      negative

      negative

      negative

      Left lingular lobe segmental resection

      9-Oct-2014

      negative

      G12D

      negative

      negative

      negative

      negative

      negative

      LUL wedge resection

      11-Feb-2016

      negative

      G12D

      negative

      negative

      negative

      negative

      negative

      LUL lobectomy

      4-Jun-2017

      negative

      G12D

      negative

      negative

      negative

      negative

      negative

      LLL resection

      9-Oct-2014

      negative

      G12D

      negative

      negative

      negative

      negative

      negative

      11

      Right pleural cell block

      21-Jul-2014

      L858R

      negative

      negative

      negative

      negative

      c.3028G>A exon 14 splicing

      negative

      Ascites

      9-Jun-2017

      T790M L858R

      negative

      negative

      negative

      negative

      negative

      negative

      12

      LUL biopsy

      24-Feb-2015

      L858R

      negative

      negative

      negative

      negative

      negative

      V600E

      Lt lung biopsy

      8-Jul-2016

      L858R

      negative

      negative

      negative

      negative

      negative

      negative

      13

      RLL biopsy

      14-Oct-2015

      negative

      negative

      negative

      negative

      negative

      c.3028+1G>T exon 14 splicing

      negative

      pleural fluid cell block

      15-Nov-2016

      Exon 19 Deletion T790M

      negative

      negative

      negative

      negative

      negative

      negative

      8eea62084ca7e541d918e823422bd82e Conclusion

      Thai populations have unique molecular alteration compared to the other ethnicities, especially, higher of BRAF V600E and MET exon14 splice site. Our population also has high co-mutation prevalence. Tumor heterogeneity is needed to explore in the larger cohort.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-10 - Circulating Cell-Free DNA (cfDNA) Molecular Profile of Thai NSCLC Patients Using Difference Variant Frequency of NGS

      12:00 - 13:30  |  Presenting Author(s): Nareenart Iemwimangsa  |  Author(s): Narumol Trachu, Vantanit Pairoj, Angkana Charoenyingwattana, Pimpin Incharoen, Supoj Detarkom, Somthawin Lukrak, Lalida Arsa, Nanamon Monnamo, Sarunporn Techasurungkul, Thanyanan Reungwetwattana, Wasun Chantratita

      • Abstract

      Background

      Detecting cfDNA in the liquid biopsy has become a promising method to explore the genetic landscape of tumor heterogeneity. We developed a pilot-study to find the suitable cutoff of variant frequencies detected from liquid biopsy by NGS to track tumor-associated mutations in NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ninety-four samples (24 early-stage NSCLC, 70 late-stage NSCLC) were collected from Ramathibodi Hospital, Thailand. Profiling cfDNA using Ion Proton NGS platform. Overall average base coverage depth from NGS was 10,000x, all variants selected have read depths >10x in order to reach 0.1% sensitivity. Each of selected variants has threshold variant quality (QUAL) >20. Droplet digital PCR (ddPCR) was performed for EGFR-mutation testing to determine the appropriated cutoff variant frequency from NGS.

      4c3880bb027f159e801041b1021e88e8 Result

      In early-stage NSCLC, a minimum-threshold variant frequencies at 0.1% could detect EGFR exon19 deletion in all samples (24,100%), with BRAF (12,50%), KRAS (21,87.5%) and other mutations in AKT1, MET, PIK3CA, PTEN, ROS1 (14,58%). None of these mutations identified when using conventional level cutoff at 3% (Table1). ddPCR observed EGFR-mutations in 2 early-stage cases only (8.3%). In late-stage NSCLC, 64 (91.4%) cases were observed multiple mutations, suggesting tumor heterogeneity. At 0.1% cutoff in NGS, Thirty-six (52.9%) cases of EGFR-mutations in NGS and ddPCR were identical. Thirteen (18.6%) samples shown partial discrepancies in the mutations. Interestingly, NGS found EGFR-mutations in 20 (28.6%) samples which ddPCR failed to detect, 12 of them contained T790M. Only one sample (1.4%) using 0.1% cutoff was unable to detect EGFR-mutation. Higher variant allele frequencies were found in EGFR-positive detected by ddPCR compared to not-detected by ddPCR.

      Table1
      Mutations detected variant allele frequencies detected from liquid biopsy by NGS at minimum threshold cut-off 0.1% variant allele frequencies detected from liquid biopsy by NGS at minimum threshold cut-off 0.1% variant allele frequencies detected from liquid biopsy by NGS at conventional level detection of somatic variants cut-off 3% variant allele frequencies detected from liquid biopsy by NGS at conventional level detection of somatic variants cut-off 3% variant allele frequencies detected from liquid biopsy by ddPCR (EGFR only) variant allele frequencies detected from liquid biopsy by ddPCR (EGFR only)
      N (%) median (range) N (%) median (range) N (%) median (range)
      BRAF (V600E) early stage total N=24 12 (50%) 0.8 (0.3-2.5) 0 (0%) 0 NA NA
      BRAF (V600E) late stage total N=70 11 (15.7%) 0.6 (0.1-1.1) 0 (0%) 0 NA NA
      KRAS early stage 21 (87.5%) 0.1 (0.1-0.5) 0 (0%) 0 NA NA
      KRAS late stage 50 (71.4%)

      0.2

      (0.1-13.6)

      3 (4.3%) 11.1 (5.8-14.3) NA NA
      AKT1 (E17K) early stage 7 (29.2%) 0.1 (0.1-0.7) 0 (0%) 0 NA NA
      AKT1 (E17K) late stage 12 (17.1%) 0.1 (0.1-0.7) 0 (0%) 0 NA NA
      MET exon 14 splicing early stage

      4 (16.7%)

      0.1 (0.1-0.1) 0 (0%) 0 NA NA
      MET exon 14 splicing late stage 3 (4.3%) 0.2 (0.2-0.2) 0 (0%) 0 NA NA
      PIK3CA early stage 9 (37.5%) 0.2 (0.1-0.8) 0 (0%) 0 NA NA
      PIK3CA late stage 19 (27.1%) 0.3 (0.1-0.7) 0 (0%) 0 NA NA
      PTEN (R233*) early stage 6 (25.0%) 0.1 (0.1-0.4) 0 (0%) 0 NA NA
      PTEN (R233*) late stage 11 (15.7%) 0.1 (0.1-0.2) 0 (0%) 0 NA NA

      ROS1

      early stage 0 (0%) 0 0 (0%) 0 NA NA

      ROS1

      late stage 4 (5.7%)

      0.55

      (0.1-0.7)

      0 (0%) 0 NA NA

      EGFR

      Exon 19 Deletion

      early stage 24 (100%)

      0.35

      (0.1-2.1)

      0 (0%) 0 1 (4.2%) 0.5 (0.5-0.5)

      EGFR

      Exon 19 Deletion

      late stage 25 (35.7%)

      0.6

      (0.1-49.0)

      6 (8.6%) 9.4 (4.5-49.5) 20 (28.6%) 0.65 (0-49.0)
      EGFR L858R early stage 5 (20.8%) 0.2 (0.1-0.5) 0 (0%) 0 0 (0%) 0
      EGFR L858R late stage 21 (30%) 1.4 (0.1-9.7) 4 (5.7%) 4.6 (4.4-6.4) 14 (20%) 1.8 (0.3-9.7)
      EGFR T790M early stage 8 (33.3%) 0.1 (0.1-0.2) 0 (0%) 0 0 (0%) 0
      EGFR T790M late stage 30 (42.9%) 0.1 (0.1-4.6) 2 (2.9%) 7.5 (5.3-9.7) 16 (22.9%) 0.15 (0-4.1)
      EGFR Exon18 (G719X) early stage 6 (25%) 0.2 (0.1-0.4) 0 (0%) 0 1 (4.2%) 0.4 (0.4-0.4)
      EGFR Exon18 (G719X) late stage 4 (5.7%)

      4.5

      (0.1-49.2)

      2 (2.9%)

      27.9

      (6.7-49.2)

      2 (2.9%) 25.6 (2-49.2)
      EGFR Exon 20 Insertion early stage 0 (0%) 0 0 (0%) 0 0 (0%) 0
      EGFR Exon 20 Insertion late stage 1 (1.4%)

      73.8

      (73.8-73.8)

      1 (1.4%)

      91.7

      (91.7-91.7)

      0 (0%) 0

      8eea62084ca7e541d918e823422bd82e Conclusion

      Detecting variant frequencies at 0.1% could reveal more hidden tumor-associated mutations compared to variant frequency cutoff at 3%. With a careful validation, profiling cfDNA using NGS can be a crucial method to accurately select treatment for NSCLC patients in the future.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-11 - Genomic Organization at Large Scales (GOALS) within Nuclei and Cell Sociology for Predicting Lung Cancer Outcomes

      12:00 - 13:30  |  Presenting Author(s): Calum Macaulay  |  Author(s): Martial Guillaud, Katey S.S. Enfield, Zhaolin Xu, Stephen Lam, Wan Lam, Paul Gallagher

      • Abstract

      Background

      Accurate prediction of the biological aggressiveness of lung cancers in patients from limited material could have utility with respect to patient treatment planning. We examined the hypothesis that the quantification of large scale DNA organization or GOALS within the nucleus combined with tumour microenvironment as quantified by cell sociology (which cells types are adjacent which cell types) could predict patient outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue (TMA cores) from patients with poor outcomes (lung cancer mortality within 24 months) and good outcomes (5+ year survivors) was stained using a stochiometric DNA stain (Feulgen-Thionin). High resolution brightfield imaging of 29 cores was performed using multiple wavelengths and spectral unmixing used to retrieve the DNA concentration at every pixel. In house software was used to automatically segment all the nuclei within each core, calculate 100+ features for each nucleus and classify each nucleus as epithelial, stromal or immune in origin. Further each nucleus was scored as coming from a patient with poor or good outcome.

      For each TMA core the percentage of these cell categories was tabulated as well as cell-cell association frequencies (for example the frequently an epithelial cell predicted to have come from a patient with good outcome was found next to a stromal cell predicted to come from a patient with poor outcome). Cell percentages and cell-cell interaction frequencies were used to predict patient outcome.

      4c3880bb027f159e801041b1021e88e8 Result

      abstract2-1.jpgMany of the individually calculated features had a statistically significant association with patient outcome. Four+ features could predict outcome with an 79% accuracy, 15+ different pairs of features could predict patient outcome with greater than 85% accuracy. Epithelial- stromal cell interactions and stromal cell – immune cell interactions were particularly predictive of outcome suggesting that microenvironment cell - tumour cell interactions predict future biological activity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This pilot study suggests that GOALS and cell sociology could predict patient outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-12 - Molecular and Immunohistochemical Correlates of RB1 Inactivation in Small Cell Lung Carcinoma

      12:00 - 13:30  |  Presenting Author(s): Navin Rajput Mahadevan  |  Author(s): Lynette M Sholl, David Hwang

      • Abstract

      Background

      Retinoblastoma (RB1) is a critical negative regulator of cell cycle progression, and serves as a tumor suppressor gene that is inactivated in many tumor types, including small cell lung carcinoma (SCLC). Because biallelic inactivation of RB1 has been observed in virtually all SCLC, loss of RB1 expression in the correct context is considered highly suggestive of SCLC or SCLC-like neuroendocrine carcinomas. However, the relationship between the genomic inactivation of RB1 and expression in SCLC has yet to be fully defined. Here, we characterize the genetic and immunohistochemical correlates of RB1 inactivation in SCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      SCLC (n=57), and combined SCLC cases with a non-neuroendocrine component (CSCLC; n=5), that had undergone targeted next generation sequencing (NGS) (Oncopanel, 309-447 genes) were retrospectively identified. Designation of the molecular mechanism of RB1 inactivation was pursued by integrative analysis of RB1 variant type, variant allele fraction, and heterozygosity of the RB1 locus. RB1 protein status was interrogated in a subset of SCLC (n=25, 19 with biallelic inactivation) and CSCLC (n=2) by immunohistochemistry (IHC).

      4c3880bb027f159e801041b1021e88e8 Result

      77% (44/57) of SCLC showed biallelic inactivation of RB1 by NGS, most commonly through a loss-of-function (LOF) variant and associated loss of heterozygosity (LOH, 65%). The most common mechanisms of RB1 genetic inactivation in these cases were nonsense (32%), frameshift (25%), and splice site (23%) variants, respectively. RB1 protein expression was lost in 89% (17/19) of SCLC with biallelic RB1 inactivation; the two remaining cases harbored RB1 splice site variants and displayed weak, patchy RB1 expression. Additionally, 80% (5/6) of SCLC without molecular evidence of RB1 biallelic inactivation showed loss of RB1 expression. Overall, 60% (3/5) of SCLC harboring splice site variants retained weak RB1 expression. 60% (3/5) of CSCLC showed molecular RB1 inactivation in all tumor cells. While one CSCLC showed loss of RB1 expression in both histologic components, the other tumor, which harbored a RB1 splice site variant, retained strong RB1 expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Genetic inactivation of RB1 in SCLC may not be identified in ~20% of cases via targeted NGS . While most SCLC with biallelic RB1 inactivation show loss of RB1 expression, retention of weak RB1 expression in SCLC does occur and may be associated with RB1 splice site variants. While additional investigation is needed to interrogate the functional and clinical significance of retained RB1 expression in SCLC, these data suggest that genetic RB1 inactivation does not always result in loss of protein expression, which may have implications for disease classification.

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      P3.09-13 - Molecular Profiling Suggests the Different Mechanisms Among Local Invasiveness in Resected Human Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Toshi Menju  |  Author(s): Terumasa Sowa, Naoto Imamura, Shigeto Nishikawa, Koji Takahashi, Ryo Miyata, Hiroyuki Ishikawa, Misa Noguchi, Masatsugu Hamaji, Daisuke Nakajima, Akihiro Ohsumi, Toshihiko Sato, Toyofumi Fengshi Chen-Yoshikawa, Makoto Sonobe, Hiroshi Date

      • Abstract

      Background

      Local invasive factors are pathologically defined as pleural or lymphovascular invasion in lung cancer. Accumulating evidences have shown that these factors are associated with metastatic activity finally leading to poor survival of the patients. Here we examined the correlations of cancer-progressive molecular markers with local invasiveness in resected human adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinical samples were obtained from the 256 cases of lung adenocarcinoma which were consecutively operated to treat from January 2001 to December 2007 in our institution. Pathological stage distribution of the cases by TNM classification was below: 1A: 118, 1B: 71, 2A: 22, 2B: 4, 3A: 23, 3B: 1, 4:17.

      Tissue microarrays were immunohistochemically (IHC) stained. The previously published IHC data of molecular markers and DNA mutation data of EGFR and K-ras using our same cohorts were integrated. These markers included TP53, E-cadherin, vimentin, TWIST, CD133, CD44, Aldehyde dehydrogenase (ALDH), Carbonic anhydrase (CA)-9, Lactate dehydrogenase (LDH)-A, Glucose transporter (GLUT)-1, Hypoxia inducible factor (HIF) 1α, Ubiquitin C-terminal hydrolase (UCH)-L 1, Grb2, GEP100, Arf6, AMAP1, EPB41L5, phosphorylated receptor tyrosine kinases (EGFR, HER2, cMet, VEGFR2).

      Statistical analyses were performed by chi-square test or log-rank test. For survival data analyses, stage4 cases were excluded.

      4c3880bb027f159e801041b1021e88e8 Result

      Positive rates for these markers were from 9.6~63.4% as shown in the table.

      The most significant correlations with pleural, lymphatic, and vascular invasion were found in EPB41L5 (p=0.0005), LDH-A (p<0.0001), and, p53 (p<0.0001) and GLUT-1 (p<0.0001), respectively.

      The probable markers predicting both the nodal metastases and the occurrence of events were associated with EMT, glycolytic, hypoxia, and Arf6-related pathways.

      004171.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The pivotal markers were different among the types of local invasiveness. Pathways commonly used in local invasiveness, nodal and distant metastases were suggested to be EMT, glycolysis, hypoxia-related.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-14 - Pathobiology of Notch2 in Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yamato Motooka  |  Author(s): Kosuke Fujino, Kazuhiro Yasufuku, Makoto Suzuki, Takaaki Ito

      • Abstract

      Background

      Notch signaling is known to be involved in the initiation, progression, and suppression of various types of cancers. The pathological significance of Notch1 has been well studied in lung cancer, but that of Notch2 is still unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Immunohistochemical study was performed to measure the expression of NOTCH2 in non-neoplastic lung tissues and lung cancers in comparison with the Clara (Club) cell 10 kD protein (CC10), and Western blotting analysis was performed to detect NOTCH2 in human cancer cell lines. Notch2 gene knockdown experiment and transient transfection of the intracellular domain of the Notch2 (N2ICD) gene were conducted to reveal the function of Notch2. In addition, we studied the relationships between the expressions of Notch1, 2, and 3.

      4c3880bb027f159e801041b1021e88e8 Result

      Immunohistochemical study of lung tissues revealed that NOTCH2 was detected in bronchiolar epithelial cells and was often colocalized with CC10, and that adenocarcinoma tissues were more positively stained than those of squamous cell carcinoma and small cell carcinoma tissues. In human lung cancer cell lines the expression of NOTCH2 was similar to that of NOTCH1 and preferentially detected in non-small cell lung carcinoma (NSCLC) cell lines. Knockdown experiments of the Notch2 gene in NSCLC cell lines showed no significant changes in the expression of molecules associated with cell differentiation, proliferation, apoptosis, and motility. The effects of Notch2 gene knockdown could have be masked by concomitant Notch1 activation, as indicated by an increase in the intracellular domain of NOTCH1. Additionally, the transient transfection of the N2ICD gene induced CC10 expression in an adenocarcinoma cell line.

      8eea62084ca7e541d918e823422bd82e Conclusion

      notch2 iaslc-1.tif
      The present study revealed that Notch2 is important in Club cell differentiation in normal lungs and in adenocarcinoma. We also determined that Notch1 and Notch2 are covariant, and the balance of the expression of Notch receptors could determine the biological behaviors of lung cancer cells.

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      P3.09-15 - Genetic Profiling of Idiopathic Pulmonary Fibrosis Associated Non-Small Cell Lung Cancer by Targeted Next-Generation Sequencing

      12:00 - 13:30  |  Presenting Author(s): Kohei Otsubo  |  Author(s): Eiji Iwama, Kentaro Tanaka, Yoshimasa Shiraishi, Yasuto Yoneshima, Hiroyuki Inoue, Tetsuzo Tagawa, Yoichi Nakanishi, Isamu Okamoto

      • Abstract

      Background

      Little is known about the pathogenesis or genetic profiles of idiopathic pulmonary fibrosis (IPF) associated non-small cell lung cancer (NSCLC). This study was performed to investigate the genetic profiles of IPF associated NSCLC and to explore the possibility of defining potential therapeutic targets by using next-generation sequencing (NGS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Oncomine Comprehensive Assay v3 (OCAv3) from Thermo Fisher was used to detect clinically relevant single nucleotide variants (SNVs), insertions/deletions (INDELs), copy number variations (CNVs), and gene fusions from 161 unique cancer-related genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Surgically resected tumor specimens from 18 patients with IPF associated NSCLC (adenocarcinoma, n=9; squamous cell carcinoma, n=9) were collected. A total of 61 gene mutations was identified by targeted NGS and a median number of mutated genes per patient was 5 (range, 2–26). No sensitizing EGFR mutation (exon 19 del, L858R, G719X, L861Q) and fusions genes (ALK, ROS1, RET) were identified. Fourteen samples had one or more mutations in oncogenes including PIK3CA (n=7, 39%), BRAF (n=5, 28%), PTEN (n=4, 22%), EGFR (n=4, 22%), MET (n=3, 17%), KRAS (n=2, 11%), HRAS (n=2, 11%), NRAS (n=1, 6%), ERBB2 (n=1, 6%) and DDR2 (n=1, 6%). In addition to these potentially druggable oncogenes, loss-of-function mutations in ARID1A (n=10, 56%) and TP53 (n=7, 39%), tumor suppressor genes regulating DNA damage checkpoint were frequently identified. Furthermore, loss-of-function deletions (P2415del) in NOTCH1 which plays a role in cell fate determination, growth, and survival was observed in six (33%) patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study demonstrated novel genetic profiles of IPF associated NSCLC using NGS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-16 - Transcriptome Profiling for Subtyping NSCLC: Off the Beaten Path(Ologist)

      12:00 - 13:30  |  Presenting Author(s): Lars Frederick Petersen  |  Author(s): Adrijana D'Silva, Michelle Dean, Mie Konno, Yaroslav Ilnytskyy, Olga Kovalchuk, Gwyn Bebb

      • Abstract

      Background

      Histopathological distinction between non-small cell lung cancer subtypes is still relevant in the age of targeted therapy due to the relatively low number of patients with actionable molecular alterations such as EGFR mutations or ALK rearrangements in squamous cell carcinomas. In addition, for patients without these alterations, the choice of most effective chemotherapy regimens is often based upon non-squamous vs squamous cell histology. However, histopathology scoring typically requires resected or biopsied tissue to be fixed, sliced, stained, and subjectively scored by a pathologist. Here we endeavor to demonstrate that subtle variances in gene expression within NSCLC patient samples can be used to classify the cancer subtype with a high degree of accuracy to pathology classification.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RNA extracted from 46 resected NSCLC cases (34 stage IIA/B, 12 stage IIIA/B; primarily adenocarcinomas and squamous cell carcinomas) were profiled using a transcriptome microarray platform (Illumina) and analyzed and compared to normal tissue using several Bioconductor R package pathway analysis tools and DAVID Bioinformatics Resources 6.8. Expression profiles were grouped by principle component score in a blinded manner.

      4c3880bb027f159e801041b1021e88e8 Result

      Clustering samples based on the top 10% most variable genes resulted in a highly accurate separation of adenocarcinoma samples and squamous cell carcinoma samples, with only one case of squamous cell carcinoma being misclassified as adenocarcinoma. The altered pathways that differentiated these samples included p53 signalling and PI3K-Akt signaling pathways, Cell adhesion molecules (CAM), ECM-receptor interactions, Wnt signalling and several other key pathways.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Due to the successes of targeted therapeutic approaches, evaluating patient biopsies or other samples for EFGR mutations and ALK rearrangements are currently the standard of care for advanced-stage NSCLC. Immunohistochemical staining for the purposes of subtyping NSCLC can aid in developing treatment strategies for patients without these molecular alterations, but this can significantly reduce the quantity of tissue available for subsequent molecular tests. Based on our data, we believe that expression variances in a relatively small pool of genes and pathway analysis is sufficient to accurately predict the subtype of NSCLC, or at least narrow the number of cases requiring input from a pathologist to a small number of more difficult cases.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-17 - Molecular Profile in Lung Adenocarcinoma. A Muticenter Study in Cordoba, Argentina.  

      12:00 - 13:30  |  Presenting Author(s): Norma Graciela Pilnik  |  Author(s): Veronica Bengio, Maximiliano Franco Canigiani, Pilar Diaz

      • Abstract

      Background

      Substantial advances have been made in the understanding of the biology of NSCLC in relation to the characterization of molecular abnormalities such as activations of oncogenes by mutations, translocations and amplifications, which are being used as molecular targets and predictive biomarkers. Molecular analysis of NSCLC, adeno carcinoma (AC) is now the standard of care for therapy selection

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We determined the frequency of molecular alterations in EGFR and gene fusion ALK in our Caucasian and Hispanic populations to decide the adequate treatment .

      206 small biopsies and resection specimens of patients with NSCLC (AC) in different institutions of Cordoba were studiesduring a period (2014 - 2018).

      In addition to Histopathology Type, we analyzed immunohistochemistry (IHC) characteristics and molecular profiles and Several clinical variables were studied.

      Different tests were used to detect alterations of EGFR and fusion gene EML4-ALK expression, with the aim to identify our own profile and decide the adequate therapeutical option. EGFR mutation was studied by therascreen kit, PCR, in order to detect genetic alterations in exons 18, 19, 20 and 21. ALK translocations were analyzed by FISH (Vysis- Break Apart, Abbott) and IHC (clon D5F3, ventana, Roche). We correlated the molecular profile with different clinical variables (age, gender, and tobacco habits). The statistical method used was the multiple regression logistic model.

      4c3880bb027f159e801041b1021e88e8 Result

      146 men and 60 women out of 206 samples were tested for EGFR expression. Twenty nine men and sixteen women expressed EGFR positive. Activating kinase-domain mutations in EGFR were identified in 45 pts (21, 95 %): exon 19 deletion = 23, L858R = 7, exon 20 insertion = 11, other = 4. EGFR alterations were associated with gender (p=0.044), women showed more alterations of the genes. Age and smoking habit of patients did not show significant association (p=0.757 and p=0.547, respectively). We used the multiple regression logistic model to correlate EGFR expression to age, gender, tobacco habits. We identified 10 pts (5%) with fusion gene EML4-ALK. ALK alterations were not related to gender (p=0.449), age (p=0.837) and smoking habit (p=0.452).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results showed a comparable frequency in EGFR mutations and gene fusion ALK in relation to the data published in western population. These results allow a proper diagnosis to provide pts with the most adequate therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-18 - Identification of MET exon 14 Skipping Mutations by FusionPlex<sup>TM</sup> Solid Tumor Panel

      12:00 - 13:30  |  Presenting Author(s): Laura J. Tafe  |  Author(s): Sophie Deharvengt, Jennifer Kilbourn, Donald Green, Jason Peterson, Francine De Abreu

      • Abstract

      Background

      MET exon 14 skipping (METex14), or splice site, mutations result in the deletion of the juxtamembrane domain of MET, leading to increased MET receptor pathway signaling. Non-small cell lung cancer (NSCLC) patients with METex14 mutations are eligible for therapy with MET inhibitors like crizotinib. METex14 mutations are diverse and complex and can be challenging to detect by targeted DNA NGS assays alone. The Archer FusionPlexTM Solid Tumor panel use anchored multiplex PCR chemistry to detect fusions and other mutations including oncogenic isoforms in 53 genes associated with solid tumors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In July 2016, we implemented the FusionPlex panel in our clinical laboratory for routine testing of NSCLC. RNA is extracted from FFPE tissue using the AllPrep DNA/RNA FFPE Kit and RNA quantity is assessed using the Qubit HS RNA Assay, and RNA quality is assessed using the PreSeq RNA QC Kit. cDNA synthesis and library preparation are performed according to the manufacturer’s recommendations. Libraries are quantified using the KAPA Library Quantification Kit, diluted to 4 nM, pooled and sequenced on the Illumina MiSeq System. Data analysis is performed using the Archer Analysis platform (v4.0.11). MET exon 14 isoforms were confirmed by an orthogonal method (DNA NGS assay and/or melt curve analysis).

      4c3880bb027f159e801041b1021e88e8 Result

      Since July 2016, samples from 275 NSCLC patients were successfully sequenced. Six (2.2%) MET oncogenic isoforms, consistent with MET exon 14 skipping mutations, were identified and subsequently confirmed. All six patients were female with an age range of 61-82 years. Two presented with stage I disease, two stage II, one stage III and one stage IV. To date, none of the patients have been treated with MET inhibitor therapy.

      slide1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The FusionPlexTM Solid Tumor NGS panel can be routinely performed in the clinical laboratory to optimize detection of MET exon 14 mutations as well as other clinically actionable gene fusions.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-19 - Matched Thai Lung Cancer Patients Tissue and cfDNA Molecular Profile by NGS

      12:00 - 13:30  |  Presenting Author(s): Narumol Trachu  |  Author(s): Supoj Detarkom, Pimpin Incharoen, Kattipong Kamprerasart, Nareenart Iemwimangsa, Lalida Arsa, Wasun Chantratita, Dittapol Muntham, Ekaphop Sirachainan, Thanyanan Reungwetwattana

      • Abstract

      Background

      Liquid biopsy is the new non-invasive technology to explore the molecular profile. We evaluate molecular alteration from matched tissue and liquid specimen in NSCLC patients using NGS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total 61 matched tumors and cfDNA in NSCLC patients were retrieved for DNA extraction. All qualified samples were analyzed by using Next Generation Sequencing (NGS) with Gene read Qiagen Lung Cancer Panel sequencing 45 Genes on Ion Torrent system.Variants from NGS with coverage of higher than 1000X of tissues and 10000X of liquid biopsy, cutoff at 3% variant frequency were considered positive. Each detected mutation was validated by the different method. EGFR-mutation detected at this cutoff was validated by Real-time PCR technique using the ARMS-PCR (Amoy DX Kit) for tissue samples and droplet-digital PCR (ddPCR) for blood samples in all samples.

      4c3880bb027f159e801041b1021e88e8 Result

      This study found 59.0% and 19.7% of EGFR mutation, 14.75% and 8.20% of KRAS mutation in tissues and cfDNA, respectively. Moreover, we found 3.29% of BRAF V600E, 1.64% of MET exon14 splice site, and 1.64% of ROS1 mutation in tissue NGS and also confirmed by the other techniques, but there was none of these mutations in the blood sample. Looking at EGFR-mutation detected by different techniques, higher sensitivity, specificity, positive-predictive value, negative-predictive values, and concordant rate were found in tissue NGS and liquid ddPCR compared with liquid NGS at cutoff 3% of variant frequency detection, when the gold standard for validation was ARMS-PCR in tissue testing (Table1).

      Table1. Performance of NGS, ARMS and ddPCR for EGFR mutation detection in matched tissue and cfDNA in lung cancer patients.

      Tissue by ARMS PCR

      Result

      Tissues by NGS

      negative

      positive

      total

      Sensitivity= 87.7%

      negative

      14

      11

      25

      Specificity= 100%

      positive

      0

      36

      36

      Positive predictive value= 100%

      Total

      14

      47

      61

      Negative predictive value= 75.6%

      Concordance = 82%

      Tissue by ARMS PCR

      cfDNA by NGS

      negative

      positive

      total

      Sensitivity= 35.7%

      negative

      12

      37

      49

      Specificity= 98.2%

      positive

      2

      10

      12

      Positive predictive value= 97.9%

      Total

      14

      47

      61

      Negative predictive value= 38.9%

      Concordance = 42.6%

      Tissue by ARMS PCR

      cfDNA by ddPCR

      negative

      positive

      total

      Sensitivity= 82.7%

      negative

      14

      14

      28

      Specificity= 100%

      positive

      0

      33

      33

      Positive predictive value= 100%

      Total

      14

      47

      61

      Negative predictive value= 69.4%

      Concordance = 77.05%

      Tissue by NGS

      cfDNA by NGS

      negative

      positive

      total

      Sensitivity= 36%

      negative

      20

      29

      49

      Specificity= 93.2%

      positive

      5

      7

      12

      Positive predictive value= 84.8%

      Total

      25

      36

      61

      Negative predictive value= 55.8%

      Concordance = 60.66%

      cfDNA by ddPCR

      cfDNA by NGS

      negative

      positive

      total

      Sensitivity= 45.5%

      negative

      25

      24

      49

      Specificity= 97.7%

      positive

      3

      9

      12

      Positive predictive value= 94.5%

      Total

      28

      33

      61

      Negative predictive value= 65.6%

      Concordance = 65.58%

      8eea62084ca7e541d918e823422bd82e Conclusion

      Using tissue for molecular profile testing is still being the gold standard testing. Liquid biopsy is less invasive, but in our study, liquid NGS performed less sensitivity, specificity, PPV, NPV, and concordance rate compared with tissue NGS. We need to explore more for proper cutoff of variant allele frequency to develop more sensitivity and specificity of liquid NGS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-20 - A Simple and Versatile Next-Generation Sequencing Technology for Co-Detection of RNA Structural Variants and DNA Mutations in Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Huiping Zhu  |  Author(s): Shobha Gokul, Gary Latham

      • Abstract

      Background

      Variants associated with non-small cell lung cancer (NSCLC) initiation and progression include DNA mutations, copy number variants, RNA fusions and splicing isoforms. Co-detection of DNA and RNA variants has become increasingly important to shorten time from samples to results and optimize personalized medicine for NSCLC. Here we describe the unification of next-generation sequencing (NGS) workflows using library pooling to reliably and sensitively quantify both DNA and RNA variants from tumor FFPE nucleic acids.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Total nucleic acid (TNA) and DNA were isolated from residual FFPE NSCLC biopsies and cancer cell lines. The QuantideX® NGS RNA Lung Cancer Kit (RUO, Asuragen) and QuantideX® NGS DNA Hotspot 21 Kit (Prototype, Asuragen) were evaluated on the MiSeq® System. DNA and RNA libraries were sequenced on a single MiSeq flow cell. Multiple library pooling strategies were assessed to provide workflow flexibility. All data was analyzed using QuantideX® NGS Reporter 3.0 software.

      4c3880bb027f159e801041b1021e88e8 Result

      The average time from sample QC to MiSeq loading was 10 hours. Including 40-hour instrument run time and data processing and analysis, the sample-to-answer time was less than three days.

      Library pooling experiments evaluated sample run capacity, coverage uniformity, and variant call accuracy from FFPE TNA and DNA. For example, a single pool of 8 RNA and 16 DNA libraries yielded >500,000 reads for each library, with RNA fusions called with 189 to 11,274 reads and DNA mutations detected down to 5% variant allele frequency. Variant calls were 100% concordant with independent results and included mutations in EGFR, RAS, PIK3CA, and BRAF, along with fusions in ALK, RET, and NRG1 and skipped METex14.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The co-detection strategy generated reliable quantitative information from low-input tumor FFPE DNA and TNA within three days. The simplicity and speed of the approach, coupled with a standardized workflow, has the potential to increase the accessibility of NGS analysis and accelerate the return of results for NSCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-21 - Mixed Mucoepidermoid Carcinoma and Adenocarcinoma of the Lung: A Case Report and a Literature Review

      12:00 - 13:30  |  Presenting Author(s): Yu-Deok Choi

      • Abstract

      Background

      Primary mucoepidermoid carcinoma of the lung is a rarely reported neoplasm. Synchronous primary malignancies of the lung comprising mucoepidermoid carcinoma and conventional adenocarcinoma are highly unusual neoplasm.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Case Report: A 75-year-old woman presented with lung mass. Chest computed tomography showed a single 3.5 cm mass over the right lower lobe.

      4c3880bb027f159e801041b1021e88e8 Result

      Microscopic examination revealed the tumor comprised two different histologic components of adenocarcinoma and muco­epidermoid carcinoma. This unique combination of lung malignancies showed characteristic morphologic and immunohistochemi­cal features. Molecular differentiation and genetic mutation analysis would be a valuable tool for the diagnosis of primary lung malignancy with two different histologic types.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Herein, we present a rare case of mixed mucoepidermoid carcinoma and adenocarcinoma of the lung. In this work, we discuss the clinicopathological features of previously reported mixed mucoepi­dermoid carcinoma and adenocarcinoma of the lung with its mutation by molecular and genetic analysis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-22 - Correlation Between Maximum Tumour Diameter Measurement on CT-Scan and Histopathological Specimen: An Indian Experience

      12:00 - 13:30  |  Presenting Author(s): Manoj Gowda  |  Author(s): Babul Bansal, Vinay Kumar, Svs Deo, Sandeep Bhoriwal, Deepali Jain, Prabhat Malik, Sachidanand Jee Bharati, Sunil Kumar

      • Abstract

      Background

      Lung cancer is staged according to TNM classification, which encodes the anatomic extent of the disease. This is the most important prognostic factor in patients diagnosed with lung cancer. CT scan is a basic imaging modality used for pre-treatment tumour staging (T staging). Each centimetre increase in size leads to worsening of prognosis. Adjuvant treatment decisions are based upon the final histopathological tumour size. Accurate clinical and pathologic correlation has been an important focus of research in many cancers. The objective of our study is to see for any discordance with respect to tumour size calculated by CT scan and final histopathological specimen in patients of carcinoma lung undergoing upfront surgery.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients of lung cancer operated upfront between 2012 to 2017 were included in the study. Any patient with chest wall involvement, significant pleural effusion and tumours of main bronchus were excluded. CT scans were acquired from the supraclavicular region through the adrenal glands using a 1.25 mm slice thickness with 1.25 mm spacing following deep inspiration. Based on tumour perimeter maximum tumour size was calculated. The largest diameter of resected lung tumour was recorded using a standard ruler by the pathologist. A mean, median and range for both the CT diameter and pathology diameter were obtained. A paired t-test was used to examine the measurement difference between CT and pathology.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 109 patients were included in the study. Most common histology was Squamous cell carcinoma (n=40,36%), followed by Adenocarcinoma (n=32,29.3%), Neuroendocrine tumour(n=27,24.77%) and other histologies(n=10,9.17%). Among these patients, 22 tumours were located in right upper lobe (20.18%), 10: right middle lobe(9.17%), 25:right lower lobe(22.93%), 31: left upper lobe(28.44%) and 21: left lower lobe(19.26%). The mean size of tumour on CT scan is 4.92cm (SD=1.852cm, range:1-10 cm) and mean size on grossing is 4.5cm(SD=1.774cm,range:0.5-9.5cm)(p<0.05). The difference between the CT diameter and histopathological size is statistically significant. Tumour location and histology did not add any difference to tumour shrinkage.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study demonstrates that there is a statistically significant difference between tumour diameter as measured by CT and its pathologic size. These differences could have implications in the treatment and prognosis of patients with lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.09-23 - Accuracy and Reproducibility of Touch Imprint Cytology in Resected Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Masatoshi Kakihana  |  Author(s): Masaru Hagiwara, Junichi Maeda, Yoshihisa Shimada, Sachio Maehara, Naohiro Kajiwara, Tatsuo Ohira, Norihiko Ikeda

      • Abstract

      Background

      With the development of high-resolution computed tomography (CT), small-sized tumors showing ground-glass opacity (GGO) on chest CT images has been more frequently encountered. However, methods such as the transbronchial biopsy and the computed tomography-guided fine-needle aspiration cytology are limited in their ability to diagnose such small lung tumors. We evaluated about the association of the cytological features with the histological examination using the surgically resected specimen.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      169 patients, age between 31–87 years old, who showed radiological signs of peripheral lung tumors less than 3.0cm in diameter on CT images, underwent surgical resection at our institution between 2015 and 2016. The histological examination was performed on surgical specimen, fixed with 10% formalin and stain with Hematoxylin–Eosin. The cytological examination was performed on stamps from surgical material by Papanicolaou staining. The morphological features were compared both histopathogical diagnosis and cytological diagnosis of imprint cyotology derived from the resected specimen. Interobserver reproducibility was assessed by Kappa coefficient providing a measure for agreement beyond chance.

      4c3880bb027f159e801041b1021e88e8 Result

      By histological examination (in the 169 cases), the diagnostic of lung cancer was given with the establishing of the histological type. In 139 cases (82.2%) of the cases diagnosed as adenocarcinoma, in 25 cases (14.8%) squamous cell carcinoma, in 3cases (1.7%) was neuroendocrine tumors, and one case each of adenosquamous carcinoma and pleomorphic carcinoma. There was 86.3% (146 of 169 cases) agreement with a k statisticvalue of 0.65. Obtained kappa values from imprint cytology showed good (from 0.60 to 0.8) for detection of epithelial cell abnormalities indicating high observer diagnostic reproducibility.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This kappa statistic method allows assessment of the diagnostic quality of a respiratory cytology. Imprint cytology for small peripheral lung cancer is a useful method for evaluating tumors. Our data indicate the fact that the cytological examination on stamps from surgical material offers a very high percentage of positive results, close to the histological one. But in the tumor size less than 1.0cm, the establishing of the histological type of lung cancer is more difficult by cytological examination. Despite this, the cytology may be extremely useful in diagnose of the small peripheral tumors. The cytological characteristics of small peripheral adenocarcinoma were little reference to the differentiation at the cellular level. Our findings indicated that the presence of several nucleoli and granular chromatin densely are the factors of adenocarcinoma.

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      P3.09-24 - The Concordance of Histological Diagnosis from Transbronchial Biopsy and Resected Specimen of Lung Cancers

      12:00 - 13:30  |  Presenting Author(s): Yoshiteru Kidokoro  |  Author(s): Tomohiro Haruki, Yuji Nozaka, Wakako Fujiwara, Tatsuya Miyamoto, Taichi Kadonaga, Takashi Ohno, Makoto Wakahara, Yuzo Takagi, Yuko Tanaka, Kanae Nosaka, Ken Miwa, Yoshimasa Suzuki, Yuji Taniguchi, Masahiro Kodani, Yoshihisa Umekita, Hiroshige Nakamura

      • Abstract

      Background

      Advances in radiological and diagnostic technics have improved the evaluation of pulmonary nodules, leading to an increase in preoperative histological diagnosis. For thoracic surgeons, it is important to know histological types of lung cancer preoperatively for the determination of surgical treatment strategy. The aim of this study is to evaluate the concordance of histological types between biopsy and resected specimens.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 653 patients with primary lung cancer were operated on in our hospital between January 2013 to March 2018. Among them there were 438 patients who underwent bronchofiberscopic examination, and 364 patients (83.1%) were diagnosed preoperatively as lung cancer. We retrospectively reviewed 316 patients who underwent both transbronchial biopsy (TBB) and then surgical resection for primary lung cancer between January 2013 to March 2018. We compared diagnosed histological types, examined the accuracy of preoperative diagnosis by TBB, and evaluated the concordance between those two kinds of specimens.

      4c3880bb027f159e801041b1021e88e8 Result

      In 302 of the 316 patients (95%), the histological types of lung cancer diagnosed from TBB matched those from resection specimens (κ=0.878). Concordance rate was the highest in adenocarcinoma (243/245; 99%), followed by squamous cell carcinoma (52/55; 95%). On the other hand, it was only 50% in neuroendocrine carcinoma (small cell carcinoma and LCNEC ± combined with adenocarcinoma / squamous cell carcinoma). Due to histological heterogeneity, 6 of 14 patients were diagnosed with different types of postoperative diagnosis, and four were due to the inconsistency of immunohistochemical (IHC) staining between biopsy and resected specimens.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We considered that lung cancer has not only histological heterogeneity but also IHC heterogeneity. If larger samples are taken, the preoperative diagnosis of histological type could be more reliable.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      Lung cancer is uncommon in young adults and there is no consensus about its behavior in this age group. The aim of this study was to compare clinical and pathological characteristics and median overall survival in young adults (≤ 40 years) and older adults (intermediate: 41-65 years and elderly: > 65 years) with lung carcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort study including information from 21,285 lung cancer cases (ICD – O: C34) diagnosed in the period 2000 – 2009 was performed. Cases were retrieved from the hospital based cancer registries in the state of Sao Paulo, Brazil. Study variables included sex, histological type, cancer staging based on the TNM System, status in the last follow-up, date of diagnosis and date of death. For 1,410 patients, who were initially considered lost to follow-up, a consultation was made through Brazilian databases, such as national registry of deceased, registry of living individuals and voting status in political elections (Brazilian compulsory voting system). After this search, 202 patients remained as loss of follow-up (1.02%). Survival analysis was performed by Kaplan-Meier curve and log-rank tests.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 21,285 patients, 19,900 were further analyzed, after exclusion of patients diagnosed with malignant neoplasms without specification, carcinoid and neuroendocrine tumors and in situ carcinomas. Most patients were diagnosed with adenocarcinoma (49.55%) or squamous cell carcinoma (27.67%) in advanced stage (clinical stages III and IV) (80.26%). Young adults were 542 patients (2.72%), intermediate adults were 10,661 (53.57%) and elderly people were 8,697 (43.70%). Adenocarcinoma was the most prevalent histological type in all age groups (63.09%, young adults vs 49.85%, intermediate adults vs 48.33%, elderly patients) and squamous cell carcinoma was the second most prevalent (14.02%, young adults vs 25.71%, intermediate adults vs 30.93%, elderly patients). In all age groups, most patients presented metastatic disease (stage IV: 58.85%, young vs 51.19%, intermediate vs 43.14%, elder adults). Median overall survival was significantly different among age groups: young adults, 9 months (CI 95%: 7.71-10.28); intermediate adults, 8 months (CI 95%: 7.74-8.25) and elder patients, 7 months (CI: 95%: 6.73-7.26)(p<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Most young adults were diagnosed with adenocarcinoma in advanced stage. Although still very troublesome, our results indicated median overall survival was longer in young adults than in older adults.

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      P3.09-26 - Concordance of Surgical Resections and Fine Needle Biopsy-Derived Cell Block Sections for PD-L1 22C3 Immunohistochemistry  

      12:00 - 13:30  |  Presenting Author(s): Joerg Schwock  |  Author(s): Hyang Mi Ko, Jessica Weiss, Carol Cheung, Scott Boerner, Ming Sound Tsao

      • Abstract

      Background

      A significant proportion of lung cancer patients presents at an advanced disease stage. Diagnosis and treatment in these patients is frequently based on small tissue samples such as fine needle biopsies. Eligibility for pembrolizumab immunotherapy requires assessment of the PD-L1 expression. Data on the concordance of PD-L1 assessment by immunohistochemistry between quantitatively limited samples, in particular cytology specimens, and resections are scant. We studied PD-L1 in formalin-fixed paraffin-embedded (FFPE) cell block sections of CT-guided transthoracic fine needle biopsies in comparison with the subsequent resection specimens of the primary lung tumors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Paired specimens of fine needle biopsy-derived cell blocks and subsequent lung tumor resections of the same anatomic site were obtained from the archives of the Department of Pathology, University Health Network. Cell blocks were produced from normal saline needle rinse fluids fixed with a final concentration of 10% neutral-buffered formalin and processed using the Histogel method for paraffin-embedding. Cytology samples treated with alcohol-based fixatives were not included. Cell block sections were reviewed for a minimum of 100 tumor cells. Cases below the cellularity threshold were excluded. Staining was performed using the 22C3 pharmDxTM assay (Agilent). All cell block and representative tumor sections were assessed by three observers (1 expert pulmonary pathologist, 2 cytopathologists). Tumor proportion scores (TPS) were recorded and a final TPS was determined using the mean between expert and second closest observer. Cases close to the ≥50% cut-off underwent multiheader microscope review. Pearson, intraclass correlation coefficients and test parameters were calculated using standard statistical methods.

      4c3880bb027f159e801041b1021e88e8 Result

      43 paired cases were informative. Mean interval between biopsy and resection was 1.5 months (range 0-4). TPS of cell blocks and resections showed positive correlation (Pearson: 0.8; range 0.78 - 0.84 for individual observers). Intraclass correlation coefficients were 0.97 (cell blocks) and 0.92 (resections). 10/43 (23%) cell blocks and 9 (21%) resections were positive at TPS≥50%. 21/43 (49%) cell blocks and 19 (44%) resections were positive at TPS≥1%. Sensitivity, Specificity, PPV, NPP and accuracy were 78/74, 91/71, 70/67, 94/77 and 88/72% for the ≥50/≥1% cut-off, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Cytology FFPE cell block sections showed strong positive correlation with resection specimens of the same anatomic site for PD-L1 assessment using the 22C3 pharmDxTM immunohistochemistry assay. Reliability between observers was excellent. Test parameters, in particular for the ≥50% cut-off value, were deemed acceptable for clinical use. Selected slide review of cases with discordant scores indicated tumor heterogeneity as cause.

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      P3.09-27 - Histopathologic Parameters Define Features of Treatment Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Annikka Weissferdt  |  Author(s): Tina Cascone, Apar Pataer, Neda Kalhor, Cesar Moran, Mara B Antonoff, Garrett L Walsh, Chantale Bernatchez, Don Lynn Gibbons, Ignacio I. Wistuba, Jack A Roth, Jianjun Zhang, Emily Roarty, Lara Carolina Alvarez de Lacerda Landry, Ara A Vaporciyan, John V Heymach, Stephen Swisher, Boris Sepesi

      • Abstract

      Background

      Previous studies indicate that neoadjuvant chemotherapy improves survival in patients with loco-regionally advanced non-small cell lung cancer (NSCLC). The amount of residual viable tumor has been associated with long-term overall survival. This histopathologic measure has potential to become a standard method for evaluation of the effectiveness of neoadjuvant therapy regimens. However, adequate comparison of chemotherapy-treated and untreated lung cancers is lacking. We analyzed histopathologic characteristics of resected NSCLC with and without prior neoadjuvant chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathologic assessment was performed of specimens obtained from patients enrolled on the immunogenomic lung cancer study (ICON), which integrates clinical, pathologic, immune, genomic and outcome data from surgically resected NSCLC. Cases included material from 10 patients who underwent neoadjuvant chemotherapy and 10 patients treated with primary surgery (adenocarcinoma, n=5; squamous cell carcinoma, n=5; for each cohort). Hematoxylin and eosin-stained tumor sections (mean, 6; range, 3-10) were evaluated and semiquantitatively scored for parameters commonly attributed to treatment response. The percentage of viable tumor was estimated by comparison to the proportion of fibrosis and necrosis on each slide. Additional parameters analyzed included the presence of inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts, giant cells and neovascularization (score 0-3). For each patient, the results for all slides were averaged to determine a mean value. P values were calculated using the Mann-Whitney test.

      4c3880bb027f159e801041b1021e88e8 Result

      All histopathologic parameters typically associated with treatment response could also be identified in untreated specimens, albeit in different proportions. Compared to the untreated cohort, samples after chemotherapy were characterized by lower proportion of viable tumor (42.4% vs 67.7%, p=0.04) and higher degrees of fibrosis (46.6% vs 26.6%, p=0.08), and necrosis (11.0 % vs 5.6%, p=0.35). Among the additional parameters, similar scores were seen for inflammation (1.54 vs 1.46, p=0.60), TLS (1.00 vs 0.80, p=0.47), LVI (0.16 vs 0.23, p=0.62), and neovascularization (both 0) while macrophages (0.94 vs 0.12, p=0.20), cholesterol clefts (0.92 vs 0.13, p= 0.03) and giant cells (0.80 vs 0.40, p=0.17) were more common among the neoadjuvant cohort.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Histopathologic variables commonly associated with chemotherapy treatment response can also be identified in treatment naïve lung cancers. However, the amount of viable tumor, fibrosis and cholesterol clefts are parameters strongly associated with neoadjuvant therapy. These results highlight the importance of assessing the type and extent of treatment response. Analysis of larger patient cohorts will reveal potential prognostic value in primary tumors, chemotherapy-treated, and eventually immunotherapy-treated tumors.

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    P3.11 - Screening and Early Detection (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
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      P3.11-01 - Methylation Markers That Correlate with Occult Lymph Node Metastases of NSCLC and a Preliminary Prediction Model

      12:00 - 13:30  |  Presenting Author(s): Wenhua Liang  |  Author(s): Jinsheng Tao, Zeyu Jiang, Jianyu Sun, Jianbing Fan, Jianxing He

      • Abstract

      Background

      Lymph node (LN) metastasis status is the most important prognostic factor and determines the treatment strategy. The current imaging approaches are not sufficiently precise to diagnose occult LN metastasis before surgery, while the invasive biopsy fails to be widely used. Therefore, more precise and non-invasive methods are warranted to determine the lymph node status preoperatively and lead to appropriate treatment strategy. Methylation alteration is an optimal candidate to trace the signal from early stage tumors due to its early existence, multiple loci and stability in blood. To build a diagnostic tool, we shall firstly screen and identify a set of plasma methylation markers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      High-throughput targeted methylation sequencing was performed on plasma and matched tissue samples from a cohort of 134 lung cancer patients with a primary lesion less than 3 cm in diameter. The methylation profiles were compared between patients with and without occult LN metastases. A preliminary prognostic model was built by random forest by integrating both top 5 hypermethylated genes and top 5 hypomethylated genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Within this cohort, 22 cases were found to have occult LN metastases found by pathological examination. Thus, we selected the other 22 cases without occult LN metastasis by matching gender, age, smoking history and tumor histology. Hypermethylation on 32 genes, such as TNFRSF1B, DMRTA2, VAV3-AS1, HIST3H2A, PALD1, NKX2-3, MAP3K12, MAPK10, were identified between the two groups. Hypomethylation on 20 genes, such as RAB42, KCNN3, UBE2L6, RARG, CRY1, MTUS2, TMEM179, MEGF11, were also detected. 25% (13 out of 52 genes) of these markers could be found in the matched tissue samples. The AUC of ten fold cross validation of the preliminary prediction model is 0.86.

      roc.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      We found some specific plasma methylation markers for occult LN metastasis of NSCLC. Further efforts should be made in establishing a non-invasive blood diagnostic tool.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-02 - Lung Cancer Screening in a High Incidence Population: Results of Low-Dose CT Screenings in a Northern Kentucky Community Healthcare System

      12:00 - 13:30  |  Presenting Author(s): Royce Calhoun  |  Author(s): Glen Turner, Gary Schmitt, Michael Gieske, Ellen Krasik, Valerie Williams, Sara Browne, Megan Lockwood, Ellen Burns, Adrienne Snow

      • Abstract

      Background

      The National Lung Screening Trial (NLST) demonstrated that low-dose CT screening increases lung cancer-related survival in at-risk patients. In the U.S., Kentucky has the highest rate of lung cancer, worst historical survival rates and could benefit greatly from a robust screening program. However, concerns have been raised that lung cancer screening performed broadly in the community may not replicate NLST results. Here we evaluate the initial 3 years of a Northern Kentucky community healthcare system lung cancer screening program.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Medical records related to screening low-dose CTs performed in the St. Elizabeth Healthcare System from January 1, 2015 through February 28, 2018 were retrospectively reviewed. Statistical significance was calculated using a two-sample t-test (p <0.05).

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, 3,496 low-dose CTs were completed. Screenings increased annually, with 218 performed in 2015, 716 in 2016, 1933 in 2017 and 629 through February 2018. Incidences of interventions resulting from screening findings were tallied (Table 1). Screenings produced a shift to an earlier stage at diagnosis (Figure 1).

      Table I

      Number Adverse Events Death
      Total Screens 3496 0 0
      Additional Imaging 428 NM NM
      Diagnostic Procedures 70 4(6%) 0
      Lung Cancers 50(1.4%) NA NA
      Surgical Resections 30 9(30%) 1(3%)
      Chemotherapy and/or Radiation 28 NM NM

      NA-Not Applicable

      NM-Not Measured

      Figure I

      graph.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      The NLST results can be replicated in a community healthcare system with a high incidence of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-03 - Implementing Lung Cancer Screening in Canada: Evidence on Adherence and Budget Impact from the Pan-Canadian Early Detection Study

      12:00 - 13:30  |  Presenting Author(s): Sonya Cressman  |  Author(s): Stuart James Peacock, Alain Tremblay, Cheryl Ho, Martin Tammemägi, Stephen Lam

      • Abstract

      Background

      High-risk lung cancer screening has favourable cost-effectiveness ratios; making it an attractive intervention for lung cancer control. Relatively little is known, however, about the implementation of lung cancer screening in universal health care systems. To address this, we characterize screening adherence rates in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan) and prepare a budget impact analysis for Canada.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively characterized screening adherence to short-term (first-year) and long-term (year-four) annual screening rounds in the PanCan study and explored association with socio-demographic and screening characteristics with logistic regression models and Mann-Whitney rank sum and Chi square likelihood tests. We did a four-year budget impact analysis using published utilization rates for screening-related and incidental healthcare resources, smoking cessation, opportunistic screening and projected market dynamics for entrant treatments in Canada.

      4c3880bb027f159e801041b1021e88e8 Result

      The PanCan study screened 2537 participants with a baseline LDCT exam; of these, 2254 (88.9%) adhered to the second annual screening exam and 1,762 (69.5%) adhered to the year four exam. After adjusting for lung cancer incidences and other-cause mortality, we found significant associations between self-reported “current smoker” status and lower, second annual scan adherence rates (p<0.05); while variables related to the delivery of the intervention—such as the use of screening autofluorescence bronchoscopy and finding a lung nodule on the baseline LDCT—were significantly associated with greater adherence (p<0.05). Adherence to year-four screening exams was positively associated with age, family history of lung cancer, baseline quality of life and prior screening exam adherence (all p<0.05). Non-adherence was significantly associated with participants who had greater than 100 pack-years of smoking history and a lower level of formal education (p<0.05). Compared to participants who adhered to their scheduled, year-four annual screening exams, non-adherent participants had a higher predicted risk of developing lung cancer at baseline (p<0.05). The budget impact analysis indicates that the incremental program costs for screening an estimated 257, 914 eligible, high-risk, Canadians would be highly favourable compared to selection based on age and smoking history alone. The budget impact was also sensitive to uncertainty around the cost to treat actionable incidental findings and the adoption of entrant systemic therapy drugs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Study participants who were at the highest risk of developing lung cancer, were the least likely to adhere to screening. Using risk selection would enable affordable programs; however, programs may be compromised by barriers to participation for individuals who are at the greatest risk of developing lung cancer.

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      P3.11-04 - Trends and Barriers in Lung Cancer Screening Implementation Across the United States.

      12:00 - 13:30  |  Presenting Author(s): Jennifer C King  |  Author(s): Angela Meredith Criswell, Andrew Ciupek, Amy Copeland

      • Abstract

      Background

      In 2010, the National Lung Screening Trial was halted after showing a 20% reduction in mortality for high risk individuals when three years of annual lung cancer screening was performed by low dose computed tomography(NEJM, 2011). Many questions remained about whether screening could be properly implemented in non-academic, community settings. Lung Cancer Alliance developed a National Framework for Excellence in Lung Cancer Screening and Continuum of Care in 2012 and began a nationwide network dedicated to responsible lung cancer screening. The Screening Center of Excellence (SCOE) designation requires a center to ensure shared decision-making, comply with best practice standards, work with a multidisciplinary care team, deliver or refer for smoking cessation, provide results in a timely manner, and meet technical specifications set by the American College of Radiology. Our aim is to promote high-quality, responsible lung cancer screening throughout the United States, including in community settings where most lung cancer is diagnosed.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 2012 through 2017, over 500 centers were designated as SCOEs. These centers represented 42 states and more than 60% were from community/non-academic centers. High-risk individuals who come to the Lung Cancer Alliance website or contact the organization by phone to find a screening center are directed to a SCOE. A data collection effort in 2017, being repeated in 2018, collected comprehensive information about the state of lung cancer screening and care at the SCOEs. Nearly 70% of SCOEs responded to the 2017 survey.

      4c3880bb027f159e801041b1021e88e8 Result

      The SCOE program data shows that screening is being performed widely across the United States, including in non-academic centers. For centers who were able to provide numbers of screenings performed and diagnoses, we identified a clear trend in diagnosis of Stage 1 lung cancer, indicating these screenings are able to find lung cancer early. We also identified a number of implementation challenges around referral patterns, insurance and billing, and determining appropriate risk criteria. Rates of adherence to both annual scans and recommended follow-up varied widely across different institutions indicating a key area of focus for future implementation research.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have shown that a patient advocacy group working with medical professionals can help deliver high quality care to a broad population. Data collection from the SCOEs provides a snapshot of the state of lung cancer screening in the United States that underscores the success of screening and the importance of early detection but also identifies barriers in implementation that still need to be addressed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-05 - Use of Electronic Medical Record (EMR)-Embedded Clinical Decision Support Tools Improves Lung Cancer Screening Rates

      12:00 - 13:30  |  Presenting Author(s): John D Doty  |  Author(s): Leisa D Lackey, Jennifer L Ersek, Daniel K Howard, Amy W Clary

      • Abstract

      Background

      Atrium Health (AH) is a large, community-based healthcare system serving approximately 1.1 million primary care patients in the southeastern United States. In this region lung cancer incidence, death rates and rate of advanced stage of disease at diagnosis are among the highest in the nation. Previous work demonstrated that primary care providers in our region were not aware of lung cancer screening eligibility requirements. AH aimed to improve lung cancer outcomes for our patients by integrating new clinical decision support tools within our electronic medical record (EMR) to increase referral rates to our lung cancer screening program.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We collaborated with the AH Information and Analytics Services team to embed new clinical decision support tools within the EMR simplifying identification of patients eligible for lung cancer screening. We first revised the smoking history section of the EMR with data fields to record the number of years a patient smoked, the average packs consumed per day and the specific quit date for former smokers. A health maintenance alert (HMA) was then designed which would appear in a conspicuous location in the charts of patients aged 55 to 77 with a 30 pack/year smoking history who were active smokers or former smokers with quit dates within the last 15 years.

      4c3880bb027f159e801041b1021e88e8 Result

      Since integration of the clinical decison support tools into the EMR, over 22,000 patients in our system who meet eligibility criteria have been identified. Lung cancer screening referrals in the first quarter of 2018 increased by almost 500% compared to quarter 1 2017.

      abstractgraph.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Clinical decision support tools embedded into the EMR have increased lung cancer screening rates among AH patients.

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      P3.11-06 - Improving Lung Cancer Screening Completion Rates in a Primary Care Practice in Large Urban Academic Medical Center

      12:00 - 13:30  |  Presenting Author(s): Linda Dowling  |  Author(s): Laura J Zimmermann, Palmi Shah, Lynda Powell, Daniel Dunham

      • Abstract

      Background

      Despite implementation of a physician-facing electronic health record (EHR) best practice alert (BPA) with robust medical decision making and documentation, only 7.3% of eligible patients (85 of 1170) throughout the institution completed a low-dose CT (LDCT) for lung cancer screening in 6 months (May 1st to November 1, 2017).

      The objective is to improve lung cancer screening by:

      1. Describing primary care referral patterns and status among eligible patients

      2. Identifying system, patient and provider-level barriers to referral and completion

      3. Developing and testing targeted interventions

      Success will be measured by reducing number of eligible patients overdue for screening by 50% in the next 6 months.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      An Epic EHR report identified patients with an overdue lung cancer screening BPA within one practice representing approximately 40% of primary care (16,000 visits in 6 months). Through chart review, we quantified number of patients at different points of the referral pathway.

      New interventions were developed for the most common categories of patients overdue for screening: Those with orders that had not scheduled the exam and those with no order and no documentation of why in the EHR.

      Lung Cancer Screening Coordinators contacted patients with current orders and began scheduling LDCT exams. (Intervention 1).

      Division leadership, medical directors, primary care providers (PCP), and the practice nurse manager were engaged to design an intervention to address patients with no LDCT order (Intervention 2)

      4c3880bb027f159e801041b1021e88e8 Result

      The total number of LDCTs performed in the first 12 weeks after starting the intervention was almost equal to the performed in the 6 month baseline period. (12 vs 14).

      The percentage of patients overdue with orders increased from 28% to 37.5%. Only 7 of the original 18 with orders not scheduled remained in that category at 12 weeks. The percentage of patients overdue with no order and no documentation decreased from 65.9% of to 51.3%.

      Fifteen of 41 with no order and no reason documented (36.5%) were newly identified at 12 weeks, i.e. not identified by the baseline query.

      The most significant limitation to measuring 12-week outcomes is that patients have not yet completed their scheduled PCP appointments and LDCT appointments.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Multiple challenges were identified at system, patient and provider levels:

      *The BPA lacks specificity.

      *This patient subpopulation has a high prevalence of comorbidities and chronic conditions.

      *PCPs expressed skepticism regarding evidence for lung cancer screening, perceived lack of benefit for some patients and competing demands.

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      P3.11-07 - The Quality of Screening: Comparing the Rush Lung Cancer Screening Program to the NLST and the VA Lung Cancer Screening Demonstration Project

      12:00 - 13:30  |  Presenting Author(s): Linda Dowling  |  Author(s): Palmi Shah, Ramya S Gaddikeri, Ashley Levitan

      • Abstract

      Background

      The National Lung Screening Trial (NLST) was conducted for the purpose of determining the efficacy of using a low dose computed tomography (LDCT) scan to screen for lung cancer screening versus chest x-ray. Findings demonstrated a reduction in mortality by 20.0%.

      In 2013, informed by the findings from the NLST, the United States Preventative Services Task Force (UPSTF) gave lung cancer screening a grade B recommendation. This recommendation eventually led to both private insurance coverage and in 2015, Centers for Medicare and Medicaid Services (CMS) coverage of low dose computed tomography (LDCT) scans to screen for lung cancer.

      In 2017, the US Department of Veterans Affairs (VA) published the experience of implementing a lung cancer screening program (LCSDP). This publication attracted the attention of the medical community and media, generating concern over the value of LDCT scans indicated to screen for lung cancer.

      The Rush University Medical Center Lung Cancer Screening Program (RLCSP) is in its third year of implementation and adheres to best practices for the evolving discipline of lung cancer screening.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To compare the structure and findings of the Rush Lung Cancer Screening Program (RLCSP) to two well-known published initiatives: the National Lung Screening Trial (NLST) and Implementation of Lung Cancer Screening in the Veterans Health Administration (LCSDP).

      4c3880bb027f159e801041b1021e88e8 Result

      1 in 29 people screened with the RLCSP has lung cancer, compared with 1 in 68 people screened with the LCSDP, and 1 in 320 screened with the NLST. The RLCSP has a more diverse demographic base, and fewer false positive scans than the NLST or LCSDP.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The NLST is a research study that was conducted for the purpose of testing the efficacy of using a LDCT scan versus chest x-ray to screen for lung cancer.

      The purpose of the LCSDP is to address feasibility of implementing a lung cancer screening program within the VA system; The LCSDP is an implementation project and not a clinical research study.

      RLCSP is a screening program that was implemented in a university hospital setting, which closely adheres to best practices with strong results. Data from the RLCSP supports findings from the NLST that LDCT is an effective scan to screen for lung cancer.

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      P3.11-08 - Lung Cancer Screening at an Academic Medical Center: Early Patterns of Practice

      12:00 - 13:30  |  Presenting Author(s): Linda Dowling  |  Author(s): Jansi Willoughby, Palmi Shah, Betty Tran

      • Abstract

      Background

      Lung cancer screening with low dose computed tomography (LDCT) is associated with a reduction in lung cancer mortality. The Center for Medicare and Medicaid Services (CMS) offers coverage for LDCT, indicated for lung cancer screening, if patients are between ages 55 and 77, are a current smoker or former smoker who has quit smoking in the past 15 years, have a greater than 30 pack year smoking history, and shows no signs or symptoms of lung cancer (hemoptysis and/or weightless).

      Rush University Medical Center has a Best Practice Alert (BPA) in Epic to notify physicians of patients who meet criteria to receive LDCT scans for lung cancer screening. The BPA fires based on patient’s age and documented pack year smoking history. Successful utilization of the BPA relies heavily on accurate smoking documentation. As part of an ongoing project characterizing the population who ultimately undergoes screening, it became evident that a significant number of patients whom may be eligible for screening are missed due to incomplete smoking documentation. These initial findings highlight the need to develop an improved, accurate, and more convenient system to document smoking history.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective chart review was performed, utilizing electronic medical records, for data from October 2015-October 2017. Data was collected on age, gender, and smoking status. Based on this timeframe, data for 50,421 patients from Rush University Medical Center (RUMC) and Rush Oak Park Hospital (ROPH) was analyzed. Age was restricted to 55-77 years to match CMS re-imbursement criteria.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 50,421 patient charts analyzed, 2,720 (5%) met eligibility criteria for lung cancer screening based on their documented smoking history. The majority of patients, 38,197 (76%), had incomplete smoking history documentation. Out of the patients with incomplete smoking history documentation, many charts were missing documentation of smoking history in pack year, and/or the number of years it has been since the patient quit smoking.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Data identifies a key weakness in electronic health record documentation of smoking history at RUMC and ROPH. Since the BPA for lung cancer screening only triggers with a documented smoking history of greater than 30 pack years, patients who may be eligible for lung cancer screening are not being identified. By advocating for more thorough documentation of patient smoking history, we can optimize use of the BPA and provide patients with better health management.

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      P3.11-09 - Shared Decision Making; A Decision Aid for the Primary Practitioner

      12:00 - 13:30  |  Presenting Author(s): Frederic Winslow Grannis

      • Abstract

      Background

      Lung cancer (LC) remains the number one cancer killer of both men and women. Despite general agreement that computerized tomographic (CT) lung cancer screening (LCS) is safe and effective, with first-dollar insurance coverage available from CMS, uptake of LCS among those at risk is currently less than 5%. Centers for Medicare and Medicaid Services (CMS) mandates shared decion making (SDM) using decision aids (DA) providing specific information. Only half of primary care practitioners (PCPs) know USPSTF guidelines and identify multiple barriers to guideline adherence. Although half of PCPs know how to work up positive test results, most prefer to refer such patients to specialists. Compounding these problems, existing DAs provide inaccurate and difficult to understand information. PCPs require accurate information to fulfill their obligation to patients in SDM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Research and clinical results from the prospective, international, multi-institutional cohort research project, International Early Lung Cancer Action Program ( IELCAP) and National Comprehensive Cancer Network (NCCN) over 20 years was reviewed and distilled into content aimed to provide accurate, up-to-date information for PCPs to use in answering patient questions during SDM consultation. Information is summarized in "stick figure" graphics.
      100stickposter.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      Multiple current LCS DAs provide gratuitously inaccurate information, e.g. that only 21% with LC in LCS survive 5-years. IELCAP and NCCN research results show that cancer detection rate with adhernce to annual CT screening is 12.5% (1 in 8) / decade in both NCCN risk groups 1 and 2. Baseline false positive rate is 10% at baseline screen; 5% during annual repeat screens. More than 80% of LC are early-stage. 10-year actuarial LC survival exceeds 80%. With guideline adherence, 10% of false positives have biopsy or surgical removal of a benign nodule and overtreatment of slow-growing, pre-invasive LC is avoidable.. Screen-detected LC are increasingly treated with minimally invasive operations, often with sub-lobar resection, with equivalent cure rates and lower morbidity. Operative mortality is less than 1%. Radiation therapy is available for treatment of early-stage LC in patients with increased surgical risk. Radiation exposure is smal; there is no evidence of substantial risk of radiation carcinogenesis in adults receiving LCS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A new DA, reflecting results in LCS from IELCAP and NCCN centers provides PCPs with accurate information for SDM sessions with patients at risk of LC. PCPs providing accurate, coherent information to patients can play a major role in prevention of many housands of unnecessary LC deaths.

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      P3.11-10 - Lung Cancer Screening Shared Decision Making: Decision-Aid for the Patient

      12:00 - 13:30  |  Presenting Author(s): Frederic Winslow Grannis  |  Author(s): Sheila Ross

      • Abstract

      Background

      Despite general agreement in the U.S. that lung cancer screening (LCS) is effective and safe, with availability of insurance coverage for those at high-risk, screening uptake is less than 5%. Patients in Medicare and Medicaid (CMS) must participate in "shared decision making" (SDM) with a primary care giver and a "decision-aid" (DA) used. A major potential contributor to low LCS uptake is inaccurate and difficult to understand information on LCS benefits and risks contained in currently-available DAs. A gratuitous example is the statement "4 of 5 patients slip through to die of LC". We offer a new DA that provides information required by CMS, based upon lessons learned from twenty years research and clinical experience in the International Early Lung Cancer Action Program (IELCAP), and reflected in the LCS guidelne of the National Comprehensive Cancer Network (NCCN).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Currently available DAs used in LCS were reviewed and compared with published results from LCS programs participating in IELCAP and NCCN with findings distilled to provide information required by CMS and understandable by patients of average intelligence.

      4c3880bb027f159e801041b1021e88e8 Result

      When an individual with NCCN risk criteria levels 1 or 2 receives a low-dose CT scan annually, as a participant in a screening program using the IELCAP or NCCN diagnostic guidelines, and reliably follows recommendations for further testing or treatment, benefits and risks described herein may be confidently anticipated. Based on recent data from LCS at the Lahey Clinic, with optimal uptake, 12.5% 1 in 8) of those screened will be diagnosed with LC over a decade, more than 80% in early stage. At baseline screen 10.4% will have a positive test result but not be diagnosed with LC during that screening cycle (false-positive). Subsequent annual repeat scans will have 5% false positives. In IELCAP centers actuarial ten-year LC-specific survival exceeds 80% after diagnosis of LC. Application of IELCAP's algorithm results in invasive biopsy or surgical resection of benign nodules in less than 10%. Patients diagnosed by LCS are increasingly treated with minimally-invasive, sub-lobar resections that offer equivalent survival with less morbidity. Fewer than 1% die after surgery. Benefits of screening will diminish and disappear over time if annual screening stops. Higher risks may be experienced if diagnostic and treatment decisions deviate from those recommended.

      8eea62084ca7e541d918e823422bd82e Conclusion

      If patients at high risk of LC participate in SDM using the DA presented, it can be confidently anticipated that LCS uptake will increase, with increased future survival and reduced LC mortality.

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      P3.11-11 - Improving Timeliness of Lung Cancer Diagnostic Services with the Implementation of Coordinated Care via a “Navigation Day”

      12:00 - 13:30  |  Presenting Author(s): Michael Alexios Gulak  |  Author(s): Chantal Bornais, Salome Shin, Liane Murphy, Jennifer Smylie, Jason Pantarotto, Michael Fung-Kee-Fung, Donna E Maziak

      • Abstract

      Background

      Lung cancer patients often experience stressful wait times and delays throughout the diagnostic phase of care. In an effort to streamline this process, a multidisciplinary team at The Ottawa Hospital (TOH) created a “Navigation Day” whereby patients and their family partake in a day-long visit and receive concurrent coordinated testing. At the Navigation Day, patients have teaching, introduction to social work, access to specialist care for symptom control, and same day appointments via dedicated test slots for positron emission tomography–computed tomography (PET-CT) scans, pulmonary function tests (PFTs) and/or magnetic resonance imaging (MRI) of the head. We evaluated the impact of this program on wait times and patient satisfaction.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with a suspicion of lung cancer on chest CT who were referred during three time periods relative to the implementation of Navigation Day were included: one year pre-launch, one year post-launch, and two years post-launch. Mean wait times for PET, PFT, and/or MRI tests were calculated for each time period. To specifically assess the impact of dedicated slots on wait times, patients within each time period were stratified according to whether they underwent their test on the same day or different day from their Navigation Day. Student’s t-test and ANOVA were used to assess for significance. Patient satisfaction was measured by examining provincially-collected data from a standardized survey used by all diagnostic assessment programs in Ontario, and data from program-specific feedback surveys distributed at TOH.

      4c3880bb027f159e801041b1021e88e8 Result

      At one year post-launch, mean wait times improved from 15.5 to 9.2 days for PET (p<0.0001, t-test), from 15.7 to 9.6 days for PFT (p<0.0001), and from 16.0 to 10.2 days for MRI (p<0.0001). These improvements were sustained at two years post-launch, and MRI wait time improved even further from 10.2 to 6.6 days (p<0.0001, t-test). Those patients who underwent tests within a dedicated slot experienced the shortest wait times for all tests, at 5.8 days for PET, 5.8 days for PFT, and 6.3 days for MRI (p<0.0001, ANOVA). Wait time dispersion also improved by 11.2% for PET, 10.1% for PFT, and 19.1% for MRI. Patient satisfaction in the categories of quality of care, rapidity of care, coordination of care, and being informed remained high following the implementation of Navigation Day.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Implementation of a Navigation Day significantly improved timeliness of diagnostic services (PET, PFT, and MRI) for potential lung cancer patients. This program represents an innovative service delivery model for other lung cancer care centers.

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      P3.11-12 - Comparison of Cancer Screening Adherence According to Smoking Status: Korea National Health and Nutrition Examination Survey 2010-2012

      12:00 - 13:30  |  Presenting Author(s): Yong Saing Kim  |  Author(s): Joohwan Park, Eun Young Kim, Hee Young Lee, Hee Kyung Ahn, Shin Myung Kang, Inkeun Park

      • Abstract

      Background

      Smokers who are aged 55 to 74 years with 30 pack-years or more of smoking-history are regarded as high risk subjects for lung cancer, and recent study revealed lung cancer screening with low-dose CT (LDCT) could reduce lung cancer mortality of high-risk individuals. The purpose of this study was to compare the general medical checkups and cancer screening practice pattern according to self-reported smoking status.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using a representative dataset from the Korea National Health and Nutrition Examination Survey (KNHANES) IV from 2010 to 2012, we compared the adherence of general medical checkups and cancer (gastric, colorectal, breast, and cervical cancer) screening practice of Korean adults (55-74 years) according to self-reported smoking status; heavy smokers (≥ 30PY), non-heavy smokers (< 30PY), and never-smokers. Socio-demographic factors (gender, age group, obesity, education, marital status, income, insurance status), health-related lifestyle behavior (drinking status, exercise), and comorbidities (HTN, DM, hyperlipidemia, and self-reported health status) were also collected.

      4c3880bb027f159e801041b1021e88e8 Result

      For the 5,480 respondents, the weighted prevalence of heavy smokers, non-heavy smokers, and never-smokers was 19.3%, 23.5%, and 57.2%, respectively. The overall screening rate was 70.7% (health), 59.1% (stomach cancer), 58.1% (colorectal cancer), 59.1% (breast cancer), and 48.9% (cervical cancer). The screening rates for colorectal cancer are lower in heavy smokers compared with never-smokers even after adjusting covariates (OR=0.71, 95% CI=0.52-0.95). The adherence of general medical checkups and other cancer (gastric, breast, and cervical cancer) screening were not different according to self-reported smoking status.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results of this study suggest that high risk subjects for lung cancer were less likely to be screened for colorectal cancer than never-smokers, however, no difference was observed in the adherence of general medical checkups and other cancer screening. This finding provides a better understanding of the screening practice adherence for this population.

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      P3.11-13 - Liverpool Identifies the Hard to Reach Population at Risk of Developing Lung Cancer.

      12:00 - 13:30  |  Presenting Author(s): Martin Ledson  |  Author(s): Ed Gaynor, Seamus Grundy, Sarah Hill, Darcy Fidoe, Sabrina Mason, Stephen Duffy, John Kirkpatrick Field

      • Abstract

      Background

      The Liverpool Healthy Lung Programme (LHLP) is an initiative aimed at improving respiratory health and diagnosing respiratory disease at a more treatable stage, taken by the Liverpool Clinical Commissioning Group (CCG) working with communities across Liverpool. Liverpool has one of the highest respiratory morbidity rates in England, with double the national lung cancer incidence, particularly in lower socioeconomic groups. The Liverpool Healthy Lung Programme was initiated in response to both the clinical problem and the health inequality.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      General practice records targeted ever-smokers and subjects with chronic obstructive pulmonary disease (COPD), 58-70y and were invited for 45-minute lung health check. Positive lifestyle messages were promoted; 5-year personal lung cancer risk calculated (www.MyLungRisk.org using LLPv2 risk model). Those who trigger the 5% threshold were offered a LDCT-scan. Spirometry was used to assess lung function (FEV1/FVC); those with abnormal results referred for potentially definitive diagnosis of COPD. Smoking advice and referrals to smoking cessation clinics were provided. Patients CT detected nodules were managed, based on BTS guidelines; referred to MDT for work-up and significant other findings (SoF) were analysed in detail.

      4c3880bb027f159e801041b1021e88e8 Result

      3,591 Healthy Lung Programme consultations (consented). 11,526 people were invited, 4,566 (40%) attended. 1,853 (52%) were male, 2,897 (81%) in the most deprived IMD quintile. 832 (23%) subjects had an existing diagnosis of COPD and 527 (15%) had a previous diagnosis of cancer. 1,173 (33%) subjects had a family history of cancer.

      1,548 (99.3% meeting LLPv2 5% risk criterion) were offered CT scan. 119 (9%) patients required further investigations (follow-up CT scan at 3 or 12 months, or immediate MDT referral), 25 (1.9% undergoing CT scan) were diagnosed with lung cancer (11 have suspected lung cancer, undergoing further investigations). Analysis of a sub-set of the SoF findings were followed up and indicated benefit to participants.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results suggest that it is feasible to achieve similar clinical outcome benefits to those observed in the US trial of LDCT screening for lung cancer, with lesser harms in terms of unnecessary diagnostic activity. However, this needs confirmation with extended follow-up, larger numbers of lung cancers diagnosed, and the addition of mortality data. Additional randomised trial results would also add to the precision of estimation of benefits and harms, in particular mortality results from the large European trial, NELSON. In the meantime, the results of LHLP suggest that it is succeeding in early detection of both COPD and lung cancer.

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      P3.11-14 - Low Rates of Lung Cancer Screening Among Doctors in Mexico

      12:00 - 13:30  |  Presenting Author(s): Omar Macedo-Pérez  |  Author(s): Saul Campos-Gomez, María Isabel Enríquez-Aceves, Fernando Talavera-Caro, Iván Lyra-González, Katya Campos-Peralta, Edgardo Jiménez-Fuentes

      • Abstract

      Background

      Lung cancer represents the leading cause of death from cancer worldwide and in Mexico. Most patients are diagnosed in advanced stages at the time of diagnosis and treatment in these cases is palliative. Lung cancer screening with low-radiation exposure tomography has shown to reduce mortality due to early detection of the disease in high-risk individuals. In Mexico more than 80% of patients are diagnosed in the metastatic stage. Our objective is to know the frequency of screening for lung cancer among neumologists, thoracic surgeons and oncologists in Mexico and the reasons why they do not.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Transversal, descriptive study, carried-out during the international congress of pneumology and thoracic surgery from April 2-6, 2018, in Guanajuato, Mexico. A survey was conducted in Mexican doctors from different specialties and different public and private institutions, they were questioned if they consider screening for lung cancer useful, if they do it, if the screening can be applied to Mexico and what are the barriers that it finds not to do it. The data were emptied into a database in the SPSS v23 system and descriptive statistics were made for the analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 147 specialist doctors were interviewed, 49% were oncologists, 43% were neumologists and 8% were chest surgeons. Despite the fact that 86% considered screening to be useful, only 36% performed it within their daily clinical practice. The main barriers they found to implement screening in our country were due to multiple factors according with response of 70% of physicians where lack of CT scan and qualified personnel to interpret image results were the most prevalent. The remaining 30% considered only one factor as the most important where the lack of infrastructure (CT scan) was the most prevalent in 14% of the answers.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although the specialists in prevention, diagnosis and treatment of lung cancer in Mexico are aware of the usefulness of screening for lung cancer, the frequency of implementation is low, mainly due to lack of appropriate infrastructure and trained personnel. It is necessary to implement public health policies to promote screening in the majority of patients who meet the high-risk criteria to increase early diagnosis and subsequently improve survival outcomes in this population.

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      P3.11-15 - Lung Cancer Symptom Perception and Intervention Preferences in the UK’s Most Deprived Communities: A Qualitative Study

      12:00 - 13:30  |  Presenting Author(s): Kate Brain  |  Author(s): Grace McCutchan, Julia Hiscock, Peter Murchie, Kerry Hood, Richard Neal, Sara Thomas, Ann Maria Thomas, Gareth Newton

      • Abstract

      Background

      People at highest risk for lung cancer- current or former smokers, aged over 40 years, with serious lung comorbidity and living in areas of deprivation- are more likely to prolong presenting to a GP with symptoms, leading to advanced stage diagnosis. This qualitative study sought to understand the influences on early presentation with lung cancer symptoms and intervention preferences in a sample of high risk, highly deprived individuals.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Semi-structured interviews were conducted with 37 high risk participants recruited purposively according to age, lung comorbidity and smoking status from primary care practices in deprived areas of England, Scotland and Wales. A lung symptom attribution task was used to explore symptom interpretations, symptom presentation and beliefs surrounding lung cancer, underpinned by Leventhal’s Common Sense model. Four focus groups with members of the public and local stakeholders (healthcare professionals and community partners) were conducted to explore intervention preferences. Data were analysed using Framework method.

      4c3880bb027f159e801041b1021e88e8 Result

      Interviews

      All participants resided in the most deprived quintile and most were unemployed or seeking benefits, and/or rented social housing. Key themes were: fixation on short term health (chest infections) leading to avoidance of longer term health (lung cancer), and the importance of the relationship with their healthcare professional to facilitate or deter help seeking. Focusing on detecting and managing ‘treatable’ chest infections led to denial of symptoms of ‘inevitable and incurable’ lung cancer. For example, participants normalised haemoptysis. Feeling judged by healthcare professionals and unworthy of medical help because of residence in a disadvantaged area or smoking habit deterred help seeking. Some participants, particularly those without caring responsibilities, anticipated refusal of treatment for lung cancer, with some contemplating suicide.

      Focus groups

      Suggestions for intervention content included information to raise awareness of lung cancer symptoms, modify negative lung cancer beliefs and highlight the importance of earlier diagnosis. Multi-faceted interventions were suggested including talks and stands in community venues, led by a trained, non-judgemental facilitator.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the context of difficult life circumstances and stigma, individuals who are high risk for lung cancer manage their lung health in the short term. Fixation on the treatment and detection of immediate health concerns may lead to avoidance and denial of important lung cancer symptoms. Community based multi-faceted interventions are required to empower highly deprived individuals to seek timely help, using a non-judgmental and welcoming approach.

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      P3.11-16 - Comparative Analysis of Health-Care Resources and Economic Costs of Lung Cancer Patients Treated Medically or Surgically in Catalunya

      12:00 - 13:30  |  Presenting Author(s): Laureano Molins  |  Author(s): Angela Guirao, Rudith Guzman, Montserrat Cleries, Emili Vela, David Magen, David Sanchez, Marc Boada, Jose A Espinas, Josep M Borras, Jose M Argimon, Alvaro Agusti

      • Abstract

      Background

      To contribute to the debate about the cost-benefit ratio of lung cancer computerized tomography (CT) screening programs, and to support the implementation of large scale lung ancer (LC) screening programs to increase the number of potential LC patients that can benefit from this treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Observational, comparative, retrospective study includes 13.415 patients who were diagnosed of LC between 2014 and 2016 in Catalunya. All of them were treated medically or surgically. We obtain information from the data bases of the “Health attention area. Information and knowledge unit.” of the following variables (both before and after LC diagnosis): vital status and autonomy level, drug dispensation, radiotherapy sessions, use of health-care resources, day-hospital visits, hospitalization events, use of nursing homes, non-urgent sanitary transport, monthly and annual costs (€) per patient (and 3 year/survival)

      Variables were compared between the group medical treatment vs. the group surgical treatment using unpaired parametric tests. Since this is an observational study, no formal calculation of sample size was pretended. Yet, post-hoc results identified a cohort of 13.415 participants, which should be enough for descriptive purposes.

      4c3880bb027f159e801041b1021e88e8 Result

      3 year/Survival after LC diagnosis was much higher in surgical patients (78,9% vs 23,3%) (p<0.001). Surgically treated patients achieve a higher level of autonomy earlier before diagnosis.

      The monthly rate of total drug dispensation, cancer drugs, radiotherapy sessions, opioid and analgesic dispensation before and after LC diagnosis were much higher in medical patients. The rate of dispensation of ansiolitic, sedatives and anti-depressives were similar in both groups.

      Hospitalization events were slightly higher in the surgical group. There were no significant differences between groups in the rate of primary care or hospital outpatient clinic visits. The use of Health-care resources and non-emergency sanitary transport peaked before diagnosis to a larger extend in medical patients.

      The average annual cost of medical and surgical patients one year after LC diagnosis and treatment was 67% higher in medical patients (17.495 vs. 10.447 €).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Surgical treatment of LC offers better clinical outcomes and is cost-efficient. These arguments support the implementation of large scale LC screening programs to increase the number of potential LC patients that can benefit from this treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-18 - Implementing One Stop Lung Clinic to Improve Diagnostic Timeliness in Lung Cancer Patients in the North of England

      12:00 - 13:30  |  Presenting Author(s): Vytis Dudzevicius  |  Author(s): Spencer Robinson, Ramamurthy Sathyamurthy, Rehan Mustafa, Richard Hartley, Giedre Andrijevskiene, Kerry Linkin, Terri Jasper, Jan Hughes, Sara Fenwick, Heidi Sircus, Nigel Clerk, Rachel Shears, Andrea Charles, Carol Taylor, Kay Dover, Angela Wood

      • Abstract

      Background

      Employing just one modification (early use of endobronchial ultrasound) has been shown to improve survival in a randomised controlled trial (Navani et al. Lancet Respir Med 2015). A new innovation set out to implement One Stop lung clinic to reduce diagnostic times as a part of of the Macmillan Integrated Cancer Care Programme on the Lung Cancer Pathway maping started in 2014, which pre-dates the National Optimal Lung Cancer Pathway. Aim of the study was to demonstrate shorter time to diagnosis for patients with suspected lung cancer referred from general practice on a '2 week wait' referral pathway in the UK.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data relating to diagnostic intervals of the patient’s attending One Stop clinic collected and interim analysis performed. The diagnostic intervals were analysed using descriptive analysis to establish the timeliness of intervals from first seen to diagnosis and discussion at the Multi-Disciplinary Team (MDT) meeting.

      4c3880bb027f159e801041b1021e88e8 Result

      33 patients attended One Stop clinic and received a CT and then either bronchoscopy, endobronchial ultrasound or pleural aspiration on the same day. 48% (n=15) of patients were diagnosed with a primary lung cancer, 16% (n=5) - with other malignancies including myeloma, lymphoma and colorectal cancer and 32% (n=10) - with non-malignant conditions. The diagnostic intervals from first seen in a lung clinic to diagnosis were in range between 9 and 37days. 39% (n=13) of patients attending the clinic were worked up for the lung MDT discussion within 9 days, 24% (n=8) of patients - within 16 days, 6% (n=2) of patients - within 23 days. In 9% (n=3) of the cases the work up took 30 days or over. 15% (n= 5) were taken off the pathway and 6% (n=2) - were referred for best supportive care.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Diagnostic intervals for a cohort of patients attending the clinic were shorter in comparison to England’s National Cancer Standard of 31 days from referral to diagnosis. It is argued that One Stop clinic which involves a CT, then either a bronchoscopy, endobronchial ultrasound or pleural aspiration completed all on the same day reduces the time to diagnosis and improves organisational performance. Interventions for expediting earlier diagnosis of lung cancer need to focus on the compliance of diagnostic services to be all aligned in a rapid one stop environment to improve the earlier diagnosis of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-19 - Improving Lung Cancer Screening Rates in an Underserved Outpatient Clinic

      12:00 - 13:30  |  Presenting Author(s): Carlos Armando Rodriguez  |  Author(s): Ana Velazquez, Alan Tso

      • Abstract

      Background

      Lung cancer is the leading cause of cancer death worldwide and in the United States. Despite its massive mortality, no screening method was available until this decade. The National Lung Cancer Screening Trial (NLST) demonstrated in 2011 that lung cancer screening in high risks patients using low dose chest computed tomography (LDCT) resulted in a 20% relative reduction in lung cancer-related mortality compared to chest X-Ray screening. Hence, the USPSTF recommended (grade B) in December 2013 annual LDCT for lung cancer screening in adults age 55-80 years, who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective review of current and former smokers evaluated by a primary care provider over a six month period in 2017 in our inner city community health center. Patients that met the USPSTF criteria for lung cancer screening were selected and data regarding LDCT ordering and completion was collected. Microsoft Excel was used for data tabulation and analysis. We aim to improve our screening compliance by 20% in 6 months by implementing electronic medical records reminders, staff educational sessions, and telephone reminders to patients.

      4c3880bb027f159e801041b1021e88e8 Result

      577 patients were identified and total of 108 patients met the USPSTF criteria for screening. A total of 287 patients were excluded as the numbers of pack per year were unable to be calculated. Of the 108 patients, 67% were current smoker and 33% former smokers. The mean age was 65 with 54% male and 46% female. A total of 57% of the patients identified as Hispanic or Latino and 70% of selected English as their primary language. A LDCT was ordered by a physician in 32% (N=35) of cases and completed in only 18 patients, resulting in a net rate of screening compliance of 17%. Among those ordered, 17 patients (48.5%) did not complete their LDCT due to multiple reasons. Appointment no-show was the most common reason reported in 73% of cases. Other reasons included insurance denial in 12%, or patient cancellation or re-scheduling in 12%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      By highlighting our poor adherence to lung cancer screening guidelines, we hope to provide improve our screening rates and provide a valuable approach for other institutions.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-20 - Patterns and Predictors of Adherence to Recommended Follow-Up After Low-Dose Computed Tomography Screening for Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Lori C. Sakoda  |  Author(s): Cecile A Laurent, Charles P Quesenberry Jr., George Minowada

      • Abstract

      Background

      Results from the National Lung Screening Trial support current guidelines to screen high-risk smokers annually for lung cancer with low-dose computed tomography (LDCT) in the United States. Monitoring the screening process, including repeat screening and follow-up, is important to ensure the benefits of screening outweigh its harms. We examined early patterns and predictors of adherence to recommended follow-up care after baseline LDCT screening in a large integrated healthcare system.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our cohort study included patients screened for lung cancer during the first year of LDCT screening at selected Kaiser Permanente Northern California facilities, when referrals for screening came directly from primary care physicians (PCPs, instead of dedicated clinician specialists as now implemented). Using electronic administrative and clinical databases, we identified 145 screening-eligible patients who had a baseline LDCT screening exam from July 2014 to June 2015, with continuous health plan enrollment for at least 14 months post-baseline. Adherence to recommended follow-up after the baseline exam was determined according to Lung-RADS classification. We defined adherence as receipt of imaging within 10 to 14 months after a negative exam (i.e., Lung-RADS category 1 or 2) and receipt of imaging or diagnostic evaluation within ±30 days of the recommended follow-up interval after a positive exam (i.e., Lung-RADS category 3 or 4). Among patients with a negative exam, we further examined whether baseline factors, including age, gender, race/ethnicity, prior healthcare utilization, smoking history, and Charlson comorbidity index (CCI), were associated with adherence, using logistic regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 145 patients, 61% were male, 71% were of white race, 76% were current smokers, and 72% had a CCI of 0-1. The median age was 66 years. Baseline exam results were negative for 122 patients and positive for 23 patients. All five patients subsequently diagnosed with lung cancer were classified as Lung-RADS category 4B at baseline. Adherence to recommended follow-up was higher after a positive than negative exam – 61% vs 23% – although low overall. Among patients with a negative exam, adherence was suggestively associated with gender and race/ethnicity, with greater adherence in women than men [odds ratio, OR (95% confidence interval, CI): 1.8 (0.8–4.1)] and patients of white than non-white race/ethnicity [OR (95% CI): 1.8 (0.7–8.3)].

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our preliminary results suggest adherence to recommended follow-up is low, particularly after a negative baseline exam, due in part to insufficient patient education and shared decision-making about LDCT screening during PCP visits. Further analyses are underway to interpret these results.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-21 - The Development of a Robust Radiology Quality Assurance (QA) Program in a Provincial High-Risk Lung Cancer Screening Pilot (HRLCSP)

      12:00 - 13:30  |  Presenting Author(s): Heidi Schmidt  |  Author(s): Michelle Ang, Redinela Mani, Gail Elizabeth Darling, Deanna Langer, Priyanka Jain, Victoria Treister, Martin Tammemägi, Simrun Flora

      • Abstract

      Background

      Lung cancer is the leading cause of cancer death in Ontario, with an estimated 7100 patient deaths occurring in 2016 (Canadian Cancer Society, 2016). Based on results from the National Institute of Health’s National Lung Screening Trial, Cancer Care Ontario (CCO) implemented the HRLCSP in 2017 to determine feasibility of provincial scale roll-out of an organized lung cancer screening program. An integral component of the HRLCSP is to ensure low-dose computed tomography (LDCT) scans would be performed, interpreted and reported in a standardized, and high-quality manner.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The HRLCSP project team coordinated with CCO’s Cancer Imaging Program (CIP) to gain insight into cancer imaging practices and protocols, and recruited clinical expertise through a Radiology QA Clinical Lead (RQACL). In collaboration with pilot site radiologists, a comprehensive QA program was developed to encompass all aspects of radiology including facility, educational, and reporting standards, in addition to defining quality improvement criteria.

      4c3880bb027f159e801041b1021e88e8 Result

      To ensure pilot centres were able to deliver high-quality LDCTs, the RQACL, site participants and clinical experts collaborated to define and implement quality parameters. Equipment standards were defined in The Radiology QA Program Manual, and agreement from pilot sites was confirmed. Collaboration with reading radiologists led to tailored educational workshops designed to ensure consistency in the reporting of lung nodules based on the Lung-RADS™ scoring criteria, adapted from the American College of Radiology. Scan interpretation considerations, scoring criteria, and reporting templates were implemented. Annual assessments have ensured compliance across pilot sites. A working group aiming to determine an algorithm to examine incidental findings is being created. LDCT scan Double Read minimums and Peer Review adjudication processes were developed to ensure expert opinion availability with radiologist discrepancies to ensure high quality scan interpretation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The design of the HRLCSP offered opportunities for implementing high quality standards around the LDCT scans. Implementation of a robust quality assurance program can ensure that the radiology component is delivered in a high-quality manner. Radiologist training programs, centre minimum requirements, and standardized reporting can ensure standards remain high. Lessons learned through the development of this comprehensive radiology QA program in the HRLCSP will allow for adoption of high-quality radiology standards on a larger provincial scale.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-22 - The Path to National Lung Cancer Screening  Program in Israel

      12:00 - 13:30  |  Presenting Author(s): Shani Shilo  |  Author(s): Abed Agbaria, Nir Peled

      • Abstract

      Background

      2500 people are diagnosed every year with lung cancer and 2000 die from the disease, the leading cause of death in Israel. The prevalence of smoking is 22.5% above 21 years of age, resulting in about 1.2 million smokers overall. The USPSTF found adequate evidence that annual screening for lung cancer with LDCT in a defined population of high-risk persons can prevent a substantial number of lung cancer–related deaths, therefore the Israeli Lung Cancer foundation (ILCF) decided to advocate for including LC screening program in Israel's medical services.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The medical services "health basket" in Israel encompasses the entire range of services, drugs, medical equipment and devices that the insured public receives. Every end of year, a health basket committee is appointed to review and approve the new services to be included in the following year health basket. The services are reviewed for their health benefit and then are chosen to fit a limited budget.

      ILCF have filled twice for the years of 2017 and 2018 to have a national LDCT LC screening program in Israel.

      4c3880bb027f159e801041b1021e88e8 Result

      LC Screening program was filled by ILCF to the 2017 Health basket committee. The committee decided that there is not enough supporting evidence and did not rank the program high enough to be included in the funding debate. Nevertheless, because the issue was raised, the ministry of health decided to gather a special committee to evaluate LC Screening program. The committee decided that there is enough evidence and recommended to have the program be part of the health system in Israel.

      For 2018-year, LC Screening program was filled by ILCF and the ministry of health LC Screening committee. This time after an additional appeal the program was ranked to enter the funding debate. Unfortunately, it was excluded from the 2018 health basket. As a result, ILCF appealed to the Israeli high court of justice against the health basket committee claiming that the decision was unreasonable. The appeal is being currently discussed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Change takes a lot of effort and collaboration. Unfortunately, lung cancer screening is not an industrial initiative, thus does not have strong lobbying power. Therefore, it is the duty of patient advocates and leading oncologists, radiologists and pulmonologists to raise the flag. Here we present a model of collaboration between a patient organization and leading oncologists and radiologists to incorporate LC Screening program in Israel.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-23 - Adherence to Annual Low-Dose CT Lung Cancer Screening at a Large Academic Institution

      12:00 - 13:30  |  Presenting Author(s): Lucy B Spalluto  |  Author(s): Jennifer A. Lewis, Kim L. Sandler, Pierre P Massion, Robert S. Dittus, Christianne L. Roumie

      • Abstract

      Background

      Annual low-dose computed tomography (LDCT) is standard-of-care in the high-risk population for lung cancer screening. We assessed adherence to annual LDCT screening in a large academic institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We assembled a retrospective cohort of patients who underwent LDCT between January 1, 2014 and September 30, 2016.

      We included patients with baseline LungRads 1 or 2 with 12-month follow-up recommendation. We excluded those who died before the time of recommended follow-up. The time interval between the recommended follow-up study date and the actual follow-up study was calculated. Patient adherence at time of due follow-up was defined by this time interval: <=90 days (adherent) and >90 days (non-adherent).

      Primary analysis was change in adherence over time. Secondary analysis included descriptive statistics of demographics.

      4c3880bb027f159e801041b1021e88e8 Result

      lcs adherence.jpg

      395 patients had baseline LDCT screening. We found a persistent, significant increase in adherence: 11% (2/18) in the 1st quarter 2015 and 70% (46/66) in the 3rd quarter 2017 (Pearson’s chi-squared test p=.008). We also identified racial disparity in patients enrolling in our Lung Screening Program (93% white).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Adherence to annual LDCT screening significantly increased from 2015 to 2017. Improvement may be due to changes in national policy and/or implementation of a dedicated program physician director and program coordinator. Future work should address racial disparities and barriers to and facilitators of annual LDCT screening.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-24 - “To Know or Not to Know ...?” Push and Pull in Ever Smokers Lung Screening Uptake Decision Making Intentions

      12:00 - 13:30  |  Presenting Author(s): Janet Tonge  |  Author(s): Melanie Atack, Phillip Crosbie, Phil Barber, Richard Booton, Denis Colligan

      • Abstract

      Background

      Despite introduction in America and calls for European implementation, lung screening isn't currently endorsed as a UK programme. Whether smokers want to be screened has been raised as an issue. This study explored uptake decision-making with ever-smokers, aged 50-80 as part of the UK’s first community based one-stop lung screening pilot service.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Thirty-three participants (22 ex-smokers; 11 smokers) men and women, aged 50-80 were recruited purposively from community settings and health facilities in Manchester, England. The setting is a city with significant deprivation and high lung cancer incidence. Six semi-structured focus groups were held with separate groups for current and former smokers to facilitate freer expression and comparison but mixed by gender, age, ethnicity and deprivation. Discussions followed semi-structured topic guides were audio-recorded, transcribed verbatim and coded using NVIVO software. Inductive thematic analysis was used to analyse data and identify key themes.

      4c3880bb027f159e801041b1021e88e8 Result

      Lung screening was widely acceptable to participants. It was seen as offering reassurance about lung health or opportunity for early detection and treatment. However, being positive ‘in principle’ didn’t always translate into uptake intention. Factors that impacted participants' desire to know about their lung health included: views about screening benefits; emotions such as worry about a diagnosis and screening tests; practicalities such as service accessibility; and smoking related factors included views about individual smoking risk and smoking stigma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Indications were that current smokers faced higher uptake barriers than ex-smokers. The uptake factors identified appeared to motivate some participants to be screened but act as a barrier for others. This factorial 'push and pull' effect is important as it indicates where action can be taken to help reduce participation barriers to lung screening. This is shown in Figure One.

      fig 1 lung push and pull diagram.png

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-25 - Analysis Indicates Low Incremental Cost-Effectiveness Ratio for Implementation of Lung Cancer Screening in Italy

      12:00 - 13:30  |  Presenting Author(s): Giulia Veronesi  |  Author(s): Simone Ghislandi, Elena Vanni, Elisa Dieci, Luca Toschi, Laura Velutti, Michela Solinas, Pierluigi Novellis, Marco Alloisio, Elio Riboli, Niccolò Navone

      • Abstract

      Background

      Given the potential of early lung cancer detection to improve survival, accurate assessment of the cost-effectiveness of low-dose computed tomography (LDCT) screening is crucial. We report the results of a cost-effectiveness analysis of screening for Italian persons at high risk of lung cancer from the public payer’s perspective

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study built on a mathematical decision model to estimate the cost-effectiveness of annual LDCT screening for 5 years in a high-risk population of smokers (at least 30 pack-years) aged 55-79 years. The stage distribution of patients diagnosed as part of the COSMOS screening study was used for the “screening arm;” the stage distribution of patients in the SEER database was used for the “usual care arm.” Treatment costs were determined using detailed individual-level administrative information from our Institutional database of lung cancer patients. Lung cancer survival in screened patients was adjusted for 2 year-lead time bias. The model estimated expected future life years using survival probabilities according to age, sex, and lung cancer stage (or no lung cancer). Quality-Adjusted Life Years (QALYs) gained and Life Years (LY) gained were estimated.

      4c3880bb027f159e801041b1021e88e8 Result

      The base-case incremental cost for each QALY gained was 4747,57 Euro. The incremental cost-effectiveness ratio (ICER) for each LY gained was 4069 Euro. An extensive sensitivity analysis showed that model outcomes were particularly sensitive to lung cancer prevalence, the sensitivity and specificity of screening, and the lead-time bias assumed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our analysis indicates that LDCT screening is associated with a low ICER of 4069 Euro, meaning that this is the yearly incremental cost of saving the life of a patient, and is lower than the ICER accepted by the Italian government. The implication is that implementation of screening throughout Italy can be achieved at a relatively low cost, a finding which should be taken into account by health policy decision-maker.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-26 - Results of Initial Low-Dose Computed Tomographic Screening for Lung Cancer from a Single-Institution in China

      12:00 - 13:30  |  Presenting Author(s): Wei Wang  |  Author(s): Mimi Zhou, Jicheng Xie, Minhua Ye, Dongqing Lv, Feng-Ming Spring Kong, Haihua Yang

      • Abstract

      Background

      Lung cancer screening using low-dose computed tomography (LDCT) has been reported to reduce lung cancer-specific mortality for smokers at high risk in patients of the United States. However, there are very few LDCT screening results from Chinese patients. We here report the screening findings at the initial round of LDCT screening program from a single-institution population-based cohort in China.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a retrospective study of a single-institution population-based LDCT screening program for lung cancer. Patients participated LDCT in Taizhou Hospital of Enze Medical Center were eligible. All noncalcified nodules with long-axis diameters of 4mm or greater in the axial plane were considered to be positive for potential lung cancer according to NLST definition. If more than three nodules were found, one dominant nodules were selected for this analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      From July 2017 through December 2017, a total of 8611 participants with LDCT screening were included in this report. A total of 78 participants with history of cancer and 437 participants were follow-up procedures were excluded in this analysis. Of the remaining 8096 participants, the median age was 51 years (range, 16-97 years). A total of 1516 (18.8%) participants were younger than 40 years, 5264 (65.2%) were 40-64 years and 1316 (16.3%) were greater than 64 years. The total proportion of positive nodules was 21.8%, slightly higher in females (535/2258, 23.7%) than males (1233/5838, 21.1%). Lung cancer was diagnosed in 26 participants (0.32%) (11 males and 14 females) of the 1768 positive nodules. The comprehensive demographics of 26 lung cancer patients (included one patients with multiple metastases tumor from pancreas) is shown table 1.

      Table 1 Comprehensive demographics of 26 lung cancer patients

      No.

      Sex

      Age

      (y)

      Smoking

      Type of nodules

      Histology

      Type of EGFRm

      TNM

      Treatment

      1

      M

      70

      Never

      8mm GGN, RUL

      ADC in situ

      Wild

      pT1isN0M0

      Wedge resection

      2

      M

      47

      Current,

      40 pack-year

      16mm solid, RUL

      ADC

      19-del

      pT1aN0M0

      Lobectomy

      3

      M

      70

      Never

      Multiple nodules;

      12mm solid, RLL

      Metastatic ADC from pancreas

      unknown

      pT1bN0M0

      without

      4

      M

      53

      Current,

      60 pack-year

      21mm sub-solid, LLL

      ADC

      unknown

      pT1cN0M0

      Lobectomy

      5

      M

      49

      Never

      6mm GGO, RLL

      ADC

      L858R

      pT1aN0M0

      Wedge resection

      6

      M

      62

      Former,

      45 pack-year

      30mm, LLL

      SCC

      unknown

      cT2aN2M0

      chemotherapy

      7

      M

      62

      Former,

      24pack-year,

      32mm solid, RLL

      ADC

      19-del

      pT4N0M0

      Lobectomy

      8

      F

      44

      Never

      12mm GGO, LUL

      ADC

      unknown

      pT1bN0M0

      Segmental Resection

      9

      F

      68

      Never

      8mm GGO,RML

      ADC

      unknown

      pT1aN0M0

      Lobectomy

      10

      M

      74

      Current,

      60 pack-year

      14mm solid, RUL

      ADC

      L858R

      pT1aN0M0

      Wedge resection

      11

      M

      74

      Former,

      40 pack-year

      15mm sub-solid, LLL

      SCC

      unknown

      pT1bN2M0

      Lobectomy

      12

      F

      55

      Never

      12mm GGN, RUL

      ADC

      unknown

      pT1aN0M0

      Lobectomy

      13

      F

      64

      Never

      11mm GGO,RUL

      8mm GGO, RUL

      ADC

      ADC

      Wild

      pT3N0M0

      Lobectomy

      14

      F

      78

      Never

      18mm solid, RLL

      ADC

      19-del

      cT1bN0M0

      Gefitinib

      15

      F

      67

      Never

      14mm GGO, RUL

      12mm GGO, RUL

      ADC;

      ADC

      unknown

      pT3N0M0

      Lobectomy

      16

      F

      73

      Never

      18mm GGO, LUL

      ADC

      unknown

      pT1bN0M0

      Wedge resection

      17

      M

      75

      Never

      10mm sub-solid, RUL

      ADC

      unknown

      pT1aN0M0

      Lobectomy

      18

      M

      71

      Current,

      60 pack-year

      30mm solid, LLL

      NSCLC

      unknown

      cT2aN2M

      Lobectomy

      19

      F

      60

      Never

      8mm solid, RLL

      ADC

      19-del

      pT1aN0M0

      Lobectomy

      20

      F

      78

      Never

      17mm solid, RUL

      ADC

      L858R

      pT1bN0M0

      Wedge resection

      21

      F

      56

      Never

      11mm GGN,RUL

      ADC

      unknown

      pT1bN0M

      Lobectomy

      22

      F

      58

      Never

      13mm solid, RUL

      ADC

      L858R

      pT1bN0M0

      Lobectomy

      23

      F

      46

      Never

      13mm sub-solid, LUL

      ADC

      Wild

      pT1bN0M0

      Lobectomy

      24

      M

      65

      Current,

      40 pack-year

      50mm solid, LUL

      SCC

      unknown

      pT3N0M0

      Lobectomy

      25

      F

      67

      Never

      9mm solid, RUL

      5mm solid, RUL

      ADC;

      ADC in situ

      L858R

      pT3N0M0

      Wedge resection

      26

      F

      47

      Never

      7mm GGO, RUL

      ADC

      20-INS

      pT1bN0M0

      Wedge resection

      GGO=Ground-glass opacity; GGN=ground glass density nodule; RML=right middle lobe; RLL=right lower lobe; RUL=right lower lobe; LUL=left upper lobe; LLL=left lower lobe; tis=carcinoma in site; EGFRm= EGFR mutation

      8eea62084ca7e541d918e823422bd82e Conclusion

      The overall rate of positive nodules is similar to previous reports, and the overall cancer detection rate by LDCT in our cohort was lower than previous reports from others (0.36-3.3%).

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.11-27 - Lung Cancer Diagnosed at Age 50-54 Years: Survival as Poor as Older Patients

      12:00 - 13:30  |  Presenting Author(s): Ping Yang  |  Author(s): Lei Luo, Yi Wang, Jason Wampfler, Dan Liu, Yuanyuan Wang, Shawn Stoddard, Yanan Yang, Hao Xie, David Midthun

      • Abstract

      Background

      The United States Preventive Services Task Force (USPSTF) recommends lung cancer screening with low-dose computed tomography among people aged 55-80 years with a 30 pack-year cigarette smoking history and, if stopped smoking, quitted within 15 years. We previously identified a prominent subpopulation that would have been too young (i.e., 50-54.9 years) yet otherwise met the USPSTF criteria and were diagnosed with lung cancer. We assessed survival outcomes in these younger patients compared to those eligible for USPSTF lung cancer screening.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We studied two cohorts of 7,390 primary lung cancer patients: a Hospital Cohort from Mayo Clinic Rochester (n=6,554) and a Community Cohort from the Olmsted County population (n=836, Minnesota, USA). All patients were diagnosed between age 50 and 80 years, had >30 pack-year smoking history and had quitted <15 years if they had stopped smoking. Two cohorts were analyzed independently to evaluate the impact of younger age (50-54.9 years) on overall survival using Cox Proportional Hazard models by hazard ratio (HR) and 95% confidence interval (CI). Known prognostic factors (age, sex, tumor stage and treatment) were adjusted. To control for age gap, the USPSTF group was subdivided into a 55–69 age subgroup (lower age USPSTF subgroup) and a 70–80 age subgroup (higher age USPSTF subgroup).

      4c3880bb027f159e801041b1021e88e8 Result

      In both cohorts, the younger age group had at least the same risk of death as patients who met the USPSTF criteria; HR=1.16 for both cohorts; p=0.08 for the Hospital Cohort and p=0.52 for the Community Cohort. Age-group stratified analyses did not change the results in either cohort.

      8eea62084ca7e541d918e823422bd82e Conclusion

      People who are 50-54.9 years of age and otherwise meet the USPSTF screening criteria for lung cancer, once diagnosed, experience a similar or potentially worse survival outcome as older patients. Benefit of screening in this younger population deserves consideration and futher study.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
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      P3.12-01 - Targeting Mitochondrial Metabolism as a Selective Therapeutic Approach in Small Cell Lung Cancer (SCLC)

      12:00 - 13:30  |  Presenting Author(s): Shantanu Banerji  |  Author(s): Subir Roy Chowdhury, Ryan Saleh, Carmen Girard, Cheryl Peltier, Danielle Desautels, David E Dawe, Versha Banerji

      • Abstract

      Background

      SCLC accounts for 13% of new lung cancer diagnoses and is the most aggressive form of the disease. Altered cellular metabolism is considered a hallmark of cancer and a target for therapeutic intervention. Mitochondria represent an important cellular compartment and selectively targeting mitochondrial bioenergetics may be an effective therapeutic approach for SCLC. Nicotinamidephospho-robosyltransferase (NAMPT) is a key enzyme in the mitochondrial nicotinamide adenine dinucleotide salvage pathway. Recent high-throughput drug screens identified SCLC as the most sensitive cancer subtype to NAMPT inhibitors like FK866. Genomic studies of SCLC have also suggested the constitutive activation of the PI3K/AKT/mTOR pathway in a significant portion of SCLC cases. Idelalisib a phosphatidylinositol-3-kinase-delta inhibitor is approved for the treatment of B-cell malignancies. We hypothesize that the inhibitors FK866 and idelalisib will alter SCLC mitochondrial bioenergetic profiles and function, and that combination therapy may enable lower drug doses in clinical use.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Mitochondrial bioenergetics profiles at baseline and in response to drug were assessed in SCLC cell lines H69, DMS79, and H209 using a high resolution Oroboros Oxygraph 2K. Corresponding cell survival was determined using ATP glow and flow cytometry. Western blot analysis was used to evaluate cell death pathways.

      4c3880bb027f159e801041b1021e88e8 Result

      Cell survival and mitochondrial bioenergetics parameters i.e. basal respiration, maximal respiration, spare respiratory capacity, and respiratory control ratio were measured in a dose-dependent manner for FK866 (0.5 – 2.5 nM) and idelalisib (1 – 50 μM) at 24 and 48 hours in SCLC. The IC50 for cell survival with FK866 in the 3 lines ranged between 1 and 8 nM. FK866 did not induce apoptosis as measured by Caspase 3 cleavage, but induced γH2X phosphorylation suggesting a role for DNA damage at lethal doses. Mitochondrial bioenergetics was inhibited as low as 0.5 nM dose of FK866 and 6.25 μM of idelalisib. Our preliminary data also demonstrate that the combination of 1 nM FK866 and 6.25 μM idelalisib significantly decreases the major mitochondrial bioenergetic parameters compared to FK866 alone after 24 or 48 hours treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Both FK866 and idelalisib affected bioenergetics profile in SCLC cells and the combined effect of both drugs is on the mitochondrial bioenergetics profile is greater than the impact of single agents. The combined use of these drugs at lower doses targeting mitochondrial metabolism may allow for a greater therapeutic index in clinical trials.

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      P3.12-02 - Dynamics of DLL3 and ASCL1 Expression in SCLC Over Disease Course

      12:00 - 13:30  |  Presenting Author(s): Anna F. Farago  |  Author(s): Kumiko Isse, Benjamin J. Drapkin, Vashine Kamesan, Marina Kem, Laura Saunders, Syed Quadri, Mari Mino-Kenudson

      • Abstract

      Background

      SCLC is a high-grade neuroendocrine malignancy highly responsive to first-line therapy, etoposide plus platinum (EP), but increasingly resistant to subsequent lines of therapy. Because SCLC is rarely biopsied following the initial diagnosis, the dynamics of expression of therapeutically relevant biomarkers in relapsed disease are poorly understood. ASCL1 is an oncogenic driver of SCLC and directs transcription of delta-like protein 3 (DLL3), an atypical Notch receptor family ligand involved in neuroendocrine tumorigenesis and the target of the antibody drug conjugate rovalpituzumab tesirine (Rova-T™). We investigated ASCL1 and DLL3 expression in SCLC patient (pt) tumor biopsies and patient-derived xenografts (PDXs) collected serially from time of diagnosis (pre-treatment) and after progression following ≥1 lines of therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Fresh cut, formalin fixed, paraffin embedded tissue from primary SCLC tumors and PDXs was sectioned and stained with mouse monoclonal antibodies against DLL3 (SC16.65) and ASCL1 (SC72.201) on the Dako platform. ASCL1 and DLL3 expression were scored as a percent of positive cells and correlated with each pt’s treatment history.

      4c3880bb027f159e801041b1021e88e8 Result

      Among biopsies and/or PDXs derived over serial time points, 6 cases had baseline positive DLL3 expression ranging from 15-80% of cells with a mean of 50% pre-EP. All 6 remained positive following progression after EP, with DLL3 expression ranging from 10-100% of cells with a mean of 66%. Up to 7 serial tissue or PDX samples were available over the course of multiple treatments for 2 pts, and DLL3 and ASCL1 expression remained consistent over time, being strongly positive in 1 case and negative in the other. Among biopsies and PDXs established at matched time points, ASCL1 and DLL3 expression were consistent in 7/7 and 7/8 cases, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      ASCL1 and DLL3 expression remain mostly consistent pre- and post- chemotherapy in pts with SCLC, suggesting that expression of these biomarkers in archival tissue likely accurately estimates expression even after intervening treatments. Furthermore, PDXs derived both from biopsies and circulating tumor cells maintain ASCL1 and DLL3 expression that reflects the pt tumor, supporting use of PDXs to model pt tumor biology.

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      P3.12-03 - Targeting DLL3 with AMG 757, a BiTE® Antibody Construct, and AMG 119, a CAR-T, for the Treatment of SCLC

      12:00 - 13:30  |  Presenting Author(s): Michael Giffin  |  Author(s): Keegan Cooke, Edward Lobenhofer, Matthias Friedrich, Tobias Raum, Angela Coxon

      • Abstract

      Background
      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with a poor prognosis and limited therapeutic options. Redirecting the potent cytotoxic potential of T cells via bi-specific T cell engager (BiTE®) antibody constructs and chimeric antigen receptor T cells (CAR-T) represents a promising new approach in the treatment of cancer, with durable complete responses observed in the clinic. a9ded1e5ce5d75814730bb4caaf49419 Method
      Differential expression profiling of SCLC tumors and normal tissues was performed using RNAseq and immunohistochemistry. BiTE® and CAR scFv constructs were converted from fully human antibodies. BiTE® and CAR redirected T cell activity was evaluated in vitro and in vivo.
      4c3880bb027f159e801041b1021e88e8 Result
      Analysis of gene expression in SCLC tumors versus normal tissues identified Delta-Like Ligand 3 (DLL3) as a highly specific tumor associated antigen for SCLC. Expression of DLL3 in normal tissues was detected at very low levels in the brain, pituitary, and pancreatic islets, and showed a cytoplasmic staining pattern by IHC.
      We have developed a novel BiTE® antibody construct, AMG 757, with prolonged serum half-life relative to that of canonical BiTE® molecules. AMG 757 showed low picomolar potency against SCLC cell lines in vitro and also demonstrated significant inhibition of tumor growth in vivo. Pharmacokinetic analysis showed AMG 757 demonstrated a serum half-life predicted to support Q2W dosing in humans. Furthermore, AMG 757 was well tolerated in a repeat-dose 28-day GLP toxicology study, with no AMG 757-related adverse findings at doses as high as 4.5 mg/kg QW. Exposures were dose-proportional and with no evidence of tissue damage.
      We have also advanced AMG 119, a CAR-T targeting DLL3, into clinical development. AMG 119 demonstrated robust ablation of target cells in vitro and significant anti-tumor activity in an in vivo mouse model. AMG 119 CAR T cells showed robust cytokine production and proliferation when cultured in the presence of DLL3-positive cells, indicating appropriate T cell signaling as a function of antigen engagement.
      8eea62084ca7e541d918e823422bd82e Conclusion
      The expression pattern of DLL3, with prevalent membranous expression in the majority of SCLC tumors and no detectable cell surface expression in normal cells, makes it an ideal target for BiTE®- and CAR-redirected T cell cytotoxicity. High potency against DLL3-positive tumor cells, coupled with an excellent preclinical safety profile suggest that AMG 119 and AMG 757 may provide a new therapeutic option for SCLC patients with DLL3-positive tumors. AMG 757 (NCT03319940) and AMG 119 (NCT03392064) are currently enrolling in Phase 1 studies for the treatment of relapsed/refractory SCLC. 6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.12-04 - Linc00173 Modulates Chemoresistance of Small Cell Lung Cancer by Binding hnRNPA2B1 and hnRNPI to Regulate CHK2 Level

      12:00 - 13:30  |  Presenting Author(s): Linlang Guo  |  Author(s): Fanrui Zeng, Qiongyao Wang, Shumei Liang

      • Abstract

      Background

      Small-cell lung cancer (SCLC), the most aggressive type of lung cancer, accounts for approximately 15% of all lung cancers. Long non-coding RNAs (lncRNAs) with length over 200 nucleotides, have been identified to play crucial regulatory roles in cell differentiation, proliferation, migration, invasion and apoptosis. Long intergenic non-protein coding RNA 173 (Linc00173) which was first identified in small cell lung cancer, and was found to be involved in chemoresistance in our previous array analysis. In this study, we aimed to explore the biological role of Linc00173 and its possible molecular mechanism in SCLC chemoresistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Linc00173 was examined in 60 SCLC patient samples by quantitative RT-PCR (qRT-PCR). The functional roles of Linc00173 in SCLC were studied by overexpression and RNA interference approaches in vitro and in vivo. The localization of Linc00173 was studied by separating cytoplasmic and nuclear RNA fractions from SCLC cells. RNA pulldown and mass spectrum experiments were performed to find the RNA-binding proteins that interact with Linc00173. RNA sequencing of RNA-binding proteins-immunoprecipitated RNA and coexpression profiles of Linc00173 and mRNAs were used to identify the gene that was regulated by Linc00173 with the RNA-binding proteins.

      4c3880bb027f159e801041b1021e88e8 Result

      Linc00173 expression was significantly associated with chemoresistance and the shorter survival time in SCLC patients. Upregulation of Linc00173 promoted the proliferation and cell-cycle progression and also induced multidrug resistance, whereas downregulation of Linc00173 expression had opposite effects both in vitro and in vivo. Linc00173 increased the expression of hnRNPA2B1 and hnRNPI in the nucleus and formed an RNA-protein complex, which further bound to the target mRNA of CHK2 that is implicated in cell-cycle progression. This interaction made the CHK2 mRNA fragile and decreased its protein level.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Linc00173 was first identified to promote proliferation and chemoresistance in SCLC. It interacts directly with hnRNPA2B1 and hnRNPI to regulate levels of CHK2. Overexpression of Linc00173 represents a biomarker of poor prognosis and chemoresistance in SCLC patients.

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      P3.12-05 - The Pattern of PD-L1 Expression in Thoracic Neuroendocrine Tumors

      12:00 - 13:30  |  Presenting Author(s): Nagla Abdel Karim  |  Author(s): Joshua Pathrose, Ihab El Desouki

      • Abstract

      Background

      Immunotherapy has assumed a pivotal role in the treatment of a number of cancers including lung cancer through up-regulation of tumor-specific cytolytic T cell activity. The level of expression of programmed death-ligand 1 (PD-L1) on tumor cells play an important role in determining the first-line of therapy in non-small cell lung cancer (NSCLC) with immunotherapy.

      Large cell neuroendocrine carcinoma (LCNEC) of the lung has an adverse prognosis, with small numbers of patients suitable for surgical resection at diagnosis. While PD-L1 expression is shown to be an overall negative prognostic factor, it is associated with a positive outcome when PD-1/PD-L1 blocking antibodies are used. In this study, we investigated PD-L1 expression in LCNEC using immunohistochemistry.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Thirty-six patients with LCNEC diagnosed between 2007 and 2013 at the University of Cincinnati Medical Center were included. PD-L1 IHC 22C3 expression was analyzed by immunohistochemistry on formalin fixed, paraffin embedded (FFPE) tissue samples using anti-PD-L1 antibody PD-L1 expression in the tumor and surrounding stromal cells was quantitated based on staining intensity (0 to 3+) and stained surface area (0-100%). A grade cutoff of PD-L1 of ≤5% was used to decide positive or negative.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that 11 of 36 patients showed stromal expression of PD-L1, but only 6 out of 36 patients demonstrated PD-L1 expression on the tumor, and 3 patients were positive for PD-L1 expression in both tumor and surrounding stromal cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, PD-L1 expression on stromal cells appears to be higher in patients with LCNEC compared to the PD-L1 expression on the tumor cells. Prior studies have shown that patients with small cell lung cancer, another aggressive neuroendocrine tumor exhibited greater levels of PD-L1 expression on stromal cells and tumor-associated macrophages suggesting a possible alternative predictive marker.

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      P3.12-06 - SLFN11 Expression and Efficacy of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study

      12:00 - 13:30  |  Presenting Author(s): Taofeek Owonikoko  |  Author(s): Suzanne Dahlberg, Gabriel L Sica, John Poirier, Lauren Byers, Charles M. Rudin, Ignacio I. Wistuba, Suresh S. Ramalingam

      • Abstract

      Background

      Veliparib (V),an oral small molecule inhibitor of poly (ADP) ribose polymerase (PARP) enhanced cytotoxic chemotherapy in preclinical models of small cell lung cancer (SCLC). The combination of V with cisplatin/etoposide (CE) doublet showed efficacy improvement as first-line therapy of extensive stage SCLC (ES-SCLC) with adjusted PFS HR: 0.63 1-sided p=0.01. There was differential treatment effect by strata (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets) highlighting the need to identify patient subset most likely to benefit. SLFN11 expression was previously shown to be associated with benefit of V when combined with temozolomide in relapsed SCLC and also predicted benefit of CE in preclinical models. We assessed the utility of SLFN11 as a predictive biomarker in the context of E2511 frontline clinical trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis looking at SLFN11 expression by immunohistochemistry. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing SLFN11 (+) and (-) patients using a one-sided 0.025 level logrank test.

      4c3880bb027f159e801041b1021e88e8 Result

      There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Clinical outcome differences based on SLFN11 expression is ongoing and will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pending ongoing analysis of correaltion of biomarker with clinical outcomes

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      P3.12-07 - MicroRNA Deregulation in a Typical Carcinoid Tumor: Potential Role of Immune Response and Invasion in Tumorigenesis. 

      12:00 - 13:30  |  Presenting Author(s): Ana Laura Seneda  |  Author(s): Rainer Marco Lopez Lapa, Tainara Francini Felix, Cristiano Claudino Oliveira, Érica Nishida Hasimoto, Daniele Cristina Cataneo, Antonio José Maria Cataneo, Julio De Faveri, Sandra Aparecida Drigo, Patricia Pintor Dos Reis

      • Abstract

      Background

      Lung carcinoid tumors comprise an uncommon type of neuroendocrine cancer, and are classified as typical or atypical according to their histological characteristics. Typical carcinoid tumors are more common and usually not associated with metastasis at diagnosis. To date, genetic and epigenetic changes, as well as regulatory mechanisms mediated by non-coding RNAs and their association with the development and progression of lung carcinoid tumors are not understood. Considering that microRNAs (miRNAs) are potent gene expression regulators associated with several cancer types, our goal was to determine global miRNA expression changes in a rare case of typical lung carcinoid tumor and its corresponding metastasis from the same patient.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RNA was isolated from two fragments of the same tumor and its paired lymph node metastasis, using the RecoverAll Total Nucleic Acid Isolation Kit for FFPE tissues (Ambion/Thermo Fisher). miRNA profiling was performed using the TaqMan Array Human microRNA card A v.3.0 platform (Life Technologies/Thermo Fisher). miRNA expression was analyzed in the Expression Suite software using the global normalization algorithm provided. Furthermore, we applied bioinformatic methods for prediction of miRNA target genes, using microRNA data integration portal, mirDIP, and to determine validated targets in lung tissue as well as molecular pathways, using miRTarBase and ToppGene Suite.

      4c3880bb027f159e801041b1021e88e8 Result

      16 miRNAs were commonly deregulated in the two fragments of tumor and the corresponding lymph node metastasis from the same patient. Of these, 15 miRNAs were significantly down-regulated (FC>=2 and p<0.01). Pathways identified were enriched for miRNA target genes associated with immune response, invasion and metastasis. Notably, many of the identified miRNAs, which were consistently down-regulated, are known to have a suppressor role in tumorigenesis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Down-regulated miRNAs may be associated with metastatic progression of typical carcinoid tumors, since a subset of 15 miRNAs were down-regulated in paired primary tumor and metastasis samples. Our results contribute to improve our understanding of miRNA regulation and disease pathogenesis in lung carcinoid tumors.

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      P3.12-08 - The Role of Contactin 1 on Acquired Resistance to Pegylated Arginase in Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Sheng Yan  |  Author(s): Shi Xu, Sze Kwan Lam, Paul Ning-Man Cheng, James Chung-man Ho

      • Abstract

      Background

      Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer cases. SCLC is characterized by easy to relapse, and current treatment lacks tumor specificity. Arginine is an important amino acid in human, but some tumors lose the ability to synthesize it. So arginine deprivation has become a targeted therapy in certain tumors. BCT-100 is a pegylated arginase with anticancer activity in arginine auxotrophic tumors, such as human melanoma, hepatocellular carcinoma and acute myeloid leukemia. Contactin 1 (CNTN1) is a cell adhesion molecule which plays an important role in drug resistance. The aim of this study is to determine the effects of CNTN1 on BCT-100 acquired resistance in SCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      BCT-100 resistant (BR) cells, H446-BR and H526-BR cells, were developed by incubating with serially increasing concentration of BCT-100 with parental H446 (adherent cell line) and H526 (suspension cell line) cells respectively. Gene chip assay was employed to fish out the potential targeted biomarkers in BR cell lines. MTT assay was used to detect cell viability on BR cell lines. Western blotting was employed to evaluate the protein expression. Knockdown of CNTN1 was performed using specific shRNA. Wound healing assay was used to evaluate the cell migration ability in H446 and H446-BR adherent cell lines. Flow cytometry was applied to detect the related biomarkers in BR cells.

      4c3880bb027f159e801041b1021e88e8 Result

      The protein expression of CNTN1 in H446-BR and H526-BR cells was 2.7 folds and 5.3 folds higher than that in parental cells respectively. Cell migration ability in BR cells was stronger than parental cells: wound healing rate was greatly increased from 48.5% to 69.9% in H446-BR cells. Epithelial-mesenchymal transition (EMT) progression and AKT activation were observed in both BR cell lines. Knockdown of CNTN1 re-sensitized BR cells to BCT-100 treatment and reversed the EMT progression via inhibiting AKT pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Contactin 1 modulates BCT-100 resistance through induction of EMT by activating AKT pathway in SCLC.

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      P3.12-09 - Smad4 Mutation Confers Acquired Neuroendocrine Phenotype in Transformation of Lung Adenocarcinoma to Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Jie Zhang  |  Author(s): Xi Ding, Liping Zhang, Bo Su

      • Abstract

      Background

      Along with the widely use of EGFR-TKI therapy, transformation from lung adenocarcinoma (LAC) to small cell lung cancer (SCLC) has been recognized and accepted as a reason of drug resistance , but the mechanism remains unclear .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      At first, we detected mutated genes in LAC and SCLC component from 9 combined SCLC cases independently by NGS, and analyzed the gene expression in pairs to find the targeted genes. And then, we knocked out the putative gene in HCC827 cell line by CRISPR/Cas9 to detect the changes of classic neuroendocrine markers (CgA, Syn, CD56).

      4c3880bb027f159e801041b1021e88e8 Result

      A high mutation rate of Smad4 gene is observed in SCLC component from 9 combined SCLC cases (66.7%, 6/9, Figure 1A), which is much higher than that in pure SCLC (1.8%, available on http://www.cbioportal.org) samples. HCC827-Smad4-/- cell line is successfully established (Figure 1B), and by IHC assay, the expression of Syn is obviously enhanced in HCC827-Smad4-/- cells when compared with HCC827-GFP cells (Figure 1C).
      13104.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The dysfunction of Smad4 protein confers the neuroendocrine phenotype of LAC, which plays a potential role in transformation to SCLC.

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      P3.12-10 - Immunogenomic Characteristics of SCLC and LCNEC Redefined Molecular Subgroups

      12:00 - 13:30  |  Presenting Author(s): Xue-Tao Li  |  Author(s): Jian Su, Dan-Xia Lu, Jin -Ji Yang, Wen-Zhao Zhong, Yi-Long Wu, Xu-Chao Zhang, Jun Hou

      • Abstract

      Background

      While small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are distinct classes of high-grade neuroendocrine carcinomas, the differential diagnosis between SCLC and LCNEC remains challenging. In fact SCLC and LCNEC overlap in clinical, histopathologic, cytologic, morphologic and genetic characteristics. Molecular profiling with microarray or next-generation sequencing has provided growing evidence suggesting that both SCLC and LCNEC are biologically heterogeneous and a great part of them are borderline neuroendocrine carcinomas falling between typical SCLC and LCNEC. On account of accumulated knowledge, we speculated that immunogenomically characterizing SCLC and LCNEC collectively as one group, or rather morphologically or cytologically separating SCLC from LCNEC has superior clinical value.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed gene expression profiles of 44 SCLCs, 56 LCNECs and 25 normal lung samples obtained from Gene Expression Omnibus. Unsupervised and supervised analyses were performed to understand molecular characteristics of samples. Pathway and CIBERSORT analyses were employed to obtain immune landscape of SCLC and LCNEC.

      4c3880bb027f159e801041b1021e88e8 Result

      Unsupervised clustering with 1189 differentially expressed genes revealed 2 distinct molecular subgroups (G1 and G2) of SCLC and LCNEC, which is not associated with histopathology. Targeted pathway analysis found that G1 was marked by activated IL-17, MAPK and Hippo signaling pathways. In contrast, transcriptional factors, such as ASCL1, INSM1, SOX2, and NKX2-1 were significantly up-regulated in G2, but not in G1. Moreover, in silico analysis of cellular composition and expression of immune genes disclosed unique immunoprofiles for G1 and G2. G1 was characterized by enriched CD4 memory cells, M1 macrophages and activated dendritic cells. While G2 was composed of high fractions of memory B cells and naïve CD4 cells. Strikingly, expression of both immunoinhibitors (IL10, PDL1, IDO1) and immunomodulators (OX40L, BAFF, GITR, IL6), as well as MHC class I and II molecules was higher in G1 compared to that in G2.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified the common intrinsic features and molecular subgroups of SCLC and LCNEC, which are beyond conventional histopathology and better associated with immunogenomics of tumors. Further research is warranted to identify potential clinical implication of SCLC and LCNEC molecular subgroups.

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      P3.12-11 - Association of the Lung Immune Prognostic Index (LIPI) with Outcomes for Immune Checkpoint Inhibitors in Diffuse SCLC Patients

      12:00 - 13:30  |  Presenting Author(s): Laura Mezquita  |  Author(s): Santiago Ponce Aix, Edouard Auclin, Alejandro Navarro, David Planchard, Ivana Sullivan, Gerard Zalcman, Julien Mazieres, Lizza Hendriks, Caroline Caramella, Margarita Majem, Pernelle Lavaud, Frank Aboubakar Nana, Enriqueta Felip, Luis Paz-Ares, Benjamin Besse

      • Abstract

      Background

      Pretreatment LIPI (Lung Immune Prognostic Index), based on derived NLR (neutrophils/[leucocytes-neutrophils] ratio) and lactate dehydrogenase (LDH) has been associated with outcomes for immune checkpoint inhibitors (ICI) in advanced NSCLC patients. We tested whether LIPI has the same role in diffuse small cell lung cancer (SCLC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Baseline dNLR and LDH and clinical data were retrospectively collected in SCLC patients, treated with ICI (PD1 inhibitor, PDL1 inhibitors +/- CTLA4 inhibitor) from April 2014 to Jan. 2018 (N=66) from 6 European centers. LIPI was calculated combining dNLR and LDH, stratifying 3 risk groups: good (dNLR<3+LDH<upper limit of normal (ULN), intermediate (dNLR>3 or LDH>ULN), poor (dNLR>3+LDH>ULN). The primary endpoint was overall survival (OS), and secondary endpoint was progression-free survival (PFS).

      4c3880bb027f159e801041b1021e88e8 Result

      Fifty-three patients (80%) were males, 58 (88%) smokers and all patients had PS ≤1, with median age 63 years (41-82). PDL1 was ≥ 1% by immunohistochemistry in 6 patients, and unknown in 60 patients. The median of prior lines was 1 (0-6). Platinum-based therapy was the prior line in 63 (95%) patients, with ORR of 88%. The median PFS and OS with ICI were 2.7 months (m) [95% CI 1.87-4.43] and 10.3 m [95% CI 5.8-12.6]. dNLR was greater than 3 in 16 (25%) and LDH> Upper Limit of Normal (ULN) in 33 (50%) patients. Based on both, LIPI stratified the population in 3 groups: 26 patients as good (40%), 29 (45%) as intermediate and 10 (15%) as poor LIPI risk groups. LIPI was an independent factor for OS (HR 2.77, 95% CI 1.07-7.14, P=0.03) and PFS (HR 3.13, 1.37-7.16, P=0.01). Median OS for good, intermediate, and poor risk groups were 11.4 m [95% CI 5.5-27.3], 11 m [95% CI 6.8-not-reached (NR)] and 2.3 m [95% CI 0.7-NR], respectively (P=0.004). Median PFS for good, intermediate, and poor risk groups were 3 m [95% CI 1.9-12.6], 2.8 m [95% CI 1.6-6.0 and 1.2 m [95% CI 0.47-NR], respectively (P=0.004).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Baseline LIPI poor risk group is associated with poor outcomes for ICI in diffuse SCLC patients. LIPI effect in a validation cohort is currently evaluated.

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      P3.12-12 - Genomic Profiling of Pulmonary Large-Cell Neuroendocrine Carcinoma (LCNEC) Reveals Distinct Mutational Landscape

      12:00 - 13:30  |  Presenting Author(s): Lin Wu  |  Author(s): Gen Lin, Xiaohua Hu, Likun Chen, Yingcheng Lin, Sheng Zhang, Zhang-Han Han, Jun-Yi Ye, Xinru Mao, Wenying Peng, Meilin Jiang

      • Abstract

      Background

      The controversial classification of lung neuroendocrine tumor has been amended a few times since recognised as a separate entity. LCNEC shares clinical features with small cell lung carcinoma (SCLC) and they were both classified as lung neuroendocrine carcinoma according to the 2015 WHO lung primary pathology classification, numerous studies have revealed barely satisfactory outcomes when it was treated as SCLC. However the underlying molecular basis for such commonalities and discrepancies are poorly understood. In this study, we interrogated the genomic landscape of LCNEC and SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids to define the molecular pattern of LCNEC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed targeted sequencing in 35 tissue samples using a panel covering 520 cancer related genes, spanning 1.6MB of human genome, with an average sequencing depth of 1,418x. Among them, 15 were diagnosed with SCLC, 9 with LCNEC, 6 with carcinoid and 5 with atypical carcinoid.

      4c3880bb027f159e801041b1021e88e8 Result

      On average, LCNEC exhibited 13.5 mutations per million base pairs (Mb) and a C:G>A:T transversion rate of 34%, which is indicative of tobacco exposure. LCNEC had SCLC (16.7 Mb) had comparable TMB (p=0.18), which is significantly higher than carcinoids (1.2/Mb, p<0.001) and atypical carcinoids (2.4/Mb, p<0.001). The most frequently mutated gene in LCNEC is TP53 (89%, 8/9), followed by NOTCH1 (33%), KEAP1 (22%), RB1 (22%) and a few chromatin modifiers, including KMT2D (33%), KMT2C (33%). Co-mutation in TP53 and RB1, a hallmark of SCLC, was found in 22% (2/9) of LCNEC patients; in contrast, 80% of SCLC patients harbored concurrent mutation. 67% carcinoid (4/6) and 20% (1/5) atypical carcinoid patients had no mutation identified from this panel. No classic lung adenocarcinoma driver mutations were found in any subtype. Copy number analyses revealed significantly higher copy number variation (CNV) in SCLC and LCNEC comparing with carcinoids and atypical carcinoids, which yield virtually no CNV. Our analysis revealed a comparable CNV status of SCLC and LCNEC (p=0.158), with an enrichment in amplification of chromatin modifiers.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study, comprehensively characterized 4 subtypes of neuroendocrine tumors, revealed a high TMB and CG:AT transversion rate in LCNEC patients as well as a distinctive mutation landscape, with an enrichment of mutations occurring at chromatin remodelers. Furthermore, LCNEC has comparable TMB and CNV status as SCLC, which are significantly higher than carcinoid and atypical carcinoids.

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      P3.12-13 - Expression of the Immune Checkpoint Axis-PVR/TIGIT in Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Hui Yu  |  Author(s): Camilla Emma-Marie Koczara, Zoltan Lohinai, Andrzej Badzio, Piotr Czapiewski, Balázs Döme, Judit Moldvay, János Fillinger, Dexiang Gao, Kim Ellison, Shengxiang Ren, Charles Caldwell Jr, Christopher J. Rivard, Fred R. Hirsch

      • Abstract

      Background

      The poliovirus receptor (PVR) is an immune checkpoint protein expressed on tumor cells. It has been reported to mediate activation of T cells via CD226 or inhibition through binding to T-cell Ig and ITIM domain (TIGIT). TIGIT competes with CD226 for binding to PVR, and exhibits stronger affinity for PVR. Recently we have found that PVR is highly expressed in SCLC cell lines. Characterizing the expression and significance of the PVR-TIGIT axis in SCLC will help us to better understand the immunology of SCLC and may lead to novel therapeutic strategies to combine checkpoint blocking agents for improved SCLC immunotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Immunohistochemistry (IHC) was performed to evaluate PVR protein expression in a TMA of 39 SCLC cell lines and a cohort TMA of 77 limited stage SCLC patients with clinical data. We analyzed both PVR and TIGIT in an independent cohort of 27 resected, limited-stage SCLC tumors.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-seven cell lines (95%, 37/39) demonstrated staining for PVR and of those, 4 cell lines (10.3%, 4/39) showed strong staining (H-score ≥ 270). In the 77 SCLC patients cohort, PVR expressed predominantly in the membrane of tumor cells, with minimal expression observed on immune cells. PVR expression in the SCLC patient cohort was 82% with an arbitrary H-score cut-off of ≥ 50. Higher PVR expression was found for male patients (P=0.040). The expression of PVR increased with the tumor progressing from stage I to stage III (p =0.007). SCLC patients who had higher PVR expression demonstrated poorer prognosis and the difference was near statistically significant (p=0.050). Using the same cut-off (H-score ≥ 50) in the independent SCLC cohort, the prevalence of high PVR expression was 89% (24/27).

      In the independent SCLC cohort, TIGIT was found to be expressed membranous or cytoplasm on the immune cells with weak to moderate staining. Immune cells with TIGIT staining were typically seen as variable size and aggregated toward the periphery of the tumor nest. TIGIT protein staining was demonstrated in 20 cases (74%). No association was found between PVR H-score and TIGIT expression by Fisher’s test (p=0.093).

      8eea62084ca7e541d918e823422bd82e Conclusion

      PVR is broadly expressed in SCLC cell lines and tumor tissues. The expression of TIGIT protein was also found in SCLC patients with weak to moderate staining. Blockade of the PVR-TIGIT pathway may represent a possible future target to immunotherapy in SCLC patients.

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      P3.12-14 - Genomic Profiling of Chinese Small Cell Lung Cancer and the Implications for Therapy

      12:00 - 13:30  |  Presenting Author(s): Hong Zhong  |  Author(s): Yu Wang, Jing Hu, Jian Guo, Yanhong Shang, Min Zheng, Jin Zhao, Yong Li, Jianjiang Xie, Honglin Guo, Jinwei Hu, Aodi Wang, Weifeng Wang, Weiwei Shi, Kai Wang, Ming Yao

      • Abstract

      Background

      Small cell lung cancer (SCLC) is one of the deadliest malignancies and accounts for nearly 15% of lung cancers. The 5-year survival rate for SCLC is very low. Previous study had revealed the genomic characterization of SCLC in Western patients. However, little is known about that in Chinese SCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      FFPE tumor and matched blood samples of 79 Chinese SCLC patients, including 60 males (median age of 60 years old) and 19 females (median age of 59 years old), were collected for next generation sequencing to detect 450 cancer related genes. All histological diagnoses were confirmed by independent pathologists. Genomic alterations including single nucleotide substitutions (SNV), short and long insertions/deletions (Indel), copy number variations (CNV), and gene rearrangement in selected genes were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      The most frequently altered genes in 79 Chinese SCLC patients were TP53 (94.9%), RB1 (83.5%), LRP1B (22.8%), KMT2D (13.9%), NOTCH1 (12.7%), FAM135B (11.4%), FAT1 (11.4%), KDR (11.4%), SPTA1 (10.1%) and STK24 (10.1%). Four of the patients harbored EGFR alterations including one EGFR fusion. Copy number variation analysis revealed that the most frequent variations occurred in the long arm of chromosome 13, including amplifications of STK24, FGF14, IRS2 and TNFSF13B (10.1%, 8/79, located at 13q32~13q34) and deletion of RB1 and BRCA2 (59.5%, 47/79, located at 13q13~13q14). Compared to the previously reported 25% mutational frequency in Western cohort reported previously, 31.6% (25/79) of our patients exhibited alterations in NOTCH signaling pathway related genes (NOTCH1, NOTCH2, NOTCH3, NOTCH4, EP300 and CREBBP). Around 15.2% (12/79) patients had PI3K/AKT/mTOR signaling pathway alterations (PIK3CA, MTOR, PTEN, and TSC2). Homologous Recombination Deficiency (HRD) related genes altered in 17.7% (14/79) patients, suggesting the potential clinical benefits from PARP inhibitors. The genomic alterations of FGF family members occurred in 25.3% (20/79) of patients. Other targetable genes included KIT (7.6%, n = 6), PDGFRA (5.1%, n = 4) and DDR2 (2.5%, n = 2).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, we characterized the genomic alteration profile of Chinese SCLC patients. Our discovery of CNV in the long arm of chromosome 13 might be helpful in understanding the pathogenesis of SCLC. Consistent with previous report, high mutation rates of TP53 and RB1 are the most important genomic features of SCLC [PMID: 26168399]. In addition, we also found several targetable gene variations including HRD, FGF family, KIT, PDGFRA and DDR2, which might provide potential targeted therapy options for SCLC patients. Further association analyses of these genomic alterations with clinical features in SCLC are still needed.

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      P3.12-15 - 68 Ga DOTA PET/CT in Staging of Broncho-Pulmonary<br /> Carcinoid Tumors. Is there a Real Benefit?

      12:00 - 13:30  |  Presenting Author(s): George Karimundackal  |  Author(s): Vijayraj S Patil

      • Abstract

      Background

      The staging of well differentiated bronchopulmonary neuroendocrine tumours (carcinoids) is complicated by the unpredictable incidence of nodal and distal metastases. PET CECT, which has become the standard for staging of lung cancers has proven ineffective in the staging of carcinoid tumours. 68 Ga DOTA NOC PET/CT which depends on radio-tracer uptake in somatostatin receptors appears to be an attractive modality for the staging of these neuroendocrine tumours

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective analysis of patients who underwent 68 Ga DOTA NOC PET/CT followed by surgical resection from October 2014 to March 2018. Data was retrieved regarding demographics, standardized uptake value (SUV), surgery performed and final histopathology report including degree of differentiation, nodal positivity and Mib index. The study included only patients who underwent resection since the focus of the study is on correlation with histopathological features. An attempt was made to correlate the SUV with diagnosis of typical vs atypical carcinoid, nodal metastases and Mib index

      4c3880bb027f159e801041b1021e88e8 Result

      During the study period 42 patients underwent surgical resection following DOTA PET. All details of imaging including SUV were available for 38 patients, while complete histopathological details was available for 42 patients. DOTA PET was not able to differentiate between typical and atypical carcinoids (35 vs 3) based on SUV. The mean SUV of typical carcinoids was 45.2( SD-42.77) whereas that of atypical carcinoids was 34.3(SD-39.7) and the difference was not statistically significant (p=0.6). 6/42 cases had nodal metastases of which DOTA PET could corrrectly identify only 1. There were 2 false positive reports and 5 false negative reports, (sensitivity 16.6% and specificity 94.1%). The mean SUV of the false positive nodes(n= 2 cases) was 7 which calls into question the specificity of the tracer. No corelation between SUV and Mib index could be demonstrated, p=0.8

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study 68 Ga DOTA NOC PET CECT could not help in predicting the histopathological nature of carcinoid tumours, atypical vs typical, presence of nodal metastases or Mib index. This study is limited by the small numbers enrolled, a larger series may help us in coming to a more definitive conclusion

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      P3.12-16 - Prognostic Impact of M Descriptors of the 8<sup>th</sup> Edition of TNM Classification for Extensive Disease-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Masayuki Shirasawa  |  Author(s): Tomoya Fukui, Seiichiro Kusuhara, Yasuhiro Hiyoshi, Mikiko Ishihara, Masashi Kasajima, Noriko Nishinarita, Shinya Harada, Satoshi Igawa, Masanori Yokoba, Hisashi Mitufuji, Masaru Kubota, Masato Katagiri, Jiichiro Sasaki, Katsuhiko Naoki

      • Abstract

      Background

      The International Association for the Study of Lung Cancer proposed the eighth edition of TNM classification of lung cancer on the basis of a new database in 2015. One of the most significant change in new criteria was that M descriptors has changed from three (M0, M1a and M1b) to four (M0, M1a, M1b and M1c). Although the 8th TNM classification is strong in the related with non-small cell lung cancer (non-SCLC) management, association between the 8th TNM classification and prognosis of SCLC patients remains unclear. In this study, we evaluated the applicability of the 8th TNM staging system to SCLC patients, especially whether prognosis of extensive disease (ED)-SCLC was related to the M descriptors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective study of consecutive 277 SCLC patients who had treated at our hospital between January 2008 and December 2016. The SCLC patients classified based on the 8th TNM classification and evaluated clinical factors and survival.

      4c3880bb027f159e801041b1021e88e8 Result

      186 (65.7%) of 277 SCLC patients were classified ED-SCLC based on the two-stage system, classically. Among the ED-SCLC patients, 10 (5.3%), 38 (20.4%), 32 (17.2%) and 106 (57.0%) were categorized into stage M0, M1a, M1b and M1c based on the 8th TNM classification, respectively. All ED-SCLC patients received systemic chemotherapy and median overall survival (OS) was 13.7 months. There were significant differences in OS [7.3 months; 95% confidence interval (CI), 5.7–8.9 months vs. 16.0 months; 95% CI, 13.2–18.8 months; p<0.001] according to the M descriptors (M0, M1a, M1b vs. M1c) and the TNM stage groups (III and IVa vs. IVb). Multivariate survival analyses showed that the M descriptor was one of prognostic factors (hazard ratio 1.50; 95% CI, 1.26–1.78 months; p<0.001) in addition to known prognostic factors such as ECOG performance status and pretreatment serum level of LDH.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, the 8th TNM classification had prognostic value in the SCLC patients treated with systemic chemotherapy. We suggested that ED-SCLC patients was divided into two subgroups based on the TNM classification. In ED-SCLC as well as non-SCLC, treatment development should be considered based on the TNM classification.

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      P3.12-17 - A Retrospective Study Examining the Role of PET-CT in the 8<sup>th</sup> TNM Staging System of SCLC

      12:00 - 13:30  |  Presenting Author(s): Salomon Tendler  |  Author(s): Vitali Grozman, Rolf Lewensohn, Georgios Tsakonas, Kristina Viktorsson, Luigi De Petris

      • Abstract

      Background

      We have recently performed a validation of the 8th TNM system in SCLC. The aim of the present study is to perform a subgroup analysis on patients (pts) who underwent a PET/CT scan, to furhter assess potential utility of this method in SCLC pts, since PET/CT is usually performed primarily to identify potentially curable cases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between January 2008 and February 2016, a total of 706 pts with SCLC were diagnosed in the Stockholm and Gotland region. A multivariate model adjusted for basic patient characteristics and PET-CT was performed.

      4c3880bb027f159e801041b1021e88e8 Result

      One third of the patients had performed a PET/CT scan (n=204). Pts were classified according to the 8th TNM. The table shows patient distrubution according to clinical variables and stage (8th TNM), as well as HR for multivariate survival analysis. Many pts (48%) were classified to stage I-III disease, while the rest had stage IV. Pts with stage I-III were treated with Surgery (n=13), Radiotherapy+ Chemotherapy (CT) (n=80) or Stereotactic body radiation (n=7). The patients who were diagnosed with stage IV disease were treated with palliative CT or did not receive any oncological therapy. In pts that did not perform PET/CT, the majority (87%) were treated with CT or did not receive treatment. The percentage of pts diagnosed with M1b-disease was slighlty higher in those who performed a PET/CT vs those who did not (7% vs 3%, respectivley).

      slide1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The 8th TNM edition has a strong prognostic impact in SCLC. Incorporating a PET/CT scan in the diagnostic workup of SCLC is relevant to distinguish potentially curable pts (stages I-III) from pts with stage IV disease, and may be of value to indentify single extra-thoracic metastases (M1b cases).

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    P3.13 - Targeted Therapy (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
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      P3.13-01 - Detecting ALK Rearrangements in NSCLC Patients: IHC, FISH or NGS Fusion?

      12:00 - 13:30  |  Presenting Author(s): Alfredo Addeo  |  Author(s): Alex Friedlander, Celine Py, Pierre-Yves Dietrich

      • Abstract

      Background

      Rearrangements of the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) represent a novel molecular target in a small subset of patients. Although ALK rearrangements are usually assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), molecular approaches have recently emerged as relevant alternatives in routine laboratories. Previous studies that compared FISH and IHC considered FISH the gold standard, although there are emerging data on ALK fusion variants that question the role of FISH.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Here, we report our personal experience with the use of the IHC, FISH and next-generation sequencing (NGS) analyses in a group of ALK rearranged NSCLC patients treated within our institution

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 13 patients with NSCLC was positive for ALK rearrangements on IHC and was subsequently tested with FISH. Interestingly 5 out of 13 patients were negative on FISH but all the patients received first line ALK inhibitors. The response rate (RR) was 79% (10/13), the progression free survival (PFS) was 19 months for the total population. Among the non-responders 2/13 were FISH negative but 1/13 was IHC and FISH positive. We are going to retrospectively perform NGS analyses to further assess the role of NGS fusion in the context of ALK patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study suggests that IHC is a valid, quick and reliable assay for the detection of ALK gene rearrangements. It also shows that FISH should not be considered the gold standard on its own for the detection of ALK gene rearrangements. We are going to present the data on NGS fusion in this group of patients at the next conference (WLLC November 2018) with the view of seeing if NGS fusion could and should be a valid alternative and replace FISH as the gold standard.

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      P3.13-02 - Lymphocytic Plevral Effusion Due to Crizotinib Usage: First Case in Literature

      12:00 - 13:30  |  Presenting Author(s): Pınar Akın Kabalak  |  Author(s): Ülkü Yılmaz, Suna Kavurgacı, Derya Kızılgöz, Tuba İnal Cengiz, Şebnem Yaman

      • Abstract

      Background

      Crizotinib is an ALK inhibitor and used for treatment in advanced stages lung adenocarcinoma patients with ALK (+). Most common side effects are; gastrointestinal disorder and visual side effects. Drugs are one of the reasons of effusion. For accurate diagnosis patients’ drug history should be questioned in details. To the best of our knowledge pleural effusion due to crisotinib treatment does not exist in current literature.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      41 years old female patient’s admitted to outpatient clinic with chest pain. There was a right hilar lesion and pleural effusion on right hemithorax (Figure 1A). Thorax tomography revealed 5 cm mass lesion in right middle lobe. Transthoracic needle aspiration biopsy reported as adenocarcinoma. Tissue was positive for ALK-rearrangement and first line crizotinib initiated. In the third month of treatment bilateral pleural effusion more in the right was occurred (Figure 1B and 1C). Primary lesion was regressed (Figure 1D). Efusion on left hemithorax was serous and exudate. Any malignant cells were observed. It was drained with pleural catheter and performed talk pleuredesis. There were lymphocytic cell predominance. Others reasons were excluded. Crizotinib treatment was interrupted, in 15th day of crizotinib free observation fluid’s amount decreased. To increase the rate of recovery methylprednisolone 40 mg/day is added.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1.pngCrizotinib started again with frequent clinical, radiological follow-up. Fluid’s amount did not increase when steroid dose was tapered. While patient take 16 mg/day crizotinib, it has been seen that left pleural fluid disappeared and right pleural thickening appeared due to talc pleuredesis (Figure 1E and 1F).

      8eea62084ca7e541d918e823422bd82e Conclusion

      To the best our knowledge there is not case report with pleural effusion related to ALK TKI treatment. Our case is the first to demonstrate the relationship between ALK TKI treatment and pleural effusion. The case which response to the treatment newly formed pleural effusion’s source may have thought as medication.

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      P3.13-03 - Real-World Anaplastic Lymphoma Kinase Testing Practices: Results from a Survey in the United States

      12:00 - 13:30  |  Presenting Author(s): A. John Iafrate  |  Author(s): Ken Bloom, Sucha Sudarsanam, Harry Hwang, Frederick Racke, Stephanie H. Astrow, Miriana Moran, Marc D. Chioda, Jenny Sheng, Julie Ramage, Jack Mardekian

      • Abstract

      Background

      Anaplastic lymphoma kinase (ALK) translocation is a clinically validated predictive biomarker in multiple cancer types including non-small cell lung cancer, and widespread adoption of diagnostic assays permits a review of test performance. This analysis presents ALK and epidermal growth factor receptor (EGFR) testing rates, expediency, and results from 4 large national laboratories.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Deidentified data from January 2013 to December 2015 were compiled from 40 states and Washington DC and included in the final analysis. ALK status was evaluated with the Vysis ALK Break Apart FISH Probe Kit; EGFR status was evaluated by therascreen EGFR RGQ PCR Kit, cobas EGFR Mutation Test, or Sanger sequencing. Results from the most recent conclusive test were used. Collection to order (time from date of biopsy to date of biomarker test order), order to results (time from date of biomarker test order to date of available results), and overall turnaround times (collection to order + order to results) were evaluated. Results were analyzed by laboratories and US regions (Northeast, Midwest, South, and West). Data were summarized with descriptive statistics.

      4c3880bb027f159e801041b1021e88e8 Result

      Results of 59,058 ALK and 50,992 EGFR tests were collected; 50,023 patients were tested for both ALK and EGFR, 9035 had results for ALK only, and 969 for EGFR only. Mean patient ages at ALK-positive (ALK+) and EGFR-positive (EGFR+) diagnoses were 62.5 and 69.0 years, respectively. Overall ALK+ and inconclusive rates were 2.8% and 6.5%, respectively, vs 10.4% and 6.2% for EGFR testing. ALK+ (2.3–5.1%) and inconclusive (1.1–17.4%) rates varied between test centers. In the western US, the ALK+ rate (3.3%) was comparably greater than in other regions (2.4–2.7%). The median turnaround time was 15 days, with a median of 10 days for collection to order and 4 days for order to results; some regional variation was seen in turnaround time (14–18 days). No correlation was seen between age and turnaround time.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EGFR+ and ALK+ rates and age distributions were consistent with prior reports. An interesting geographic difference in ALK rates was seen that warrants further investigation. The average turnaround time was longer than current guidelines recommend, suggesting an opportunity to improve current testing practices.

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      P3.13-04 - Lorlatinib in Anaplastic Lymphoma Kinase and Proto-Oncogene Tyrosine-Protein Kinase ROS-Positive Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Marthe Sentijna Paats  |  Author(s): Jorien Minnema-Luiting, Robin Cornelissen, Joachim G.J.V. Aerts

      • Abstract

      Background

      In this case series we present ten patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) treated with lorlatinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lorlatinib is highly potent and selective third generation ALK and ROS1 tyrosine kinase inhibitor (TKI) with known activity against most resistance mutations. In a phase 1 study, lorlatinib showed intracranial and systemic activity in ROS1-positive and ALK-positive patients with advanced NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      Thus far, we treated 6 ALK- and 4 ROS1-positive stage IV NSCLC patients with lorlatinib in a compassionate use program. Best response was complete remission in two of our patients. One ROS1-positive patient with CNS metastases has now ongoing complete response for 27 months; the other patient with a ALK-positive NSCLC with CNS metastasis has now been treated with lorlatinib for 16 months. Three patients showed a partial response with an ongoing progression free survival of respectively 3, 5 and 8 months. Two of our patients (one ALK-positive and one ROS1-positive NSCLC) showed progressive disease as best response. In three patients response data is not (yet) available. There were no significant side effect apart from hypercholesterolemia, which occurred in four of our patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib shows promise in the treatment of ROS1-positive and ALK-positive patients with advanced NSCLC.

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      P3.13-05 - Use of Crizotinib in a Patient with a Ros Mutation Causing Elevated CPK and Resulting in Dose Limiting: Case Report

      12:00 - 13:30  |  Presenting Author(s): Ana Cecilia Barbalho De Vasconcelos  |  Author(s): Bárbara Maria Lafayette Viana da Luz, Candice Amorim De Araujo Lima Santos, Renata Silva AragÃo

      • Abstract

      Background

      The use of target therapy in lung cancer has changing the story of this disease. However, the toxicity sometimes can be a challenge.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We report a clinical case in a patient with advanced lung cancer with mutation in ROS 1 that had an excelent response with Crizotinib, but developed high levels of CPK.

      4c3880bb027f159e801041b1021e88e8 Result

      Man, 75y, with an adenocarcinoma of the right lung with lesions in pleura. Tumor was assessed for EGFR mutation and ALK translocation, but were not found. We started chemotherapy with Carboplatin and Pemetrexed with partial response and, after four cycles, we continued treatment with Pemetrexed isolated. After thirteen cycles, he had bone progression and the chemotherapy was changed to Docetaxel. After that, he was submitted to three more lines of chemotherapy and immunotherapy with Nivolumabe. After four years of metastatic disease, a new bone progression with a sternal mass. new biopsy was made and found a mutation in the ROS 1 gene. He was very symptomatic, limitted performance status (ecog 4) and was admmited in the hospital. We started treatment with Crizotinib 250 mg twice daily and he had a dramatic response. After two months, ECOG was one and a PET-CT showed almost a complete response. However, the patient started cramps in the abdomem and laboratory showed a CPK of 4500 u/l. the dose of the Crizotinib was adjusted to 250mg/day and the levels of cpk started to fall. We tried to reintroduce the full dose, but the levels of CPK increases to 4800 u/l again. So, we reduced the dose with maintenance of response and better tolerability.

      image.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      The increased levels of CPK with inibithors of alk is described with Alectinib. This relation with Crizotinib is not well estabilished. In this case, there was an excellent response, but the dose was limited by the increase of CPK.

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      P3.13-06 - Analysis of ALK Rearrangement Non-Small Cell Lung Cancer Cell Blocks from Pleural Effusion

      12:00 - 13:30  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Wu Zhuang, Gang Chen, Yuwang Tian, Jianping Xu, Meiyu Fang, Tang Feng Lv, Yong Song

      • Abstract

      Background

      Anaplastic lymphoma kinase (ALK) rearrangements occur in 1% to 7% of non-small-cell lung cancers (NSCLCs). Crizotinib, an ALK inhibitor, has been demonstrated to provide dramatic clinical benefits in ALK rearrangement advanced NSCLC. The aim of this study is to investigate the clinical value of ALK rearrangement NSCLC blocks cell from pleural effusion.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two hundred and fifteen cases of ALK rearrangement non-small cell lung cancer (NSCLC) blocks cell from pleural effusion, Four hundred and four cases of tissues were detected by reverse transcription polymerase chain reaction (RT-PCR) method. The consistency of ALK rearrangement was examined in 74 cases of patients with tissues and cell blocks.

      4c3880bb027f159e801041b1021e88e8 Result

      ALK rearrangement was found in 26 of 215 cell blocks (positive detection rate of 12.09 %). ALK rearrangement was detected in 25 of 404 tissue blocks (positive detection rate of 6.19%). There were 67 cases in the 74 (90.54%) cases had the same consistency as tissue block. ALK rearrangement was detected in 11 of 74 (14.86%) cell blocks, and 14 of 74 (18.92%) tissue blocks.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The rate of ALK rearrangement in cell blocks of NSCLC is higher than in matched tissue blocks. The patients with malignant pleural effusion are likely to tend ALK rearrangement.

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      P3.13-07 - The Effect of Crizotinib in Patients of Non Small Cell Lung Cancer with Brain Metastases: A Retrospective Analysis

      12:00 - 13:30  |  Presenting Author(s): Jiexia Zhang

      • Abstract

      Background

      Crizotinib is a tyrosine kinase inhibitor targeting the anaplastic lymphoma kinase gene (ALK) and exhibited a prominent effect in treating ALK-positive non-small cell lung cancer (NSCLC). This retrospective study aimed to evaluate therapeutic effects of crizotinib in patients with brain metastasis (BM) from ALK-positive NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients diagnosed with BM caused by ALK-positive NSCLC from November 2010 to October 2015 and treated initially by crizotinib were enrolled and reviewed. The median and 95% confidence interval (CI) of the intracranial and whole-body progression-free survival (PFS) and the overall survival (OS) were calculated by Kaplan-Meier approach. And the candidate prognosticator of the survivals was checked by a log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally 41 patients were eligible for analysis. The median whole-body PFS, intracranial PFS and OS were 8.00 (95% CI, 6.96-9.04), 8.00 (95%, CI 6.99-9.01) and 23.0 (95% CI, 15.8-30.2) months, respectively. Compared with multiple BM, single BM seemed to lead to a better OS when crizotinib was administered (P = 0.029). Totally 5 patients (12.2%) developed crizotinib-related adverse events. Except 1 patient terminated crizotinib treatment because of interstitial pneumonia, the other 4 cases exhibited only adverse events of grade 1.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Crizotinib could bring an ideal control on BM from ALK-positive NSCLC and were well tolerated. It might be a feasible treatment for patients with this kind of disease.

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      P3.13-08 - Assessment of EGFR Gene Mutations In cf-DNA in Monitoring of Response to EGFR TKIs in Patients with Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Kamila Wojas-Krawczyk  |  Author(s): Marcin Nicoś, Pawel Krawczyk, Izabela Chmielewska, Magdalena Wojcik-Superczynska, Katarzyna Reszka, Robert Kieszko, Anna Gora-Florek, Malgorzata Dudek, Daria Swiniuch, Wojciech Papiewski, Paulina Calka, Marzanna Ciesielka, Rodryg Ramlau, Janusz Milanowski

      • Abstract

      Background

      Molecular analysis of cf-DNA in NSCLC patients enables detection and monitoring of EGFR mutations. It allows for detection of the acquired resistance for 1st and 2nd generation of EGFR-TKIs caused Thr790Met substitution. The third generation of EGFR-TKIs (osimertinib) could overcome the resistance in patients with Thr790Met mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The studied group included 23 Caucasian patients (8 male and 15 female, median age 71±9) with diagnosed lung adenocarcinoma and with EGFR mutations detected in tumor samples. Blood samples were collected before administration of EGFR-TKIs in all patients, and re-collected repeatedly from 10 patients during therapy. EGFR mutations and content of mutated cf-DNA were analyzed using ctEGFR Mutation Analysis Kit (Entrogen, USA) in Rotor-Gene Real-Time PCR device (Qiagen, Germany).

      4c3880bb027f159e801041b1021e88e8 Result

      Analysis of EGFR activating mutations in cf-DNA showed 82.61% concordance/sensitivity (19/23) with tumor samples. The mean content of mutated cf-DNA was 7.44% and it was significantly lower (p<0.000035) than in tumor samples (34.54%). Concentration of mutated cf-DNA positively correlated with advanced stage of the disease. Monitoring of EGFR status in cf-DNA showed reduction and stabilization of mutant DNA content with the emergence of response to EGFR-TKIs treatment. Primary Thr790Met substitution was undetectable in cf-DNA and in tumor samples. Acquired resistance in Thr790Met mechanism during EGFR-TKIs treatment was detected only in one patient (1/10). This patient responded to osimertinib therapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Analysis of EGFR mutations in cf-DNA shows lower sensitivity than in DNA isolated from tumor samples. Multiple evaluations of EGFR status may be useful in monitoring of therapy and allows for early detection of acquired resistance.

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      P3.13-09 - ALTER-0303 Study: Tumor Mutation Index (TMI) For Clinical Response to Anlotinib in Advanced NSCLC Patients at 3rd Line

      12:00 - 13:30  |  Presenting Author(s): Baohui Han  |  Author(s): Jun Lu, Wei Zhang, Bo Yan, Lele Zhang, Jie Qian, Bo Zhang, Shuyuan Wang

      • Abstract

      Background

      Anlotinib is an effective multi-targeted receptor tyrosin kinase inhibitor (TKI) for refractory advanced Non-Small Cell Lung Cancer (NSCLC) therapy at 3rd line. ALTER-0303 clinical trial has been revealed that Anlotinib significantly prolongs progression free survival (PFS; Anlotinib: 5.37 months vs Placebo: 1.40 months) and overall survival (OS; Anlotinib: 9.63 months vs Placebo: 6.30 months) with the objective response rate (ORR) of 9.18% and the disease control rate (DCR) of 80.95%. Here, we sought to understand the gene mutation determinants for clinical response to Anlotinib via next generation sequencing (NGS) upon cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) at baseline.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Totally 437 advanced NSCLC patients enrolled in ALTER-0303 study, and 294 patients received Anlotinib therapy. Of the 294 patients, 80 patients were analyzed in the present study. Capture-based targeted ultradeep sequencing was performed to obtain germline and somatic mutations in cfDNA and ctDNA. Response analyses upon discovery cohort (n = 62) and validation cohort (n = 80) were performed by use of germline and somatic (G+S) mutation burden, somatic mutation burden, nonsynonymous mutation burden, and unfavorable mutation score (UMS), respectively. Based on the above independent biomarkers and their subtype factors, tumor mutation index (TMI) was developed, and then used for response analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Our data indicated that the patients harbouring less mutations are better response to Anlotinib therapy (G+S muatation burden, cutoff = 4000, Median PFS: 210 days vs 127 days, p = 0.0056; somatic mutation burden, cutoff = 800, Median PFS: 210 days vs 130 days; p = 0.0052; nonsynonymous mutation burden, cutoff = 50, Median PFS: 209 days vs 130 days; p = 0.0155; UMS, cutoff = 1, Median PFS: 210 days vs 131 days; p = 0.0016). TMI is an effective biomarker for Anlotinib responsive stratification (Median PFS: 210 days vs 126 days; p = 0.0008; AUC = 0.76, 95% CI: 0.62 to 0.89) upon discovery cohort and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0006). Lastly, integrative analysis of TMI and IDH1 mutation suggested a more promising result for Anlotinib responsive stratification upon validation cohort (Median PFS: 244 days vs 87 days; p < 0.0001; AUC = 0.90, 95% CI: 0.82 to 0.97).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study provide a biomarker of TMI to stratify Anlotinib underlying responders, that may improve clinical outcome for Anlotinib therapy on refractory advanced NSCLC patients at 3rd line. Clinical trial information: NCT02388919.

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      P3.13-10 - Factors Associated with Long-Term Survival of Stage IV NSCLC Patients on First-Line EGFR-Targeting Therapy

      12:00 - 13:30  |  Presenting Author(s): Amanda Jane Williams Gibson  |  Author(s): Adrijana D'Silva, Roxana A. Tudor, Anifat A. Elegbede, Shannon Mary Otsuka, Gwyn Bebb, Desiree Hao

      • Abstract

      Background

      To determine factors associated with long term survival in Stage IV, non-small cell lung cancer (NSCLC) patients receiving EGFR-targeting agents (EGFR-TA) as systemic anti-cancer treatment in the first-line setting at a Canadian tertiary cancer centre.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective analysis was conducted on patients diagnosed with Stage IV (AJCC 7th edition) NSCLC between 1999 and 2014, and receiving EGFR-TA as first-line treatment. Demographic, clinical, histopathological, treatment and outcome data was extracted from the large, population-based institutional Glans-Look Lung Cancer Database. Long-term survivors (LTS) were defined as those surviving ≥ 18 months post EGFR-TA initiation. Correlates of survival were investigated via univariate analysis, Kaplan-Meier analysis using the log-rank test, and multivariate Cox regression.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 117 eligible patients. Median age was 65 (IQR 54.5-74) years, 61% female, 91% adenocarcinoma, 60% never smoking history, and 80% were identified as EGFR-mutant (remainder were untested and accessed EGFR-TA before routine testing was performed). Most common ethnicity (by place of birth) was North American (47%), followed by Asian (37%). 21% survived ≥ 18 months post-EGFR-TA initiation, with a median overall survival (mOS) of 46 vs. 13 months in those surviving < 18 months post-EGFR-TA initiation (p <0.001).

      LTS were more likely to be over the age of 65 years at diagnosis (76% vs. 46%, p=0.012), receive palliative radiation therapy (72% vs. 27%, p<0.001), and possess Asian ethnicity (60% vs. 30%, p=0.044), although impact of age and radiation therapy did not retain prognostic significance in multivariate analysis after controlling for other measured confounders; Asian ethnicity was retained as a favorable prognostic factor for survival [HR: 0.5, 95%CI 0.3-0.8, p=0.005)]. Patients with Asian ethnicity revealed no significant demographic or clinical characteristics (notably gender, smoking status and EGFR mutation type) between LTS and non-LTS, with the exception of age. Asian LTS were significantly more likely to be ≥ 65 years of age at diagnosis (87% vs. 32%, p<0.001), a factor which retained significance as a favorable prognostic factor in multivariate analysis [HR: 0.3, 95% CI 0.2-0.7), p=0.004)].

      8eea62084ca7e541d918e823422bd82e Conclusion

      Analysis of this population-based cohort identifies Asian ethnicity, and within this ethnic group, older age at diagnosis, as favorable prognostic factors for patients with Stage IV, NSCLC accessing EGFR-TA in the first-line setting. These findings help identify patients who derive the most benefit from EGFR-TA, and suggest that older, Asian patients represent a unique sub-population within metastatic NSCLC, who may possess different biological underpinnings of NSCLC, outside of a propensity to harbor EGFR mutations.

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      P3.13-11 - Advanced Nsclc Treated with Gefitinib or Erlotinib for Five Years or Longer - Retrospective Slovakian Study

      12:00 - 13:30  |  Presenting Author(s): Peter Berzinec  |  Author(s): Peter Kasan, Juraj Mazal, Igor Andrasina, Andrea Cipkova, Gabriela Chowaniecova, Marian Martak, Michal Urda, Milada Vesela, Lukas Plank

      • Abstract

      Background

      Median PFS in the key phase III trials with gefitinib or erlotinib for advanced NSCLC with EGFR sensitizing mutations was less than 12 months. There are only a few data about the treatment results and toxicity of long-term treatment lasting 5 years or over. Purpose of this study was to find patients treated with either gefitinib or erlotinib for at least 5 years and to evaluate the treatment results in this group of patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective multicentre study, approved by the Ethical Committee of the Specialised Hospital of St Zoerardus Zobor, Nitra. All thoracic oncology centres in Slovakia were involved. Data regarding patients were obtained from the databases of participating institutions and patient files. Descriptive statistics was used for the data analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Seven patients were included. Patients characteristics and the treatment results are summarised in the Table. Median PFS in this exceptional group was not reached, but it will be over 75 months. There was only one patient with the decreased dose of erlotinib (from 150 to 100 mg QD) due to skin toxicities. All the other patients had the common and manageable grade I – II toxicities only, and there were no unexpected drug-related AEs.

      table.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our group of patients with advanced NSCLC treated with gefitinib or erlotinib for over 5 years the treatment was safe and effective. The NGS analysis of the available samples will be retrospectively done to assess the specific genetic features of these long-term responders.

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      P3.13-12 - A Lung Adenocarcinoma with Concomitant EGFR and de novo MET Amplification Response Well to Combination of TKI and Bevacizumab

      12:00 - 13:30  |  Presenting Author(s): Qian Chu  |  Author(s): Jizong Jiang, Shanshan Huang, Peng Zhang, Yuan Chen

      • Abstract

      Background

      Patients with NSCLC who are carrying concomitant de novo EGFR and MET amplification were commonly reported to have poor response to therapy. Here, we presented a case of a patient harboring concomitant de novo MET and EGFR, who obtained favorable response to combinatorial therapy of TKI and bevacizumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We presented a lung adenocarcinoma patient harboring dual EGFR-MET alterations, and evaluated his response to combinatorial therapy of TKI and bevacizumab. In vitro experiments were performed in HCC827(EGFR-19del) and HCC827-GR (EGFR-19del+MET amplification) cells to validate the effect of bevacizumab on MET pathway.

      4c3880bb027f159e801041b1021e88e8 Result

      A 44-year-old male stage IV lung adenocarcinoma with left lung tumor was detected harboring of EGFR-19del and MET amplification using PCR and FISH. The patient was treated with erlotinib+bevacizumab and achieved partial response (PR) with a PFS with 13 months. After PD, NGS performed on both tissue and plasma biopsies revealed that the patients obtained first-generation resistant mutation EGFR-T790M, concomitant with EGFR-19del. The patient was treated with osimertinib+bevacizumab and achieved PR. He developed PD again with a PFS of 10.2 months, and repeated biopsies sequencing identified concomitant EGFR-19del and MET amplification. Then, the patient was treated with crizotinib+bevacizumab and the best curative effect was stable disease. Four months later, he developed PD and the third biopsy still revealed positive EGFR-19del and MET amplification. The patient received osimertinib+crizotinib+bevacizumab and he achieved PR one month after treatment initiation. He is still under the treatment and the PFS is more than eight months. In vitro data revealed that, under gefitinib treatment, cell viability was higher in HCC827(EGFR-19del) than HCC827-GR (EGFR-19del+METamp). However, the patient harboring dual EGFR-MET alterations in this study obtained a PFS of 13 months to erlotinib, similar with patients with EGFR-19del only (mPFS was 13 months to erlotinib as reported), suggesting the efficacious treatment of EGFR-TKI and bevacizumab than TKI alone. We observed that VEGFR-2 was expressed at relatively high levels in HCC827-GR than other cell line without METamp, and VEGF pathway inhibition by bevacizumab resulted in decreased phospho-c-Met in HCC827-GR cell lines. This result provided in vitro evidence that bevacizumab can reduce MET pathway activation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study provided basic knowledge and evidence for patients harboring concomitant EGFR and de novo MET amplification who may obtain favorable response to combinatorial treatment of TKI and bevacizumab. Encouraging antitumor activity of TKI+bevacizumab support further development of this combination for patients with advanced NSCLC and other solid tumors.

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      P3.13-13 - Afatinib in Lung Adenocarcinoma Harboring de novo EGFR Exon 20 Insertions.

      12:00 - 13:30  |  Presenting Author(s): Marcos André Costa  |  Author(s): Jairo Lewgoy

      • Abstract

      Background

      NSCLC, particularly adenocarcinoma, has been successfully treated with upfront targeted therapies according to respective oncogenic mutations in a tailor-made model. EGFR-TK inhibitors (TKi) have exhibited major responses, improving PFS, RR and even mOS (a subset treated with afatinib). This drug has emerged as the best option for those with uncommon mutations, but until now is broadly unknown its action in exon 20 mutations, which accounts for nearly 3% of all and, classically, is associated to worse response to 1st-generation TKi.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Here, in this retrospective analysis, is reported the past medical history and clinical outcomes of two patients who presented with de novo EGFR exon 20 insertions: D770_N771insSVD and Ser768_Asp770dup. The patient were treated in two differents Cancer Centers in Brazil and the mutations were identified with Next Generation Sequencing (NGS) by Illumina HiSeqs of Foundation Medicine (FM) and the other by a local certified laboratory using Ion Torrent-PGM Thermo Fischer v5.0. Analysis were performed in tissue samples extracted from FFPE. The follow-up was obtained from electronic charts.

      4c3880bb027f159e801041b1021e88e8 Result

      Patient 1: never-smoker 66 y/o lady, without comorbidities, presented 12 mo ago with dry cough, thoracic pain and -10% of weight. CT scan revealed extensive ground-glass infiltration area and multiple bilateral pulmonary nodules. Lung biopsy pointed out a mod. differentiated adenocarcinoma of predominantly lepidic pattern (IHC: AE1/2+, CK20-, CK7+, Napsin A+, TTF1+). With this, rtPCR (Cobas Mu test v.2) detected an exon 20 insertion, thus ineligible to upfront EGFR-TKi. However, was chosen to re-analyze it using NGS (FM). After a TAT of only 2 weeks, we retrieved the result which showed a poorly described mutation: EGFR exon 20 insertion D770_N771insSVD. Afatinib 30mg/day was started and, only three days after the initiation, the patient decreased the dry cough and fatigue. CT scans showed stable disease after 45 days of continuous use. Patient 2 had a more extensive past medical history: 1L chemo, followed by nivolumab and docetaxel. Lastly, NGS revealed an uncommon EGFR exon 20 insertion (Ser768_Asp770dup). Rapid clinical improvement was observed (less fatigue and dyspneia), but occured liver progression in the first control, 4w after initiation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study confirms that rare mutations have been increasingly seen due to the employment of improved sensitivity genetic techniques, like NGS. Furthermore, reveals two rare examples of rapid clinical response to afatinib in patients harboring EGFR exon 20 insertions. Finally, despite it could be an option for management of this broadly unknown situation, it suggests caution because of the short-lasting benefit in some.

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      P3.13-14 - Identification of Novel Mutations by High-Throughout Sequencing in T790M Wildtype/cMET Unamplified NSCLC with Acquired Resistance to EGFR TKIs

      12:00 - 13:30  |  Presenting Author(s): Chenguang Li  |  Author(s): Bin Zhang, Changli Wang

      • Abstract

      Background

      Lung cancer remains the leading cause of cancer-related death worldwide. Though most patients with EGFR activating mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs), tumors will inevitably acquire resistance to first generation EGFR TKIs. EGFR T790M mutation and cMET amplification are common mechanisms. Further study is needed to explore unknown genomic alterations contributing to drug resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the screening period of ASTRIS (D5160C00022) study of single center, tumor and blood samples from 69 stage ⅢB-Ⅳ NSCLC patients defined as acquired resistance to first generation EGFR TKIs (Gefitinib, Elortinib or Ecotinib) were collected. The cobas® and Droplet digital PCR (ddPCR) were used to detect T790M mutations in tumor samples and plasma ctDNA. cMET amplification were evaluated by Fluorescence in situ Hybridization (FISH). Exome sequencing were performed in four T790M wildtype/cMET unamplified samples.

      4c3880bb027f159e801041b1021e88e8 Result

      The T790M mutation rate of FFPE tissue cobas, plasma cobas and plasma ddPCR testing were 54.5%, 21.3% and 30.4% respectively. Taking all testing methods into account, the T790M positive rate was 52.2%. In 21 samples which tumor re-biopsy was performed, 14 were T790M positive (66.7%). cMET amplification were identified in 3 out of 7 T790M negative samples. Exome sequencing in 4 T790M wildtype/cMET unamplified samples and paired white blood cells identified a cohort of candidate key mutated genes including BRAF, FGFR1, PAK1, PCNT, PEBP4 and SOX3.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EGFR T790M mutation and cMET amplification are main mechanisms leading to EGFR TKI resistant in lung adenocarcinoma. These key mutated genes identified in the present study would need further functional study validation.

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      P3.13-15 - First-Line Afatinib Dose Initiation and Adjustment in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Chong-Kin Liam  |  Author(s): Gwo-Fuang Ho, Chee-Shee Chai, Adlinda Bt Alip, Yong-Kek Pang

      • Abstract

      Background

      The recommended starting dose of afatinib is 40mg od with 20mg, 30mg and 50mg tablets available for dose adjustment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a retrospective observational study of starting dose, dose adjustment and optimal dose of first-line afatinib in patients with EGFR mutant advanced non-small cell lung cancer in University Malaya Medical Center from 1st December 2014 to 30th April 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 22 patients on first-line afatinib, the starting dose was 40 mg od in 12 patients and 30 mg od in 10 patients (Figure 1). Among the 12 patients started on afatinib 40mg od, 4 (33.3%) did not require dose adjustment, 4 (33.3%) needed dose reduction to 30mg od, 2 (16.7%) needed dose reduction to 20mg od, and 2 (16.7%) had dose escalation to 50mg od. Among 10 patients started on afatinib 30mg od, 6 (60%) did not require dose adjustment, 1 (10%) needed dose reduction to 25mg od and 3 (30%) had dose escalation to 40mg od.

      Dose reduction was to reduce the cost of treatment in 1 patient and to reduce drug-related side-effects in the rest. Dose escalation was exclusively to improve disease control. The overall response rate and disease control rate was 80% (8/10) and 90% (9/10) in patients who did not require dose adjustment; while the respective rates were 85.7% (6/7) and 100% (7/7) in patients who had dose reduction.

      The optimal dose of afatinib defined by good disease control and tolerable side-effects was 50mg od in 9.1% (2/22), 40mg od in 31.8% (7/22), 30mg od in 31.8% (7/22), 25mg od in 13.6% (3/22) and 20mg od in 13.6% (3/22) of patients.

      figure 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      We suggest starting afatinib at 30mg od and adjust the dose accordingly because dose adjustment is not required in most cases on this starting dose and it is the commonest optimal dose.

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      P3.13-16 - Concomitant EML4-ALK Rearrangement and EGFR Mutation in Non-Small Cell Lung Cancer Patients: Data from Eastern Indian Hospital.

      12:00 - 13:30  |  Presenting Author(s): Prasanta Raghab Mohapatra  |  Author(s): Sourin Bhuniya, Manoj Kumar Panigrahi, Susama Patra, Pritinanda Mishra, Suvendu Purkait, Saroj Kumar Dasmajumdar, Sudipta Mohakud, Suprava Naik, Satyajeet Sahoo, Suman Kumar Jagaty, Siladitya Mohankudo, Yera Dhanurdhar, Santosh Kumar Panigrahi, Mujeeb Rahman, Dilip Kumar Muduly

      • Abstract

      Background

      Clinical guidelines recommend routine testing for genetic mutations in all adenocarcinoma of lung, including ALK EML4 gene rearrangement. The coexistence of EGFR mutations and EML4- ALK rearrangements have been described as extremely rare. Perhaps this is due to its low prevalence and the sensitivity of available diagnostic modalities. All India Institute of Medical Sciences, Bhubaneswar, is an upcoming institute of national importance situated in eastern India. No report on EGFR mutation and EML4- ALK rearrangement has been published so far from this region of India.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analysed the available data of patients from June 2014 to April 2018. Genetic testing was done from tissue block specimens immediately after establishing the histology. EGFR mutation analysis were done using commercially available Real Time PCR and ALK-positivity was assessed with immunohistochemistry (IHC) by VENTANA ALK (D5F3) CDx Assay. We investigated the course of disease with the efficacy of targeted therapy in EGFR/ ALK co-altered NSCLCs

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 251 NSCLC cases, 198 had adenocarcinoma and only four patients (1.6%) had concomitant EGFR/ALK co-alterations. Of the EGFR mutations, two were positive for Exon 19 and other two were positive for Exon 21. Mean age for Exon 19 and Exon 21 positive patients were 40 and 63 respectively. All four patients were male and had advanced stages of lung cancer. Mutation in all the four patients were detected from initial tissue biopsy and they were negative for ROS1. Three patients had received platinum based doublet regimen followed by EGFR-TKI and one patient received Erlotinib. None had received Crizotinib yet.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The coexistence of EGFR mutations and EML4- ALK rearrangements is low but higher than other geographical areas. Since the two alterations may coexist from the beginning of diagnosis, future perspective in management could be finding potential efficacy of a double inhibition of both ALK and EGFR mutations.

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      P3.13-17 - A Retrospective Study: Central Nervous System Response to Osimertinib in Patients with Advanced NSCLC

      12:00 - 13:30  |  Presenting Author(s): Yuxin Mu  |  Author(s): Puyuan Xing, Xuezhi Hao, Yan Wang, Junling Li

      • Abstract

      Background

      Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). More than 30% of patients who progress during or after treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have CNS metastases. Osimertinib, a third-generation EGFR-TKI, has been demonstrated promising intracranial efficacy in patients with advanced NSCLC from several large scale randomized control trials. We aimed to explore clinical impact of osimertinib for patients with CNS metastases, advanced NSCLC in real world setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced NSCLC who received osimertinib after progression of prior EGFR-TKIs and CNS metastases on baseline brain scan were retrospectively collected from Cancer Hospital Chinese Academy of Medical Sciences. Primary outcome was objective response rate (ORR) and secondary objectives were disease control rate (DCR), progression-free survival (PFS), time to tumor response, median best percentage change from baseline in CNS target lesion (TL) size and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Between Apr 1, 2017, and Dec 30, 2017, 22 patients met selection criteria, 15 with ≥1 measurable CNS lesion (RECIST 1.1) were included in CNS evaluable for response (cEFR) set. The median duration of follow-up was 6.5 months. For overall 22 patients, ORR and DCR were 40.9% and 86.4%, respectively, with median PFS of 8.5 months (95% CI 4.1, 13.0). Of 15 patients in cEFR set, CNS ORR was 53.3% with complete responses reported in 3 patients (20.0%). Median best percentage change from baseline in CNS TL size was -40% (range: -100% ~ +60%) and median time to CNS tumor response was 1.3 months. CNS DCR was 80.0%. Median CNS PFS was not reached. Safety profile was acceptable and no new unexpected findings were found.

      瀑布图15人.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      This real world analysis further confirmed that osimertinib was indeed demonstrated clinically meaningful efficacy against CNS metastases in Chinese patients with advanced NSCLC.

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      P3.13-18 - Mechanisms of Acquired Resistance to Afatinib Clarified with Liquid Biopsy

      12:00 - 13:30  |  Presenting Author(s): Tomomi Nakamura  |  Author(s): Chiho Nakashima, Kazutoshi Komiya, Shinya Kimura, Naoko Sueoka-Aragane

      • Abstract

      Background

      While the elucidation of the mechanisms of acquired resistance to 1st and 3rd generation EGFR-TKI progresses, there have been few clinical investigations into the mechanisms of acquired resistance to 2nd generation EGFR-TKI, afatinib.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed 20 patients with advanced lung adenocarcinoma who acquired resistance to afatinib including EGFR-TKI re-challenge. We examined EGFR T790M, C797S, BRAF V600E, MET amplification by MBP-QP method and droplet digital PCR using ctDNA and re-biopsy samples at pre and post afatinib treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      Just before afatinib treatment, 15 patients were T790M negative, and 5 were positive with ctDNA. Among T790M negative patients, 40.0% (6/15) turned to positive at PD to afatinib. T790M positive patients showed synchronous change of T790M allele frequency with treatment efficacy of afatinib. C797S was not detected just before afatinib treatment, and it appeared in 3 patients with very low level of allele frequency. Two of 3 patients were both C797S and T790M positive, who achieved PR to osimertinib. However, PFS with these patients was a trend shorter than T790M only. BRAF V600E was detected in one patient at PD to afatinib. MET amplification was never detected in this study.

      8eea62084ca7e541d918e823422bd82e Conclusion

      T790M was related with acquired resistance to afatinib like 1st generation EGFR-TKI, but the frequency is relatively lower. The influence of C797S for resistance to afatinib would be less than T790M, but existence of C797S possibly causes shorter PFS of osimertinib.

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      P3.13-19 - Surgery for  cIIIB Lung Adenocarcinoma After Response to Erlotinib, Survival and Management of Postoperative Oligoprogressions

      12:00 - 13:30  |  Presenting Author(s): Danail Borisov Petrov  |  Author(s): Georgi Yankov, Mariana Atanassova, Anatoli Semkov, Stoyan Bichev

      • Abstract

      Background

      Down-staging of epidermal growth factor receptor (EGFR) activating mutation-positive (EGFR M+) advanced non-small-cell lung cancer (NSCLC) after first-line EGFR tyrosine kinase inhibitor (TKI) therapy may lead to primary tumor resection. Unfortunately, most patients’ disease will progress postoperatively even with the use of adjuvant TKI therapy mainly due to EGFR T790M mutation. Osimertinib, a third-generation inhibitor of EGFR T790M mutation, is with reduced toxicity profile as compared to non-selective EGFR TKI. Our aim is to assess a survival benefit of salvage lung resection in Stage IIIB lung adenocarcinoma after response to TKI and a management of oligoprogressions in the postoperative period.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Caucasian age 56 female lung adenocarcinoma patient (ECOG PS-0) was initially staged as cT2aN3M0 on October 10, 2015. Pretreatment biopsy specimens from ipsilateral scalene lymph node harbored EGFR mutation (exon 19 E746-T751insI deletions). After six months of first-line treatment with erlotinib150 mg/daily, which patient tolerated very well, a FDG-PET scan showed a 21/16 mm formation of the left upper lobe with SUV-2 without other abnormalities, down-staging with cT1cN0M0. Radical left upper lobectomy with 20 negative dissected mediastinal lymph nodes was carried out (May 17, 2016). Postoperative pathomorphological and mutational studies of residual tumor revealed adenocarcinoma and EGFR exon 19 mutation.

      4c3880bb027f159e801041b1021e88e8 Result

      Adjuvant erlotinib therapy was started for 3 months. Four months after its discontinuation by patient decision a 3 cm left supraclavicular mass (SUV-2.0 on FDG-PET) was diagnosed and totally resected. Adenocarcinoma involvements of 3 lymph nodes, as well as EGFR exon 19 mutation, were confirmed. The patient continued on erlotinib, but after 6 months on FDG-PET scan 2 left cervical lymph nodes (SUV 4.6 and 6.1 on FDG-PET) were diagnosed. Systematic left cervical dissection was performed with resection of four metastatic lymph nodes. Again adenocarcinoma histology was confirmed, but EGFR T790M mutation was identified as well. Three months later, even without signs of residual tumor mass on computerized tomography scan, Osimertinib therapy in dose 80 mg orally once daily was administered. The last follow-up FDG-PET scan revealed no signs of progression (April 30, 2018). The patient is with ECOG PS-0 and perfect quality of life without drug-related adverse events.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Radical surgery of oligoprogression following salvage surgery for Stage IIIB (EGFR M+) lung adenocarcinoma after response to TKI, while continuing to use TKIs (specifically osimertinib in EGFR T790M mutation), can result in prolonged overall survival. The pending question is whether the EGFR-TKI therapy can be discontinued in these patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-20 - Frequency of EGFR Mutations in Patients with Adenocarcinoma Lung Cancer. Comparative Study Between Public and Private Mexican Health Services

      12:00 - 13:30  |  Presenting Author(s): Jeronimo Rafael Rodriguez-Cid  |  Author(s): Guillermo Martos Ramírez, Vanessa García Montes, Diana Bonilla-Molina, Jorge Arturo Alatorre Alexander, Guillermo Olivares Beltrán, Victoria Imaz-Olguín, Dan Green Renner

      • Abstract

      Background

      The frequency of the EGFR mutation in pulmonary adenocarcinoma varies between 15-40% depending of population reported. Study descriptive, observational, retrospective and multicentric was conducted to determine the frequency of this mutation in public and private centers service in Mexico

      a9ded1e5ce5d75814730bb4caaf49419 Method

      They were selected patients with diagnosed of pulmonary adenocarcinoma between January 2011 and January 2016 from three oncology centers, two private centers (ABC Medical Center and the Spanish Hospital) and one public (National Institute of Respiratory Diseases). The total sample was 328 patients, subdivided by the presence or not of EGFR mutations. The primary objective was the mutation in EGFR and the secondary the type of mutation, frequency by sex, type of treatment and clinical stage at the time of diagnosis.

      4c3880bb027f159e801041b1021e88e8 Result

      The sample was formed by 136 (41%) men and 195 (59%) women, the average age of diagnosis was 62.4 years, the clinical stage in 75.7% was IV at the time of diagnosis. The total frequency of the EGFR mutation was 42.7% (140 patients), the most prevalent being Del19 (66.4%) and L858R (30%). These mutations were present in 113 patients of INER (34.5%) and by both private centers was 27 patients (8.2%), this difference was significant when comparing hospital types (public vs. private, p 0.033). Men showed a protective factor for the EGFR mutation compared to women with HR 0.88 (p 0.028), there were differences between the possibility of presenting the EGFR mutation in patients with lung cancer, with less possibility of presenting it if medical attention was done in a private medium compared to the public medium with a HR 0.81 (p .001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is a significant difference in the frequency of mutations in EGFR between the public and private hospital, probably associated with ethnic, genetic, environmental and social differences between the two populations.

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      P3.13-21 - Apatinib Plus Icotinib as First-Line Therapy For EGFR Co-Mutations NSCLC in Chinese Patients: An Exploratory Study

      12:00 - 13:30  |  Presenting Author(s): Yanhong Shang  |  Author(s): Xiaofang Li, Ran Huo, Mengmeng Ji, Zizheng Song, Bin Liu, Youchao Jia, Yumiao Li, Jin Jiao, Junping Shi, Yan Zhang, Xiaoqian Chen, Ming Yao, Xiaofang Zhang, Aimin Zang

      • Abstract

      Background

      To date, the phenomenon of EGFR co-mutated with other genes in untreated NSCLC patients was common, which might be the reason of EGFR-TKI primary resistance. In our previous research, samples from 81 NSCLC Chinese patients were tested with next-generation sequencing (NGS) based targeted panel assay, 49% (40/81) patients had EGFR co-mutations,the top-ranked co-mutant genes were TP53 (35%, 28/81) and cell cycle pathway related genes (19%, 15/81). Clinical data indicated that antiangiogenic drug combination with EGFR-TKI might reverse EGFR-TKI acquired resistance. Apatinib is a new antiangiogenic drug targeting vascular endothelial growth factor receptor 2 (VEGFR2), and Icotinib is a potent and specific EGFR-TKI, which were both made in China. In this study, we aim to assess the efficacy and safety of Apatinib plus Icotinib as first-line therapy for EGFR co-mutations NSCLC in Chinese patients, and compare the differences of curative effect among EGFR co-mutant subgroups.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This single-arm, open-label exploratory study will recruit 50 Chinese patients with stage IIIB/IV NSCLC who have never received any anti-tumor treatment previously. Tumor tissue and matched blood of each patient will be collected for NGS-based 450 cancer related genes panel assay, designed to comprehensively assess EGFR mutation and co-mutations. Meanwhile, ctDNA extracted from blood samples will be collected for NGS-based 329 cancer related gene before treatment as baseline, and every 2 months after enrollment until disease progression, to evaluate the evolution of genomic variation and effects of drug efficacy. The analysis of genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene rearrangement in selected genes and also tumor mutation burden (TMB) calculated as total somatic substitutions and indels per megabase. Patients with EGFR-sensitizing mutations accompanied with other genomic alterations will receive Apatinib 250mg, qd, po and Icotinib 150mg, tid, po until disease progression, or unacceptable toxicity. The primary endpoint of this study is progression free survival (PFS), and the secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality of life (QOL) and drug-safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-22 - Real World Study of Afatinib in First-Line or Re-Challenge Setting for Patients with EGFR Mutant Non-Small Cell Lung Cancer.

      12:00 - 13:30  |  Presenting Author(s): Hisashi Tanaka  |  Author(s): Kageaki Taima, Masamichi Itoga, Yoshiko Ishioka, Keisuke Baba, Toshihiro Shiratori, Yoshihito Tanaka, Hideyuki Nakagawa, Takeshi Morimoto, Yukihiro Hasegawa, Hideo Yasugahira, Koichi Okudera, Shingo Takanashi, Sadatomo Tasaka

      • Abstract

      Background

      Afatinib is the second generation epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), and approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in real world practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients who received afatinib for advanced EGFR-mutant NSCLC in 5 institutions in Aomori, Japan from October 2014 to January 2017 were included into the analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      In total, 128 patients were analyzed. Seventy-six patients received afatinib as first-line setting and 52 as re-challenge setting (i.e., prior first generation TKIs used and third generation TKI were not adapted). In first-line setting, patient characteristics were as follows: a median age 68 yrs (42- 88 yrs), 67% female, and 88.1% PS 0/1. The median progression-free survival (PFS) was 17.8 months (95% CI: 13.7- 21.5 months). The overall survival (OS) was 39.5 months (95% CI: 34.4- not reached). There was no difference in median PFS and OS according to age (< 74, 75 ). Though 58 patients (76.3%) had to reduce the dose due to adverse events, it did not affect its efficacy in terms of OS (39.5 months in the reduction group vs. not yet reached in the no reduction group) (P= 0.37). Moreover, the reduction group showed even longer PFS than the no reduction group. (18.0 months in the no reduction group vs. 7.9 months in the reduction group) (P= 0.016). The response rate (RR) was 64% (CR/PR/SD/PD/NE: 1/48/16/1/10). Twenty-eight patients among 48 who had PD underwent re-biopsy, and 16 patients (57.1%) were T790M positive. In re-challenge setting, patient characteristics were as follows: a median age 65 yrs (37- 90 yrs), 78% female, and 90.3% PS 0/1. The median PFS was 8.0 months (95% CI: 4.9- 9.5 months). The RR was 24% (CR/PR/SD/PD/NE: 1/12/29/6/4). Most common adverse events leading to dose modification and treatment discontinuation were diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the real practice in Japan, afatinib in first-line and re-challenge settings showed comparable or better efficacy compared with previous clinical trials.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-23 - EGFR-TKIs Combined Hydroxycamptothecin Improved Outcomes in EGFR-Mutant NSCLC Patients Who Harboring Pericardial Effusion.

      12:00 - 13:30  |  Presenting Author(s): Xiyi Lu  |  Author(s): Xiaomeng Wang, Jiaqi Yao, Renhua Guo

      • Abstract

      Background

      Pericardial perfusion of hydroxycamptothecin (PCPH) is the effective treatment for malignant pericardial effusion(MPCE). Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs) have shown greater efficacy in clinical trials than chemotherapy in patients with EGFR-mutant non-small cell lung cancer (NSCLC), but little information is available on EGFR-mutant NSCLC patients who harboring MPCE. We therefore investigate the advantage of EGFR-TKIs with PCPH for these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled patients with MPCE, stage Ⅳ, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. These patients were divided into 2 groups by different treatments: EGFR-TKIs in combination with PCPH and chemotherapy combined with PCPH. Retrospectively analyzed the survival of different treatment programs and their prognostic factors.

      4c3880bb027f159e801041b1021e88e8 Result

      Between January 1, 2010, and December 31, 2016, 644 patients were screened. MPCE occurred more frequently in patients with EGFR-mutant than those with EGFR wild-type (10.62% vs. 5.20%; p = 0.046). 29 patients were enrolled, 15 to EGFR-TKIs/HCPT group and 14 to chemotherapy/HCPT group. The progression free survival (PFS) was significantly longer with EGFR-TKIs/HCPT group (360 days) than chemotherapy/HCPT group (90 days; P=0.003). The effusion control rate for pericardial lesions showed statistical difference between two groups (93.33% vs. 71.43%, P = 0.038). Toxicity of EGFR-TKIs/ HCPT groups were characterized by skin rash (40.0% vs. 7.1%; P=0.039), whereas the proportions of patients with leucopenia (42.9% vs. 6.7%; P=0.023) and thrombocytopenia (42.9% vs. 6.7%; P=0.023) were higher in chemotherapy/HCPT group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EGFR-TKIs combined with PCPH is preferable for advanced NSCLC patients with EGFR-mutant and MPCE.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-24 - <sub>Efficacy of EGFR-TKIs Compared with Chemotherapy as First-Line Therapy in Patients with EGFR Rare Mutation Advanced Lung Adenocarcinoma </sub>

      12:00 - 13:30  |  Presenting Author(s): Huijuan Wang  |  Author(s): Haixia Li, Mina Zhang, Guowei Zhang, Xiaojuan Zhang, Zhiyong Ma

      • Abstract

      Background

      Clinical activity of epithelial growth factor receptor tyrosine kinase inhibitors or platinum-based chemotherapy as firstline therapy in patients with EGFR rare mutation advanced lung adenocarcinoma remains unknown, This retrospective study assesses the activity and long-term survival of the two treatment regimens.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      3856 patients diagnosed with lung adenocarcinoma from Henan Cancer Hospital received EGFR gene detection during January 2, 2012 to November 1, 2017. 1643 patients with EGFR mutation and phase IIIB/IV were identifed. Among them, 130 cases (7.9%) with EGFR rare mutations, excluded 64 patients(4 cases of patients coexist with uncommon mutations and common mutations, 17 cases of insertions in exon 20, 42 cases of T790m and T790m complex mutations, and 1 loss of follow-up), 66 cases of EGFR uncommon mutations(G719X, L861Q, S768I and compound mutations)enrolled in the evaluation of efficacy, of whom 34 patients received EGFR-TKIs alone and 32 patients received platinum-based chemotherapy as frstline therapy. All EGFR-TKIs were first-generation drugs, details were gefitinib (250 mg/day), erlotinib (150 mg/day) and eclectinib (125 mg tid/day), all patients received at least 4 weeks of EGFR-TKIs. All chemotherapy drugs were third-generation in combination with platinum, details were pemetrexed (500 mg/m2), vinorelbine (25 mg/m2 d1, 8), or gemcitabine (1000 mg/m2 d 1, 8) platinum-based chemotherapy, every 3 weeks as a treatment cycle.

      4c3880bb027f159e801041b1021e88e8 Result

      Regardless of whether EGFR-TKIs or chemotherapy, the objective response rate (ORR: 28.6% vs 36% P>0.05) and disease control rate (DCR: 82.1% vs 84% P>0.05) were similar. EGFR-TKIs showed superior progression-free survival than chemotherapy group (7.1 vs 4.9 mts; HR=0.717, P=0.166), but there was not statistically difference. However, compared with chemotherapy, we found that overall survival (OS: 14.6 vs 20.3 mts; HR=1.879, P=0.019) was significantly lower in patients with EGFR-TKIs, which was statistically significant. In multivariate analysis, first-line use of targeted therapy (HR = 0.447 P = 0.006) and smoking history (HR = 3.824 P = 0.003) were found to be a signifcant independent prognostic factor for OS in lung adenocarcinoma patients with EGFR uncommon mutation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Compared with chemotherapy, first-line use of the first generation of EGFR-TKIs can improve the short-term efficacy of patients with EGFR rare mutation advanced lung adenocarcinoma, but longer survival in patients with first-line platinum-based chemotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-25 - Development of a Comprehensive Genomic Profiling System to Detect Actionable Genetic Alterations and Tumor Mutation Burden  

      12:00 - 13:30  |  Presenting Author(s): Francesca Cavallo  |  Author(s): Sian Jones, Samuel V. Angiouli, Kelly Gerding, Laurel Keefer, James Hernandez, James Robert White, John Simmons, Mark Sausen

      • Abstract

      Background

      Current non-small-cell lung cancer (NSCLC) treatment includes targeted therapies for EGFR, ROS1, BRAF and ALK. Patients treated with immunotherapies have shown both high and durable response rates. Tumor mutational burden (TMB) has emerged as a promising biomarker, with multiple clinical studies correlating high TMB with better response to immunotherapy. However, in order for widespread adoption to be successful, the community needs more clarity and guidance around TMB analytical performance before implementation into routine diagnostic practice. First, analytical accuracy across a broad dynamic range of mutation burden is critical. Second, comparison to a common reference and standardization of reporting TMB is also required for clinicians to translate results across different technologies and methods. Here, we describe the development and analytical validation of a decentralized comprehensive gene profiling kit to determine TMB and other clinically relevant somatic variants from a 507-gene next-generation sequencing panel.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Identification of somatic mutations with sufficient accuracy is critical for inferring mutational load from a targeted gene panel. We developed a machine learning algorithm to optimize sensitivity and specificity for somatic mutation detection across the entire coding sequence of a 507-gene panel. We compared the overall accuracy of this approach using simulated and experimentally validated whole-exome and targeted gene analyses. We then assessed the accuracy of the 507 gene panel for prediction of TMB in silico across a wide dynamic range using several cohorts of publicly available NSCLC whole exome sequencing datasets. Then, cases from an independent NSCLC cohort were experimentally evaluated and compared to whole exome sequencing results to demonstrate the analytical accuracy across a spectrum of tumor mutational loads. Finally, sensitivity and specificity of clinically relevant genetic alterations in NSCLC were determined using both contrived and clinical samples compared to orthogonal methods.

      4c3880bb027f159e801041b1021e88e8 Result

      Our results indicate that the 507-gene system, combined with proprietary software leveraging machine learning algorithms, accurately identifies somatic mutations, and achieves high analytical accuracy for determining TMB across a broad dynamic range. In addition, this system has the capability to detect somatic genetic variants that are important for therapeutic stratification in NSCLC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This 507-gene decentralized system provides accurate results for the determination of TMB across a broad range of mutational burden, and detects clinically relevant genetic alterations important in NSCLC.

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      P3.13-26 - Outcomes of Patients with Metastatic Lung Cancer Presented in a Multidisciplinary Molecular Tumor Board

      12:00 - 13:30  |  Presenting Author(s): Lisa Pei Chu  |  Author(s): Karen Kelly, David R. Gandara, Primo Lara, Alexander Borowsky, Frederick Meyers, John McPherson, Rachel L Erlich, Nava Almog, Alexa B Schrock, Siraj M Ali, Jeffrey S. Ross, Vincent A Miller, Andreas Heilmann, Jonathan W Riess

      • Abstract

      Background

      With the adoption of broad genomic profiling, interpretation of genomic data in NSCLC has become increasingly complex. Approved targeted therapies against oncogenic driver mutations have improved clinical outcomes for patients whose lung cancers harbor these genomic alterations. However, for other patients, the benefit of broad genomic sequencing is not fully proven. Multidisciplinary molecular tumor boards (MTB) may improve clinical outcomes by appropriately matching targeted treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed clinical, pathologic, and molecular data of metastatic lung cancer patients presented at the UC Davis MTB from January 2016 through May 2017. Genomic alterations were identified by hybrid capture-based comprehensive genomic profiling to a median coverage depth of >500X for 315 cancer-related genes (FoundationOne®).

      4c3880bb027f159e801041b1021e88e8 Result

      Out of 48 patients presented, 19 (39.6%) had lung cancer. Fourteen patients (73.7%) had adenocarcinoma, 1 SCLC, 1 squamous, 2 neuroendocrine, and 1 mixed histology. Seventeen patients were available for follow-up.

      Median number of prior treatments was 2 (range: 0-7) and median number of prior targeted therapies was 2 (range: 0-5). On average, each tumor sample had 5.3 genomic alterations (range 2 – 14). Every sample had ³1 actionable mutation, in that matched targeted therapy was available in the form of an FDA-approved drug for NSCLC, FDA-approved drug in another tumor type, or genomically informed clinical trial. Tumors harbored an EGFR mutation (N=7), HER2 amplification (N=2), BRAF V600E (N=2), or mutation in BRCA1 (N=1), KIT (N=1), or PTCH1 (N=1). All 7 patients with an EGFR mutation had previously received EGFR-targeted therapy, six with progressive disease (PD) on prior EGFR-TKI.

      Thirteen patients (76.5%) received targeted therapy, including FDA-approved therapy for NSCLC (N=4), FDA-approved therapy for another tumor type (N=6), or a genomically informed clinical trial (N=3). The other four patients were either on an immunotherapy clinical trial (N=2) or could not tolerate treatment (N=2). Out of the 13 patients who received targeted therapy, 4 patients had a partial response (31%) (3 EGFR, 1 BRAF V600E), all other patients had stable disease or PD. Median PFS on MTB-selected treatment was 4.8 months (range: 25% 2.2 – 75% 10.7 months).

      8eea62084ca7e541d918e823422bd82e Conclusion

      MTB at an academic medical center matched a high percentage of patients to either a targeted treatment or clinical trials with targeted therapies or immunotherapy. A subset of patients had clinical benefit to targeted therapies in this pretreated population. Multidisciplinary expertise at MTB can guide treatment for NSCLC, but new targeted treatments are needed to improve clinical outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-27 - Clinical Outcomes of Patients with Lung Adenocarcinoma Harboring Concomitant Driver Mutations in a Brazilian Cancer Center

      12:00 - 13:30  |  Presenting Author(s): Marcos André Costa  |  Author(s): Marcelo Oliveira Santos, Carlos Henrique Teixeira, Jacques Tabacoff

      • Abstract

      Background

      NSCLC, particularly adenocarcinoma, has been successfully treated with upfront targeted therapies according to respective oncogenic mutations in a tailor-made model. It has led to improvement in clinical outcomes (CO) and QoL, however, some evidences sugest that the occurrence of concomitant driver mutations (OCDM) is responsible for poorer results than expected. Questions, thus, have emerged regarding the best strategy to this population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this retrospective study, we reviewed lung cancer patients treated in our institution in the last four years in order to identify the OCDM. The vast majority of patients performed Next Generation Sequencing (NGS) using Illumina HiSeqs of Foundation Medicine (FM). The f/u was obtained from our electronic charts.

      4c3880bb027f159e801041b1021e88e8 Result

      From apr/14 to apr/18, 5 patients were elegible for this analysis, 2M / 3F, mean 59y/o. Patient 1: treated with crizotinib because of MET amplification harboring concomitantly ATM deletion exons 11-50. Died after pneumonia before first radiologic evaluation. Patient 2: osimertinib for EGFR T790M harboring BRCA-2 c1528G>T. Derived partial response (PR) with PD after 9 mo. Patient 3: immunotherapy because of TMB 18 + PD-L1 e PD-L2 amplification, harboring STK11 Q159fs*2 as well. Curiously, the previous report of PD-L1 (22C3) by IHC had been negative. Still in PR, lasting 14 mo. Germline analysis (to Peutz-Jeghers) will soon be performed. By FM, Everolimus or Temsirolimus were sugested. Patient 4: crizotinib and alectinib for ALK-EML4 fusion harboring concomitantly BRCA2 S1074R. Had PR lasting 9 mo and only 6 mo respectively. Curiously, previous FISH had not identified the translocation. Patient 5: treated with crizotinib because of ALK-EMLA4 translocation harboring concomitantly Kras mutation. This is a rare condition and, until recently, de novo rearrangements of ALK was thought to be mutually exclusive to Kras. Not surprisingly, and in line with some reports of literature, the patient experienced rapid progression, saw already in the first control in 8 weeks.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study confirms that the OCDM has been increasingly seen due to the employment of improved sensitivity genetic techniques, like NGS. Additionally, provides the clinical outcomes of patients with lung adenocarcinoma harboring more than one of those mutations, which is broadly unknown yet. Finally, previous reports account that, particularly, patients with concomitant ALK fusion and Kras mutation carry poorer results with anti-ALK than expected. This study reinforces this observation and argues that the best management of these patents is still to be clarified.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-28 - Heterogeneity, Prevalence and Prognostic Significance of PDL1 Expression in Early Resected NSCLC

      12:00 - 13:30  |  Presenting Author(s): Michelle Dean  |  Author(s): Angela Chan, Emeka K Enwere, Haocheng Li, Amanda Jane Williams Gibson, Adrijana D'Silva, Anifat A. Elegbede, Roxana A. Tudor, Shannon Mary Otsuka, Donald Morris, Gwyn Bebb

      • Abstract

      Background

      The interaction between the programmed death protein-1 receptor (PD1) and its membrane-bound ligand (PDL1) is one mechanism by which tumor cells evade the immune system. Cancer immunotherapies target this interaction by blocking the function of either protein, allowing for T-cell activation and destruction of the tumor. Because PDL1 expression in tumor is used to identify patients who might benefit from immune-modulating treatment, its detection plays a key role in clinical recommendations. Our objectives are to assess the prevalence of PDL1 expression in early stage non-small cell lung cancer (NSCLC) patients, determine its association with clinical outcomes using the Glans-Look Research (GLR) database (Calgary, AB), and validate these findings using a cohort from the Manitoba Tumor Bank (MBTB).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A tissue microarray (TMA) was built using pre-treatment resected and biopsy tissue samples from 459 GLR database patients with early stage NSCLC, diagnosed between 2003 and 2010. Cell lines expressing varying levels of PDL1 were generated, embedded into HistoGel™ and co-mounted onto the GLR and MBTB arrays. Fluorescence immunohistochemistry was performed using anti-PDL1 E1L3N (Cell Signaling Technology), and PDL1 expression was evaluated as percent-positive and intensity scores in the cytoplasmic compartment of tumor and stromal cells using HALO™ automated image analysis software. Cell line PDL1 intensity scores served as on-slide reference standards to normalize PDL1 expression in patient specimens using R Programming software. PDL1-percent-positive tumor scores were generated to assess the cut-points of ≥50%(“PDL1-strong”), ≥1%-to-49%(“PDL1-weak”), and <1%(“PDL1-negative”), indicated by the FDA-approved companion diagnostic anti-PDL1 22C3 (Dako) for pembrolizumab. Clinicopathological outcomes were analyzed, and overall survival was assessed using the Kaplan-Meier method and compared using the log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Preliminary analyses indicate PDL1-weak/negative GLR patients with adenocarcinoma experienced higher median OS (3.50yrs) compared to PDL1-strong patients (1.91yrs) (p=0.0043). This trend was not significant over all histologies, or when using mean scores. The opposite trend was found with the MBTB cohort (2.52yrs vs. 1.76yrs OS, PDL1-strong vs. PDL1-weak/negative maximum scores, p=0.0410).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Variations across datasets illustrate the difficulty in harmonizing PDL1 testing. Heterogeneity of protein expression, TMA sampling error, and differences between study cohorts can translate into variable correlations between PDL1-positivity and survival estimates. Increased survivorship in GLR adenocarcinoma patients with PDL1-weak/negative staining could challenge the notion of using PDL1 as a prognostic biomarker. Comparisons between the E1L3N and 22C3 anti-PDL1 assays will be performed, E1L3N percent-positive cut-points will be refined according to the lowest intensity-based statistical p-value, and further outcome findings will be presented and discussed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-29 - Patient-Derived Xenograft Models(PDX) of Lung Squamous Cell Carcinoma(SCC) for Preclinical Studies

      12:00 - 13:30  |  Presenting Author(s): Tae Ho Kim  |  Author(s): Junghee Lee, Byungjo Park, Hong Kwan Kim, Jinseon Lee, Eunjoo Hwang, Heekyoung Lee, Kevin Koo, Hanna Lee, Seungjae Lee, Hwanseok Rhee, Jong Eun Lee, Yoon-La Choi, Jhingook Kim

      • Abstract

      Background

      Non-small cell lung cancer is the most prevalent type of lung cancer, and one of its subtype, squamous cell carcinoma has limited targeted therapeutic options in comparison with adenocarcinoma. For this reason, we established the patient-derived xenograft models of primary lung cancer and then focused on the SCC PDX models to be used for the discovery of target mutations through the molecular profiling of lung tumors and their association of therapeutic responses

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PDX models were established using the tissues of patients who underwent surgery as primary lung cancer at Samsung Medical Center during the period between October, 2014 and September, 2017. Briefly, tumor tissues from patients were subcutaneously engrafted and passaged two more times in NOD-scid-IL2Rγnull mouse. Then we are analyzing histological characteristics and molecular profiles of established SCC PDX by whole exome sequencing and whole transcriptome sequencing.

      4c3880bb027f159e801041b1021e88e8 Result
      Mutation profiles of squamous cell carcinoma Patient Tumors and their PDX models

      Patient tumor

      PDX

      ID

      Gene

      Mutation

      Frequency

      Gene

      Mutation

      Frequency

      PDL-040

      HRAS

      JAK1

      PTEN

      TP53

      GNAQ

      U2AF1

      G13V

      N136fs

      -78fs

      Y236C

      T96S/M59L

      G167C

      1.000

      0.397

      0.488

      1.000

      0.143/0.080

      0.080

      PDL-041

      CTNNA2

      FRG1

      M672I

      C159Y

      0.278

      0.042

      PDL-089

      EP300

      AMER1

      RB1

      EP300

      AMER1

      RB1

      0.473

      0.576

      0.500

      AMER1

      RB1

      EP300

      R142K

      I425fs

      G438V

      0.851

      0.472

      0.479

      PDX-073

      PDX-079

      DNMT3A

      BRAF

      TP53

      FRG1

      F571L

      V600E

      R249S

      Q137K

      0.606

      0.524

      0.571

      0.521

      BRAF

      TP53

      FRG1

      DNMT3A

      V600E

      R249S

      Q137K

      F571L

      0.377

      1.000

      0.026

      0.444

      PDX-100

      DDR2

      BRAF

      GNAS

      TP53

      E757D

      G469A

      Q286P

      156_157RV>L

      0.484

      0.388

      0.583

      0.671

      BRAF

      DDR2

      TP53

      GNAS

      G469A

      E757D

      156_157RV>L

      Q286P

      0.941

      0.212

      0.500

      0.180

      PDX-114

      PDX-186

      KEAP1

      PIK3R1

      L281M

      M200fs

      1.000

      0.464

      PDX-190

      PDX-205

      PDX-207

      TP53

      ATRX

      C176F

      S1944R

      0.617

      0.537

      TP53

      C176F

      1.000

      PDX-231

      MET

      STK11

      KEAP1

      RPSAP58

      GNAS

      L829V

      D115N

      G333C

      Q113H

      V57M

      0.494

      0.410

      0.551

      0.426

      0.488

      KEAP1

      MET

      STK11

      GNAS

      RPSAP58

      SMO

      G333C

      L829V

      D115N

      V57M

      Q113H

      R138L

      1.000

      0.485

      1.000

      0.318

      1.000

      0.400

      PDX-252

      HLA-A

      HLA-A

      HLA-A

      HLA-A

      HLA-A

      HLA-A

      TSC1

      FRG1

      ATRX

      EEF1B2

      R38W

      G80R

      A114D

      S129P

      T187P

      T187R

      S487C

      Q137K

      Q929E

      R122H

      0.500

      0.267

      0.617

      0.611

      0.091

      0.231

      0.293

      0.026

      0.870

      0.227

      PDX-271

      TSC1

      KDR

      M322T

      V297I

      0.357

      0.300

      PDX-302

      JAK1

      TP53

      E667Q

      N268I

      0.514

      0.488

      PDX-318

      ARID1A

      NF1

      TP53

      FRG1

      SMO

      SOX17

      TRRAP

      H203Q

      R2556T

      LRKKGEPHH289fs

      A151G

      F332fs

      R147L

      A598V

      0.125

      0.168

      0.472

      0.048

      0.456

      0.200

      0.349

      PDX-364

      TSC2

      T927I

      0.575

      PDX-366

      KDR

      TP53

      NOTCH1

      FRG1

      A1103D

      V173L

      L107F

      Q137K

      0.494

      0.609

      0.600

      0.496

      NOTCH1

      TP53

      FRG1

      CHD4

      KDR

      L107F

      V173L

      Q137K

      R1825L

      A1103D

      0.160

      1.000

      0.035

      0.061

      0.270

      PDX-372

      CDKN2A

      TP53

      D33H

      A161fs

      0.377

      0.534

      CDKN2A

      TP53

      D33H

      A161fs

      1.000

      0.461

      PDX-402

      PIK3CA

      FRG1

      FRG1

      FRG1

      V344G

      L150S

      A151T

      C159Y

      0.503

      0.443

      0.445

      0.455

      PIK3CA

      GNAQ

      FRG1

      V344G

      T96S

      C159Y

      0.173

      0.098

      0.050

      PDX-409

      DNMT3A

      KEAP1

      KMT2D

      F511L

      G158C

      P1912fs

      0.653

      0.467

      0.669

      KEAP1

      KMT2D

      GNAQ

      FRG1

      DNMT3A

      G158C

      P1912fs

      T96S

      C159Y

      F511L

      0.917

      0.446

      0.063

      0.043

      0.460

      PDX-410

      TP53

      KEAP1

      KEAP1

      C124G

      G480V

      G186R

      0.564

      0.585

      0.737

      KEAP1

      KEAP1

      TP53

      G480V

      G186R

      C124G

      0.298

      0.656

      1.000

      PDX-415

      DNMT3A

      NFE2L2

      NFE2L2

      CREBBP

      TP53

      APC

      CDKN2A

      I247F

      R18Q

      D11N

      S2356F

      R337L

      ENDNG1530fs

      R52fs

      0.494

      0.584

      0.568

      0.600

      0.469

      0.559

      0.531

      AMER1

      AMER1

      APC

      CDKN2A

      CREBBP

      NFE2L2

      NFE2L2

      TP53

      DNMT3A

      FLT3

      H619R

      H619N

      -1530fs

      R52fs

      S2356F

      R18Q

      D11N

      R337L

      I247F

      M799I

      0.703

      0.698

      0.478

      0.462

      1.000

      0.364

      0.250

      1.000

      0.628

      0.076

      PDX-420

      HLA-A

      NOTCH1

      TP53

      K292E

      G427C

      H179R

      0.067

      0.575

      1.000

      PDX-434

      NOTCH2

      RRAS2

      KEAP1

      KMT2D

      TP53

      V968L

      Q72L

      Y54F

      D4400fs

      P301fs

      0.366

      0.422

      0.512

      0.509

      0.482

      IGF1R

      KEAP1

      NOTCH2

      TP53

      RRAS2

      P266S

      Y54F

      V968L

      P301fs

      Q72L

      0.204

      1.000

      1.000

      0.477

      0.792

      PDX-454

      TNFAIP3

      R52T

      0.431

      NF1

      TNFAIP3

      TP53

      LTTILKN58fs

      R52T

      P152fs

      0.476

      0.458

      0.455

      PDX-473

      CREBBP

      FLT3

      Q913R

      I920V

      0.410

      1.000

      PDX-480

      TSC2

      NF1

      NF1

      NF1

      TP53

      RRAS2

      EEF1B2

      V1695E

      N793S

      K798Q

      F1287L

      R158L

      Q143R

      R122S

      0.831

      0.169

      0.160

      0.210

      0.828

      0.034

      0.166

      NF1

      TP53

      TSC2

      W784L

      R158L

      V1695E

      0.838

      0.875

      0.516

      rsquare3.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In PDX models of 49 patients, successful lung SCC PDX engraftment and identical histomorphology was achieved. And the 30 sets of exome sequencing analyses showed that the somatic mutations were relatively preserved. Among them, some interesting targetable mutations including BRAF(V600E) were identified. We identified consistency of transcriptome profiles of PDX models during the passages.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-30 - Driver Mutation in Heavy Smoker Patient with Squamous Cell Carcinoma Metastatic Lung Cancer: Case Report

      12:00 - 13:30  |  Presenting Author(s): Bárbara Maria Lafayette Viana da Luz  |  Author(s): Ana Cecilia Barbalho De Vasconcelos, Candice Amorim De Araujo Lima Santos, Renata Silva Aragao

      • Abstract

      Background

      Nowadays, guidelines recommend to assess the presence of a driver mutation in tumors that contains an element of adenocarcinoma regardless of the clinical characteristics of the patient or squamous cell carcinoma in a patient that never smoked.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reported a clinical case of a pacient that had a squamous cell carcinoma with a driver mutation in EGFR, despite the fact that he was a heavy smoker. the case occured in our service in the northeast of Brazil.

      4c3880bb027f159e801041b1021e88e8 Result

      Woman, 63 years old, current smoking, presented in a public health service in Brazil with history of cought and dyspneia 3 months earlier. In the investigation, CTS showed mass hilar in the right lung and enlarged lymphonodes in the mediastinum IPSI and contralateral, but there was no evidence of secondary lesios in other organs. She was submitted to a core biopsy CT guided that confirmed squamous cell carcinoma. The planned treatment was radiotherapy and concomitant chemotherapy. As in our service the time to start the radiotheraphy is about 3 months, we started a platin based chemotherapy and made sequencial radiotherapy. After that, she was submitted to new CTS that showed partial response in the lung and lymphnodes, but there was evidence of bone metastatis in the sacrum and left iliac. In our service, there was a trial in which all patients diagnosed with lung cancer had it’s tissue avaliated for driver mutation, and we received the results with a driver mutation in exon 19 of EGFR. So, we started a treatment with Erlotinib with a great response and, now, after 9 months, it’s still responding.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This case represent a rare case of a squamous cell carcinoma with a driver mutation in a current smoking, and maybe justified by the fact that the tumor had an adenosquamous component. If the patient wasn’t tested for driver mutations, she would never received an target therapy. Thus, maybe we should assessed all non small lung cancers for the driver mutations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-31 - Creating a Precision Medicine Pipeline for Lung Cancers.

      12:00 - 13:30  |  Presenting Author(s): Paola A Marignani  |  Author(s): Jinhong Kim, Wenda Greer, Zhaolin Xu

      • Abstract

      Background

      The vision of High Mortality Cancer Precision Medicine Pipeline (HMCPMP) is to improve high mortality cancer outcomes. Our mission of HMCPMP is to establish precision medicine pipelines for high mortality cancers that start with the patient and ends with precise treatments for the patient based on their lung cancer’s unique molecular profile. HMCPMP leverages expertise areas of i) single-cell gene-discovery that allows for the identification of new barcodes and therefore new targets, ii) animal models that recapitulate human cancers, and patient-derived xenographs that allow for pre-clinical trials in mouse models to test novel drugs and drug development, iii) immunology and cancer stem cell biology to explore the role the immune system and stem cell niche impact tumourigenesis, iv) single-cell fluidics/3D organ systems that allow for understanding the heterogeneity of cancers and vi) data mining that allows for better treatment choices and the discovery of new treatment options based on their lung cancer’s barcodes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have created a patient-centered precision medicine pipeline that moves resected lung cancers from the surgical suite to banking, through to single cell molecular diagnostics to validation (Figure 1). pipeline_lung_cancers.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      Single-cell genomic profiling of resected lung cancers were prepared using a microfluidics platform Fluidigm C1 followed by transcriptome sequencing per single cell. We identified differentially expressed genes (DEGs) for stage, sex, and smoking status, followed by validation by quantitative PCR. We are currently pursuing new barcodes that differentially distinguish between the stratified subgroups of patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The significance of HMCPMP research is improved health, survivorship, and quality of life for people living with lung cancer. Although the economics of lung cancer are important and likely drivers of federal, provincial and regional research initiative, HMCPMP considers the human when faced with the diagnosis of lung cancer.

      PAM is funded by the Dalhousie Medical Research Foundation and the Canadian Cancer Society

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-32 - Drug Sensitivity of Lung Adenocarcinoma Towards Inducers of Epigenetic Modifications

      12:00 - 13:30  |  Presenting Author(s): Isabelle Moneke  |  Author(s): Sonam Dhamija, Andrea C Becker, Manfred Jung, Alexander-Thomas Hauser, Micheal Luebbert, Bernward Passlick, Sven Diederichs

      • Abstract

      Background

      Over the last decade, epigenetic regulation of gene expression emerged as a central mechanism in tumorigenesis and metastasis. In contrast to DNA mutations, epigenetic modifications are reversible and therefore suitable targets for pharmacological therapy.

      To understand which patients will benefit the most from which drug regime remains a challenge in everyday clinical practice. The aim of this study is to characterize the tumor drug sensitivity and epigenetic modifications on a molecular level induced by different compounds, in order to improve tumor-specific treatment for patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We tested a total of 40 epigenetically active compounds (partly known and partly unknown/unpublished) in two different concentrations in 56 lung adenocarcinoma cell lines and 3 control cell lines for cell viability.

      4c3880bb027f159e801041b1021e88e8 Result

      The resulting 14000 data points were split according to sensitivity of the tumor cells to the compounds into three different groups (high sensitivity: < 25% viable cells, medium sensitivity: 25%-75 viable cells and low sensitivity: >75% viable cells). Six compounds showed broad effectiveness with high sensitivity in more than half of the cell lines while 15 compounds inhibited proliferation in only a few cell lines and are therefore of special interest for the discovery of new predictive biomarkers. The remaining compounds did not show high sensitivity in any cell line.

      Notably, we found that different compounds targeting the class of histone acetyltransferases (HAT) can have very different impacts on the survival of the tumor cells, and that the epigenetic modification of opposing mechanisms (e.g. HAT- and HDAC-inhibitors) may give rise to similar results

      8eea62084ca7e541d918e823422bd82e Conclusion

      Taken together, we demonstrate the differential effectivity of drugs inducing epigenetic modifications in lung adenocarcinoma cells in vitro. By combining the sensitivity data with molecular profiles of RNA and protein expression which we have generated, we are identifying molecular determinants for the individual sensitivity of the tumor to the respective drugs, which could be further developed in vivointo predictive biomarkers for drug response.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-33 - Lung Adenocarcinoma Harboring RET Fusion and Dramatic Response to Combination of Vandetanib (VAN) and Everolimus (EVE): A Case Report from Brazil

      12:00 - 13:30  |  Presenting Author(s): Carolina Kawamura Haddad  |  Author(s): Isabella Drumond Figueiredo, Ricardo Yudi Nishimoto, Suellen Nastri Castro

      • Abstract

      Background

      The identification of oncogene addicted NSCLC and the development of target therapies lead to improvement in survival rates and quality of life. In addition to other drugable targets such as EGFR mutation and ALK translocation, RET fusion has been shown to be an oncogenic driver in 1 to 2% of patients with NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Here we report a 23-year old never-smoker male patient (Pt) diagnosed with lung adenocarcinoma, metastatic to lymph nodes, bones and lungs. Tumor biopsy was performed during broncoscopy. Tissue molecular testing was negative for EGFR (cobas) and ALK (FISH), and PDL-1 tumor proportional score (22C3) was 5%. Pt presented rapid disease progression after one cycle of cisplatin and pemetrexed, with pleural effusion and respiratory distress. Since initial tissue biopsy paraffin had been exhausted, next generation sequencing in cell-free tumor circulating DNA in plasma was performed (Guardant360). CCDC6-RET fusion and TP53 mutation (T256I) were identified.

      4c3880bb027f159e801041b1021e88e8 Result

      Based on promising activity of the combination of VAN with EVE previously reported, and the lack of clinical trials in this setting in Brazil, Pt started oral target therapy with VAN 300 mg and EVE 10 mg daily. He had unequivocal clinical improvement over the following weeks, with discontinuation of pain medications and relief of respiratory symptoms. After 30 days on treatment, restaging CT scans demonstrated a dramatic response. Adverse events were grade (G) 1 cutaneous rash, G1 stomatitis and G1 diarrhoea. Pt also presented G1 pneumonitis that resolved rapidly with EVE temporary discontinuation. He remained without disease progression at 4+ months. After 5 months, he presented pneumonitis recurrence with respiratory failure.

      VAN is a multi-targeted tyrosine kinase inhibitor of EGFR, VEGFR and RET, with limited activity in RET-rearranged NSCLC phase 2 trial. However, the concurrent inhibition of RET and the mammalian target of rapamycin (mTOR) has shown promising activity for RET-rearranged tumors in preclinical models. Among the 6 evaluable NSCLC patients with RET fusions treated with VAN and EVE in phase I trial, 5 achieved partial responses (83%) and 1 stable disease (16%). In particular, it has been suggested that CCDC6-RET subtype shows higher sensitivity to VAN.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This case report corroborates the promising activity of combination of VAN and EVE in RET-rearranged NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-34 - RET Gene, a New Choice for NSCLC

      12:00 - 13:30  |  Presenting Author(s): Yinghui Xu  |  Author(s): Yucong Wang, Kewei Ma

      • Abstract

      Background

      RET gene, accounting for 1-2% of non-small cell lung cancer (NSCLC), has been identified as a novel target molecule which has been reported that could not coexist with other gene mutations such asrejected with the other mutation like KRAS, EGFR, BRAF, MEK1, HER2 and ALK.The emerging targeted agents Cabozantinib and Vandetanib have been recommended by NCCN guidelines for non-small cell lung cancer with RET fusion, based on a series of clinical trials.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We presented a case of lung adenocarcinoma with KIF5B/RET fusion. The patient was a 50-year-old, male, non-smoker, diagnosed as left upper lobe adenocarcinoma lung cancer. We performed a radical resection of pulmonary carcinoma for two years ago. Subsequently,he completed four cycles of chemotherapy with gemcitabine and cisplatin. However, half years later, pleural metastasis made him have to receive systemic treatment but no chemotherapy due to his worse tolerance. We then performed a gene examination with the PCR method using the intraoperative specimen, and finally found positive KIF5B/RET fusion gene. From then on June 10,2017, he started to take cabozantinib for treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      He started to take cabozantinib (140 mg orally, once daily) for about nine months. His disease sustained SD during that period (please see Figure 1). No serious adverse events (AEs) except rash (Ⅱ grade) occurred in the whole treatment process.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We found that the RET gene is a new alternative for lung adenocarcinoma patients without common mutations such as EGFR, ALK, ROS1 and so on. This case report supports a useful reference for the therapy of lung adenocarcinoma patients with RET mutation and may provide a new choice for this kind of NSCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.13-35 - Antitumor Effect of Neratinib Targeting HER2-Altered Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yusuke Ogoshi

      • Abstract

      Background

      Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), as in breast and gastric cancers. However, the benefit of HER2-targeted therapy is much less defined. The aim of the study is to investigate the antitumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), in NSCLC cells harboring HER2 alterations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We examined the sensitivity of neratinib against normal bronchial epithelial cells BEAS-2B which ectopically overexpressing wild-type or mutant HER2. Human cDNAs encoding full-length HER2 (wild-type and its variants A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D, and S310F) were inserted into the pIDT-SMART (C-TSC) vector, pCMViRTSC. Furthermore, we examined the antitumor activity of neratinib in several NSCLC cell lines harboring HER2 alterations in vitro and in vivo experiments, and investigated the association between their genetic alterations and sensitivity to neratinib treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D, and S310F) showed constitutive auto phosphorylation of HER2 and activation of downstream signaling by Western blotting. These BEAS-2B cells were sensitive to neratinib, but insensitive to erlotinib, a first generation EGFR-TKI. Neratinib significantly inhibited the growth of HER2-altered (H2170, Calu-3, and H1781) NSCLC cell lines with an average IC50 value of 0.00347µL, 0.0428µL, and 0.0119µL. Neratinib administration showed strong antitumor effect on tumor growth in mouse xenograft model using HER2-altered lung cancer cell lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study strongly suggests that neratinib is a promising therapeutic option for the treatment of HER2-altered NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
    • +

      P3.15-01 - Long-Term Outcomes of Pulmonary Metastasectomy: A 12-Year Dual Centre Experience

      12:00 - 13:30  |  Presenting Author(s): Phillip Antippa  |  Author(s): Nima Yaftian, Francis Cheung, Gavin Wright

      • Abstract

      Background

      Pulmonary metastases are a common site of spread for many cancers. We describe the long-term outcomes of surgical resection of pulmonary metastases at two major cancer centres.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study institutions thoracic surgery databases were searched for all patients who underwent pulmonary metastasectomy between 2005 and 2017.

      4c3880bb027f159e801041b1021e88e8 Result

      There were a total of 489 patients who underwent pulmonary metastasectomy. Mean age at time of surgery was 45.6 ± 11.6 years. There were a total of 658 operations performed with 105 (21.5%) patients having repeat pulmonary metastasectomy. Of these patients 68 (64.8%) had 1 repeat operation, 20 (19.0%) had 2 repeat operations, 11 (10.5%) had 3 repeat operations, 2 (1.9%) had 4 repeat operations and 4 (3.8%) had 5 repeat operations.

      The most common primary lesions were colorectal cancer (CRC) in 35.3% (173/489) of patients, sarcoma in 23.7% (116/489) of patients, melanoma in 16.2% (79/489) patients, renal cell carcinoma (RCC) in 7.2% (35/489) of patients and germ cell carcinoma (GCC) in 4.5% (22/489) of patients. Other cancers accounted for the remaining 13.1% (64/489) of patients.

      Mean follow-up was 41.2 ± 1.6 months and was complete for 91.8% of patients. Survival was 85.6% (95%CI: 81.9 – 88.9%) at 1-year, 45.2% (95%CI: 39.7 – 50.5%) at 5-years and 27.8 (95%CI: 21.2 – 34.6%) at 10-years follow-up (figure 1). On univariate Cox regression analysis CRC (p = 0.027) and GCC (p = 0.016) were associated with improved survival while melanoma (p = 0.039) was a risk factor for mortality. On multivariate Cox regression analysis CRC (p = 0.025) and GCC (p = 0.011) were associated with improved survival.
      pulmonary mets kaplan-meier 300dpi.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pulmonary metastasis is associated with survival of less than 30% at 10 years follow-up. CRC and GCC cancers were associated with better long-term mortality while melanoma was associated with worse long-term mortality.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-02 - Carboplatin Dose Calculated Using Different Formula for eGFR and Their Comparison with Actual Dose Administered in Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Digambar Behera  |  Author(s): Valliappan Muthu, Kuruswamy Thurai Prasad, Navneet Singh

      • Abstract

      Background

      Carboplatin dosage for chemotherapy is usually estimated using AUC-based dosing. Several equations are available for estimating GFR(eGFR); including Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI), and a recent equation(1). However, while calculating dosage of carboplatin, several factors other than estimated-GFR[including performance status(PS), vial package strengths] merit consideration. Do we require high degree of precision in eGFR and how does each of these equation perform in real-life settings?

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective audit of lung cancer patients undergoing first-line chemotherapy at our centre, with the aim of determining discrepancies between actual doses of carboplatin administered versus those calculated using different equations. Calvert formula was used to calculate carboplatin dose, with the eGFR being obtained from Cockcroft-Gault, CKD-EPI and the Janowitz-equation.(J Clin Onc2017;35(24):2798-805) Dose derived from GFR estimated using latter was considered reference standard. Carboplatin dose was also calculated using manufacturer’s instructions[body surface area(BSA) in kg/m2 x 300 for GFR>60 mL/min; BSA×250 for GFR=41-60 mL/min; BSA×200 for GFR≤40mL/min]. Absolute dosage differences and percentage errors(PE) for above equations were calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      77 subjects received carboplatin-based chemotherapy(Jan-Aug 2017). Dosage calculated by Cockcroft-Gault based GFR and manufacturer’s recommendation had significant variation as compared to new equation-based dose. However, the actual administered doses were lower than both Cockcroft-Gault-based and manufacturer’s recommended doses. Significant proportion(n=48, 62.3%) had >20% absolutePE of carboplatin dose as compared to reference standard. Carboplatin dose PEs(actual administered, calculated as per Cockcroft-Gault, CKD-EPI equation and manufacturer’s recommendation) were plotted against the reference standard as waterfall chart(Figure 1A-D). All, except six(7.8%) patients(none of them were≥20% higher than the predicted), received doses≤ that calculated from the reference.figure 1 jco final.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Actual carboplatin administered is lower than the predicted in majority(irrespective of equation used for eGFR). Hence the probability of administering a potentially toxic dose, owing to incorrect eGFR might be negligible. Thus, using more accurate equations/measuring GFR may not be required.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-03 - Capturing the Patient Experience for the Treatment of EGFR Exon 20 Mutations in Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Aaron Galaznik  |  Author(s): Jill Bell, Laurie Roberts, Milenka Jean-Baptiste, Dennis Revicki, Gabriella Salvatore, Shuanglian Li

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) accounts for 80−85% of new lung cancer cases, which presents as metastatic disease 40−50% of the time. The prevalence of NSCLC patients with a mutation in the epidermal growth factor receptor (EGFR) varies by ethnicity, ranging from 15−50%, and EGFR exon 20 insertion mutations specifically account for 7−12% of all EGFR mutations.

      Health-related quality of life (HRQOL) was widely used, as generic measures may lack the sensitivity required to demonstrate clinical change related to new therapies. Assessments of disease-specific patient-reported outcomes (PROs) play an important role in clinical trials to evaluate the benefits of new treatments on HRQOL and in making treatment decisions for patients. This study aimed to better understand the overall symptom experience and HRQOL impact from the perspective of NSCLC EGFR exon 20 patients to evaluate the effectiveness of new treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A targeted literature review was conducted in Embase and Medline (2007−2017) to identify PROs used in previous NSCLC studies for evidence of content coverage. Interviews with expert clinicians were conducted to explore the clinical perspective on treatment and observed patient experience. Following approval from an independent review board, semi-structured qualitative interviews were conducted with NSCLC patients identified through the International Cancer Advocacy Network.

      4c3880bb027f159e801041b1021e88e8 Result

      Five oncologists were interviewed, reporting a wide range of NSCLC symptoms, notably shortness of breath, chest pain, bone/other pain, and substantial emotional impacts. Ten patient interviews were conducted (median age 55 [42−83] years; 60% female, 90% EGFR exon 20 insertions, median disease duration 1.8 [<1−6] years, 60% self-reported brain metastases). The most frequently reported disease related symptoms included fatigue (90%), pain (70%), shortness of breath (70%), cough (60%), weakness (30%), phlegm/congestion (30%), and hemoptysis (20%). Symptoms indicative of brain metastases included issues with vision and headaches (both 30%), speaking (20%), and balance (10%). All patients mentioned experiencing a psychological or emotional impact, with 60% describing worry/anxiety around treatment, the future, or finances. Patients also described experiencing negative impacts on daily activities, including household chores and self-care (60%), work (50%), social activities (50%), and family life (40%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Incorporation of the patient voice provided valuable in-depth insight on the NSCLC patient experience. Symptom and HRQOL impact concepts identified will inform the iterative development of a conceptual disease model. Results show the significant social, emotional, and physical impact on patients’ lives, which fill an important gap and help to inform treatment decision making.

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      P3.15-04 - An Interdisciplinary Educational Program Dedicated to Non-Small Cell Lung Cancer Patients to Improve their Quality of Life 

      12:00 - 13:30  |  Presenting Author(s): Laurence Bigay-Gamé

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) guidelines require access for patients and their family to an educational program to help them managing their treatments, symptoms in order to improve their quality of life. Outpatients’ treatments are now very common, giving the patient more autonomy. However, to get the best therapeutic compliance and to improve the disease control, a patient education is necessary. This study describes an educational program and assessed its impact on patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ETOILE is an educational program dedicated to patients with advanced NSCLC treated by oral or intravenous treatment. First an educational diagnosis is made with the patient, then a tailored program is proposed with individual or collective educational sessions (informations about lung cancer, how to manage side effect, stress management, nutrition, smoking cessation, well-being...). An interdisciplinary team is dedicated to this program including medical doctor, coordinating nurse, psychologist, sophrologist, dietitian, social worker, tobacco specialist nurse, physiotherapist and social esthetician. A weekly meeting is organised to present every patient included in the program and to discuss the need of each patients. Assessments included skills acquisition by the patients and the program evaluation.

      4c3880bb027f159e801041b1021e88e8 Result

      In 2016, 94 patients (66% were men, median age : 59 years), entered the ETOILE educational program. Ninety-six percent of the patients were satisfied or very satisfied with the ETOILE program. They reported an improvement in their quality of life. For 81% it allowed to have a better knowledge of their illness, for 85% to know better their treatment, 76% to manage their symptoms and adapt the food, 86% to take care of them and to have better information about all helps that can be provided. For 72% of the patients, the educational program permits to manage their stress and help their relatives throughout the disease and treatment trajectory.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Providing a tailored educational program is important for patients with advanced NSCLC throughout the disease trajectory even if the disease prognosis remain poor for many patients. Our experience shows that an educational program dedicated to NSCLC patients is feasible and useful.

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      P3.15-05 - Patient Reported Outcomes (PROs) as Performance Measures After Surgery for Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Majken Munk Brønserud  |  Author(s): Maria Iachina, Anders Green, Mogens Grønvold, Erik Jakobsen

      • Abstract

      Background

      In Denmark and other countries, quality in lung cancer care is measured using performance indicators from clinical registries. The registries and the indicators are based on data from professionals taking care of patients and their treatment. What is missing in this quality measurement, however, is the patients’ perspective. The objective of this study was to examine if patient reported outcomes (PROs) from patients with lung cancer could be used in performance measurement after surgery. Would it be feasible to use PROs in benchmarking, comparing treatment quality in different regions of Denmark?

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients registered in the Danish Lung Cancer Registry(DLCR) from 1 October 2013 until 30 September 2015, who received curatively intended surgical treatment, were eligible(N=1,718). They were asked to complete the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire six months after surgery. From the questionnaire we chose the global health score (GHS) and role functioning (RF) as indicators, and the threshold for good performance was set to 65 points (on a scale 0-100 where 100 is the best). Information about the patients’ socioeconomic position was obtained from Statistics Denmark. Results were compared between the five regions within Denmark, using the patients’ home address. Patient characteristics of the five groups were compared using t-tests and chi squared tests.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 1,615 patients alive six months after surgery, questionnaires were completed by 999 patients (61.9%). Patient characteristics of the five groups differed significantly in e.g. performance status, cancer stage, and income. There were difference in GHS between groups, but mean RF varied significantly (see table).

      Global health score (GHS) and Role functioning (RF) for the five regions
      All patients Region 1 Region 2 Region 3 Region 4 Region 5 p
      N = 999 N = 154 N = 207 N = 212 N = 256 N = 170
      GHS mean (SD) 66.8 (22.0) 65.9 (20.5) 65.7 (23.5) 68.2 (21.8) 67.4 (21.7) 66.5 (22.5) 0.706
      % with GHS ≥ 65 63.6 62.3 61.8 67.5 64.8 60.0 0.581
      RF mean (SD) 68.9 (29.5) 66.0 (29.6) 67.4 (28.1) 71.5 (28.6) 69.8 (29.8) 68.9 (31.3) 0.013
      % with RF ≥ 65 69.8 62.3 71.5 73.1 69.5 70.6 0.239
      8eea62084ca7e541d918e823422bd82e Conclusion

      In a population with lung cancer receiving surgery, it may be feasible to use PROs for benchmarking. The next step in our study is to examine whether differences in GHS and RF are a consequence of different outcomes, or of different patient populations.

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      P3.15-06 - Capillary Leak Syndrome in a Primary Lung Adenocarcinoma Patient with Thrombocytopenia from Interleukin-11 Treatment

      12:00 - 13:30  |  Presenting Author(s): Huafei Chen  |  Author(s): Youcai Zhu, Kaiqi Du, Xiaofeng Li, Lixin Wu, Wenxian Wang, Chunwei Xu, Meiyu Fang

      • Abstract

      Background

      Capillary leak syndrome (CLS) is an uncommon complication characterized by generalized edema and hypotension. We report a 62-year-old male patient with lung and liver metastasis who had underwent liver radiofrequency ablation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      He was treated with interleukin (IL)-11 (3 mg per day) because of chemotherapy induced thrombocytopenia.

      4c3880bb027f159e801041b1021e88e8 Result

      After 9 days of therapy, the patient complained of abdominal distension and with bilateral edema of all four extemities. Chest computed tomography and B ultrasound of the abdomen showed pleural effusions and ascites. IL-11 was then discontinued, fluid resuscitation was performed, fresh frozen plasma and packed red blood cells were transfused, and methylprednisolone therapy was administered. The patient had recovered after 12 days of treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This case report demonstrates that patients with lung cancer can develop this rare form of CLS after treatment with IL-11. The manifestation of IL-11-induced CLS indicates that it may be a severe side effect of IL-11 treatment in cancer.

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      P3.15-07 - A Literature Review and Assessment of Lung Cancer Quality Indicators

      12:00 - 13:30  |  Presenting Author(s): Kim-Lin Chiew  |  Author(s): Bin Jalaludin, Puma Sundaresan, Shalini K Vinod

      • Abstract

      Background

      Quality indicators (QIs) are used to assess various aspects of the quality of healthcare services received by patients in the “real-world”. They provide a measurement tool to be utilised in care settings to develop standards or benchmarks, identify variations in care, guide performance improvement, monitor changes over time and promote accountability. The management of lung cancer is complex and rapidly evolving. Care often involves multidisciplinary assessment and management with multimodality treatment that requires a comprehensive and co-ordinated approach. Evaluating the quality of care received in “real-world” everyday care is crucial for optimising health outcomes for lung cancer patients. We reviewed quality indicators in lung cancer and assessed their utility.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A medline search was conducted using the search terms “quality indicators” and “lung neoplasms” and grey literature using a web search of government and relevant health organisations. Full-text review was performed to include only articles that fulfilled inclusion criteria of original research that developed or applied specific QIs related to the care of lung cancer patients. Data was collected on the characteristics, frequency, use and testing for each indicator.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 43 articles or reports were analysed. These included 293 distinct QIs, the most frequently reported indicators were related to surgery (n=66), then symptom assessment and management (n=43) and diagnosis and staging (n=38). There were fewer indicators related to systemic therapy (n=30), radiotherapy (n=17) or combined treatments (n=10). Analysis of the characteristics of process and structure QIs was undertaken and classified as meeting all ideal or a minimum set of desirable characteristics for QIs. Of these 60 met the minimum set and only five the ideal characteristics. These included 12 related to diagnosis and staging, four to pre-treatment assessment, five to surgery, 12 to systemic treatment, six to radiotherapy, three to combined treatment, three non-specific to treatment, three to symptom assessment, 11 to supportive care and one to palliative care.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A wide range of quality indicators have been developed and used in lung cancer. The most frequent are treatment related and surgical based, which only reflects a small proportion of all lung cancer patients. In order to assess their usefulness, we classified QIs according to fulfilling accepted desirable characteristics. We present these as the most useful for implementation as quality metrics. QIs must also be feasible and relevant, which must be tailored to the health service for application.

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      P3.15-08 - Patient-Reported Outcomes (PROs) in Patients with Lung Resection: Open Versus Minimal Invasive Surgery

      12:00 - 13:30  |  Presenting Author(s): Qiuling Shi  |  Author(s): Wei Dai, Xiaoqin Peng, Xiaojun Yang, Qiang Li

      • Abstract

      Background

      As a novel and cutting-edge indicator to evaluate the quality of surgery, e.g. minimal invasive surgery (MIS), Patient-Reported Outcomes (PROs) has not been implemented in patients with lung resection in the real world. This study aims to profile PRO-measured symptom burden in patients with lung resection of either open surgery (OS) or MIS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a prospective study on lung resection patients from November 22, 2017 to April 23, 2018. MD Anderson Symptom Inventory-lung cancer module (MDASI-LC) was used to assess the severity of perioperative symptoms and how they interfered with daily functioning. MDASI-LC was administered on the pre-operation day and daily after surgery up to the day of discharge. Trajectories of symptom severity and interference were compared between OS and MIS via mixed effects models.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 78 lung resection patients, 22 received OS and 56 received MIS. Most of the resection types were lobectomies (74.4%). All patients completed pre-operation assessment and the missing rate after surgery was less than 10%. There were no statistically significant differences between OS and MIS in pre-operation variables including age, BMI, hemoglobin, neutrophil ratio, platelets and creatinine. Within the first week after surgery, the most severe symptoms were pain, cough, fatigue, disturbed sleep and dry mouth for OS patients and pain, fatigue, cough, disturbed sleep and shortness of breath for MIS patients. MIS patients reported better physiological functioning (walking, general activity and work) than did OS patients in the first 7 days post surgery (p=0.013). Among patients with MIS, those with stage II-IV reported more severe fatigue than did stage I patients over the hospitalization (p=0.018).

      fig 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      This real world data preliminarily profile patients’ experiences over a short period after lung resection. Compared to OS, MIS did not show a significant advantage in symptom severity, but related to better functioning on daily living. Additional recruitments and follow-up will expand patients’ perceptions to the full trajectory of recovering from lung resection.

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      P3.15-09 - Are Lung Cancer Patients Receiving Education Materials? The Healthcare Provider Perspective on Distribution Gaps and Possible Solutions

      12:00 - 13:30  |  Presenting Author(s): Andrea Ferris  |  Author(s): Upal Basu Roy, Margery Jacobson, Kayla Haskins

      • Abstract

      Background

      While new treatments for lung cancer bring new hope, they can also make understanding a lung cancer diagnosis and making treatment decisions a challenge for both patients and caregivers. Education is imperative to understanding the diagnosis and making informed treatment decisions. However, many patients and their caregivers report that they do not receive materials from their doctors. We fielded a study of healthcare providers (HCP) to understand their attitudes and practices on disseminating patient education for lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted an IRB-approved sequential mixed-method study of 216 HCPs (130 oncologists, 52 pulmonologists, and 34 nurse navigators/clinic or hospital administrators) from academic research centers, community cancer centers, and private practice to get a full and broad picture of education for lung cancer patients based on the specific role each HCP group plays in the treatment journey. The quantitative survey was followed by a qualitative interview of five HCPs to contextualize the survey findings. Questions of the study delved into perception, usage, distribution, and development of education materials.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the HCPs surveyed, surprisingly only 75% report that lung cancer educational materials are distributed. Nurse navigators/clinic administrators were more likely to distribute patient education materials than oncologists and pulmonologists (p<0.05). Notably, there is a discrepancy in who actually does the distributing: nurse navigators and community cancer center administrators say oncologists most often distribute them (80%), while oncologists and pulmonologist claim they only distribute some of the time (56%). Information format also was reported as a factor in distribution; HCPs are interested in information that can be both electronic and printable (79% of HCPs report that they distribute information via printed resources, and 59% of them still prefer printed materials, given the choice). Overall, community cancer centers report a higher rate of distribution than private practices and hospitals (p<0.05). However, there is typically not a point person for material review in any of these settings, and most HCPs report using information from multiple sources, such as self-created materials and materials created by other organizations.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Distribution practices for educational materials are not standard and tend to be subject to the HCP’s own discretion, leading to inconsistent delivery of materials. In-depth interviews with HCPs suggest possible solutions, including customization to patient/caregivers’ unique type of lung cancer, availability of multiple formats of education materials for distribution, and white-labeling of materials to allow re-branding to an HCP’s unique practice setting.

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      P3.15-10 - Survival Impact of Peripheral Blood Ratios in Lung Cancer According Clinical Stage

      12:00 - 13:30  |  Presenting Author(s): Claudio Flores  |  Author(s): Alfredo Aguilar, Daniel Enriquez, Luis Alberto Mas Lopez, Jesus Schwarz, Carlos Vallejos

      • Abstract

      Background

      Lung cancer represents one of the most frequent and letal neoplasms in many regions, where most patients are still diagnosed as advanced disease, and many biomarkers have been studied unsuccessfully. Peripheral blood ratios as Neutrophil-to-lymphocyte ratio (NLR), Monocyte-to-lymphocyte ratio (MLR) and Platelets-to-lymphocyte ratio (PLR) have been studied as potential biomarkers of systemic inflammation but cut-off values are still difficult to stablish. We explored the survival impact of different cut-off values according clinical stages in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed medical records of 193 patients with lung cancer treated at ONCOSALUD–AUNA 2011-2014. Peripheral blood data was obtained retrospectively from the first medical visit and we calculated optimal cut-off values using the maximally selected rank statistics according every clinical stage (CS). Overall survival (OS) was evaluated using Kaplan-Meier method and survival curves comparison was performed using log-rank test or Breslow.

      4c3880bb027f159e801041b1021e88e8 Result

      Median age was 67 years (range: 34-88), 51% were women and 71.5% had 0-1 ECOG scale. The 9.8, 11.4, 18 and 60% were CS I, II, III and IV. The most common metastatic sites were brain, bones, cervical and supraclavicular nodes. Patients with I CS underwent to lobectomy, and 59% of II and most III-IV CS received chemotherapy. The median follow-up was 4.9years, median OS was 1.4years (95%CI: 1.1-1.9) and 2 and 5years OS were 42% and 25%, respectively. The next table shows survival impact of blood ratios according CS. Optimal cut-off values were different according every CS of lung cancer, however in the IV CS group the cut-off of 2.6 and 0.31 for NLR and MLR showed significant survival impact on OS.

      table.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that exists different cut-off values for blood ratios according every clinical stage that needs to be explored among larger population data-bases to confirm it. In advanced disease, NLR and MLR show significant survival impact in this study.

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      P3.15-11 - Association Between Peripheral Blood Ratios and Clinical Stage Disease in Lung Cancer.

      12:00 - 13:30  |  Presenting Author(s): Claudio Flores  |  Author(s): Daniel Enriquez, Alfredo Aguilar, Luis Alberto Mas Lopez, Carlos Vallejos

      • Abstract

      Background

      Many attempts have been described to stablish peripheral blood ratios as systemic immune biomarkers in lung cancer, unfortunately they are not still considered because of lack accuracy and sensibility. In this study, we explore and correlate clinical stages to median values of peripheral blood ratios as Neutrophil-to-lymphocyte ratio (NLR), Monocyte-to-lymphocyte ratio (MLR) and Platelets-to-lymphocyte ratio (PLR) among patients with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospectively, we review clinical and laboratory data from 193 patients with lung cancer treated at Oncosalud – AUNA from 2011 to 2014. The laboratory data (hemoglobin, leukocytes, neutrophil, lymphocyte and monocyte) were collected from blood routine test obtained from the first clinic visit. The median (range) and mean (± SD) of the ratios were determined according every clinical stage and compared using the U Mann Whitney test.

      4c3880bb027f159e801041b1021e88e8 Result

      Median age was 67 years, and 63 (34-79), 64 (37-83), 69 (44-88) and 67 (38-86) years in I, II, III and IV CS, respectively. In early disease (I-II), female patients were slightly more frequent that men. Median hemoglobin was 13.6, 12.4, 13 and 12.7 gr/dl for I, II, III and IV CS, respectively. Peripheral blood levels (leukocytes, lymphocytes, monocytes and platelets) show a slightly higher level among patients with advanced disease. Median NLR, MLR and PLR are described in the following table, there was a significant difference between early and advanced disease (III and IV CS) for NLR and MLR.

      table 2.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      These results suggest that there are higher levels of peripheral blood ratios related to advanced disease; but larger studies are needed to confirm it. Only NLR and MLR showed differences between early and advanced disease.

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      P3.15-12 - Survival Impact of Patient Enrollment in Antineoplastic Drug Trials for Stage IV Non-Small Cell Lung Cancer (NSCLC)

      12:00 - 13:30  |  Presenting Author(s): Bernardo H.L. Goulart  |  Author(s): Emily T Silgard, Kari Stricker, Keith D Eaton, Renato G Martins

      • Abstract

      Background

      Patient enrollment in antineoplastic drug trials (ADT) is essential for the development of effective therapies in stage IV NSCLC. An open question is whether NSCLC patients derive a survival benefit by enrolling in ADTs. We hypothesized that patient enrollment in ADT is associated with longer overall survival (OS) because of access to novel therapies and closer follow up, compared with no ADT enrollment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed electronic medical records of 193 patients diagnosed with biopsy-proven, stage IV NSCLC between 01/01/2007 and 12/31/2014, who received treatments at the Seattle Cancer Care Alliance. Other inclusion criteria were age > 18 and receipt of ≥ 1 antineoplastic agent within 180 days from diagnosis. We abstracted patient clinical characteristics, tumor histology, EGFR and ALK mutation status, receipt of chemotherapy, targeted therapies, and immunotherapy up to 5 consecutive lines, participation in ADTs, and OS from diagnosis to death. We fitted multivariate Cox regression models to estimate the risk-adjusted effect of ADT participation on survival, compared with no trial participation.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients’ mean age was 63.4; 53.9% were female; 28.5% were never smokers; 75.1% had ECOG PS of 0-1; 95.3% had non-squamous histology; 27.5% had brain metastases; 20.7% and 4.1% had EGFR+ and ALK+ NSCLC. Fifty-three (27.5%) enrolled in ≥ 1 ADT, of whom 17 (32.0%) received trial drug(s) that later became FDA approved, and 44 (83.0%) and 13 (24.5%) enrolled in phases I/II or III trials. Adjusting for ECOG PS, smoking, EGFR mutation status, type of first line therapy, and number of treatment lines, participation in ≥ 1 ADT was associated with a hazard ratio for death of 0.62 (P = 0.02; Table 1).

      Trial Participation ( ≥ 1) Median OS (months)

      Adjusted Hazard Ratio

      (95% CI)

      P-value
      No ( n=140) 12.4 reference
      Yes (n=53) 19.7 0.62 (0.42; 0.94) 0.020

      8eea62084ca7e541d918e823422bd82e Conclusion

      Participation in therapeutic trials is associated with longer OS in NSCLC. Besides supporting drug development, trial enrollment may improve patient outcomes. Efforts should focus on increasing patient enrollment in drug trials.

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      P3.15-13 - Surgical Management of Huge Pulmonary Arteriovenous Malformations: Our Experience

      12:00 - 13:30  |  Presenting Author(s): Fadil Gradica  |  Author(s): Lutfi Lisha, Dhimitraq Argjiri, Alma Cani, Fahri Kokici, Valbona Rexha, Flora Lala Gradica, Safet Beqiri, Shqiptar Demaci, Saud Maliqi

      • Abstract

      Background

      Pulmonary arteriovenous malformations are rare lesions with significant clinical complications. These lesions are commonly seen in patients with hereditary hemorrhagic telangiectasia (formerly Osler-Weber-Rendu syndrome). Formerly called Osler-Weber-Rendu, HHT is an inherited disorder of the vasculature associated with AVMs and telangiectasias. The prevalence of HHT is 1 in 5,000 to 10,000 patients.) are present, the diagnosis is definite. If two criteria are present, the diagnosis of HHT is probable. If less than two criteria are present, the diagnosis is unlikely.Management of arteriovenous malformations (AVMs) remains challenging because of their unpredictable behavior and with high risk mortality. A multidisciplinary approach based on a new classification scheme and improved diagnostic techniques may improve their management.

      Objectives:The purpose of this study was to review our surgical experience with surgical to manage arteriovenous malformations (AVMs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We diagnosed a 1 patient A. female birthday 02.09.1990 with pulmonary arteriovenous malformacion (PAVMs) .She has been admitted to the thoracic surgery clininic in QKUK Pristine in July 2015 with massive hemoptisis. Unknwn initially diagnose .She was presented to QKUK hospital urgently with such clinical signs, epistaxis ,cough, hemopstisi, weakness, sweat, fever, dyspnoea, thoracic malaiseand ,massive right hemothorax with clinical signs of hemorrhagic shock with massive hemoptisi, tachycardia, weak pulse, hypotension, severe anemia et hypovolemiv shock .She was treated with right pleural drainage (avarage 2000ml)and intensive therapy et hemotransfusion (8 flacons).She was treated initially with intensive therapy and hemotransfuzion and after that with hemodynamic parameters stable were treated with surgery.Pacient were completed with all the necessary of emergency examinations as thoracic radiography, biochemical examinations, CT scaner toracal, MRI ,Bronchoscopy, EKG ,cardiac echo and cateterisation ,gaseous exchange . The patient continued with the above-mentioned concerns with dyspnoea epistaxis from time to time. Cyanosis of the lips, fingers in the hands of drumsticks, petekie and ecimosis in the skin and mucous membranes, sleep disorders. After 1.5 years it is re-examined in the cardiology clinic "Nene Hospital Theresa "and is diagnosed with giant dexter pulmonary arteriovenous fistule by Pulmonary angiography..She was treated by surgical approach in 10.06.2016 .Right posterolateral thoracotomy ,segmentectomy IV-r and fistul artereovenosectomy ,pleural deainage.

      4c3880bb027f159e801041b1021e88e8 Result

      Arteriovenous malformation size ranged. to 10x 8 cm located in the right lung middle lobe.She was treated by anatomical 4-th segmentectomy. Operator and post operative period is good. Clinical and imaging image of ultimate control is smooth.No mortality ,no major complication.Hospital days stay was 5 days.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Diagnosis and management of AVMs by surgical therapy resection was with very good results and with limited morbidity and low mortality and no recurrence during early follow-up.

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      P3.15-14 - Using Creative Co-Production to Develop a Treatment Decision Support Tool for People with Malignant Pleural Effusion

      12:00 - 13:30  |  Presenting Author(s): Angela Mary Tod  |  Author(s): Cheryl Grindell, Remi Bec, Rahul Bhatnagar, Parthipan Sivakumar, Matthew Evison, Anna Morley, Maryam Ahmed, Liju Ahmed, Daniel Wolstenholme

      • Abstract

      Background

      Malignant pleural effusion (MPE) is a common, serious problem predominantly seen in metastatic lung and breast cancer and malignant pleural mesothelioma (MPM). Recurrence of MPE is common, and symptoms significantly impact on people’s daily lives.

      No ideal treatment strategy for MPE currently exists. However, there are four main treatment options aimed at relieving symptoms and improving quality of life. These include aspiration, thoracoscopy with pleurodesis, bedside pleurodesis and indwelling pleural catheter Choosing which option is best depends on many factors and making decisions can be challenging in pressured clinical environments. This project aimed to develop a support tool to help this decision making process for people with MPE.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pleural teams from three sites in the UK undertook a creative co-production (CC-P) approach led by the translating knowledge into action (TK2A) team of the NIHR Research Collaboration and Leadership in Applied Health Research and Care Yorkshire and Humber.

      The geographical distance between the three sites and the ill-health of service users meant a novel distributed model of CC-P was used. This comprised of three locally run workshops with clinicians, patients and carers that were designed and structured by the TK2A CC-P experts. This was followed by a joint national workshop with representatives from all stakeholder groups to consider findings and outputs from local meetings.

      The design team worked with participants to develop outputs including patient timelines and personas. These were used as the basis to develop and test visible and tangible prototype ideas.

      4c3880bb027f159e801041b1021e88e8 Result

      Some key messages emerged that informed prototype development. Understanding and managing their pleural effusion was the priority for patients, not their overall cancer journey. Preferred methods for receiving information were varied but visual and graphic approaches were favoured. The main influences on people’s decisions about their MPE treatment were personal aspects of their lives (e.g. how active they are, what support they have at home).

      The design team developed a first prototype (i.e. a video representing a web-based support tool) to help people identify personal priorities and guide shared treatment decisions. This requires further development before implementation into practice.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The creative design methods and distributed model of co-production used in this project overcame many of the barriers to traditional co-production methods such as power, language and time. They allowed specialist pleural teams and service users to work together to create a patient-facing decision support tool owned by those who will use it.

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      P3.15-15 - ALI Could Be a One of Prognostic Survival Factor for Non-Small Cell Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Yoichiro Hamamoto

      • Abstract

      Background

      Patients with terminal non-small cell lung cancer become greatly concerned about where they will die. And the Advanced Lung Cancer Inflammation Index (ALI, body mass index × albumin/neutrophil-to-lymphocyte ratio) has been demonstrated to be a prognostic factor of survival in some solid cancers. We examined the survival times of such patients according to their place of death; i.e., whether they died at home, at a hospice, or at hospital and analysis with ALI.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort study of patients who were followed from their first chemotherapy session for non-small cell lung cancer until death was performed. Specifically, the study compared four groups, those that died at home, at a hospice, at hospital or alive. The study was based on mortality data from the single institute National Hospital in Japan, for the period between April 2010 and December 2015.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 313 patients recruited, 214 were analyzed in this study: 90, 49, and 75 received hospital-based, home-based, and hospice-based palliative care, respectively. The patients who died at a hospice exhibited significantly longer survival than those that died at hospital (estimated median survival time, 420 days [95% confidence interval (CI), 325-612 days] vs. 252 days [95% CI, 201-316 days]; P<0.0001), and the patients that died at home also demonstrated significantly longer survival than those that died at hospital (estimated median survival time, 420 days [95% CI, 325-612 days] vs. 341 days [95% CI, 293-460 days]; P<0.0001). No significant difference in survival was detected between the patients that died at home and those that died at a hospice.

      At the time of data cut-off, ALI before chemotherapy in 4 groups was evaluated. There was no significant difference in BMI and NLR. However, ALI assessment showed that ALI had a higher value in the surviving patient group with a statistically significant difference from the group who died in the hospital.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients who died at a hospice or home exhibited significantly longer survival than those that died at hospital. Social background and spiritual factors are also taken into consideration, but ALI before treatment also considered factors that contribute to prognosis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-16 - Management of Patients with ALK-Translocated NSCLC: A Simulation-Based Assessment of Medical Oncologists’ Practice Decisions

      12:00 - 13:30  |  Presenting Author(s): Emily Van Laar  |  Author(s): Tara Herrmann, Martin Warters, Cayla Cason

      • Abstract

      Background

      The past several years have witnessed unparalleled changes in treatment for patients with ALK-translocated NSCLC. The objective of this study was to evaluate oncologists’ competence regarding the use of ALK tyrosine kinase inhibitors in the management of NSCLC and the impact of virtual patient simulation on narrowing gaps in clinical practices.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A CME certified virtual patient simulation (VPS) was made available via a website dedicated to continuous professional development. The VPS consisted of 2 cases presented in a platform that allows oncologists to assess the patients and make diagnostic and therapeutic decisions supported by an extensive database of diagnostic and treatment possibilities matching the scope and depth of actual practice. Clinical decisions were analyzed using a sophisticated decision engine, and instantaneous clinical guidance (CG) employing up-to-date evidence-base and faculty recommendations was provided after each decision. Oncologists were able to revise each decision post-CG, if desired. Rationales for clinical decisions were also collected in real time. Data were collected between 08/01/2017 and 10/31/2017.

      4c3880bb027f159e801041b1021e88e8 Result

      At the time of assessment, 178 oncologists had fulfilled the participation criteria for completing the simulation. Assessment of their practice choices revealed:

      · In a patient with newly diagnosed NSCLC, up to 30% of oncologists did not order testing for a tumor’s ALK translocation status. Moreover, only 37% ordered the appropriate therapeutic regimen. CG led to a 9% improvement in testing and 20% increase in evidence-based treatment (P<.001) Crizotinib remained the initial systemic treatment of choice despite data from the ALEX trial.

      · In a patient whose disease has progressed on crizotinib with significant disease burden, 24% of oncologists would not discontinue therapy. CG resulted in a 23% improvement in evidence-based treatment decisions (P=0.003). The primary rationales for the selected treatment differed based on the chosen regimen, disease control (26%) for continued treatment with crizotinib, better efficacy profile for the patient (24%) with use of ceritinib, andrecommended by guidelines (25%) for alectinib.

      · A majority of oncologists initially ordered side effect counseling in each case. CG resulted in a 18% (P=0.014) increase in the case for progression on crizotinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study, using an immersive VPS, provided insights into oncologists’ real world practices, and the rationales behind them, in an evolving treatment landscape and uncovered a lack of clarity about identification of the most appropriate regimen for patients with ALK-translocated NSCLC. Our findings demonstrate a continued need to educate oncologists about how to select and prescribe treatment for these patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-17 - Lung Cancer Symptom Burden and Quality of Life: Findings from the Cancer Experience Registry

      12:00 - 13:30  |  Presenting Author(s): Julie S Olson  |  Author(s): Alexandra Katherine Zaleta, Melissa F Miller, Shauna McManus, Linda House, Joanne S Buzaglo

      • Abstract

      Background

      Given earlier diagnosis and personalized treatment, lung cancer (LC) survival rates are increasing. LC can be associated with significant emotional distress, which affects health-seeking behaviors and health care utilization. This study examines LC patients’ quality of life compared to other US population groups and cancer-related correlates of depression and anxiety.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      149 individuals with LC enrolled in the Cancer Support Community’s online Cancer Experience Registry and completed surveys including the Patient-Reported Outcomes Measurement Information System (PROMIS-29v2.0). Using multiple regression analysis, we identify predictors of PROMIS T-scores for depression and anxiety. Independent variables included sociodemographic factors (age, gender, education, race), clinical history (time since diagnosis, relapse, LC type, line of therapy, currently receiving treatment, type of therapies received), and symptom burden (number of comorbidities, physical functioning, fatigue, pain interference). Variables significant in bivariate analysis (p<.05) were included in multivariate models.

      4c3880bb027f159e801041b1021e88e8 Result

      The sample was 66% female, 86% White; mean age 62 years (SD=9), mean time since diagnosis 3 years (SD=5). 14% had SCLC, 86% NSCLC. 76% received chemotherapy, 20% immunotherapy; 53% reported current treatment. 23% experienced a relapse, and 42% were ever metastatic.

      PROMIS scores for LC patients were worse than national averages (95% CI) for anxiety (54.2-57.6), fatigue (55.4-58.8), sleep disturbance (51.6-54.6), physical functioning (39.3-41.9), and social functioning (43.1-46.2). Moreover, LC patients reported worse quality of life (>1SD) than the national average for physical functioning (54% of respondents), fatigue (38%), social functioning (34%), anxiety (36%), pain interference (29%), depression (26%), and sleep disturbance (20%).

      Eight predictors explained 51% of the variance in anxiety (R2=.51, F(8,121)=15.64 p<.001); and, greater anxiety was associated with female gender (semipartial r=.18, p<.01), lesser time since diagnosis (semipartial r=-.19, p<.01), worse self-reported health (semipartial r=-.17, p<.01), greater fatigue (semipartial r=.22, p<.01), and greater pain interference (semipartial r=.24, p<.001).

      Nine predictors explained 51% of the variance in depression (R2 = .51, F(9,119)=13.74, p<.001); and, greater depression was associated with female gender (semipartial r=.17, p<.05), not being treated with immunotherapy (semipartial r=-.18, p<.01), poorer self-reported health (semipartial r=-.14, p<.05), greater fatigue (semipartial r=.25, p<.001) and greater pain interference (semipartial r=.23, p<.01).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Substantial proportions of LC survivors experience worse health-related quality of life compared to the general U.S. population. Symptom burden, especially fatigue and pain interference, was associated with anxiety and depression. These results suggest the need for more comprehensive symptom management efforts throughout survivorship care, including increased access to palliative and supportive care services.

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      P3.15-18 - Comparison of Pain Control Effects and Side Effects Early After VATs Lobectomy Between IV-PCA, Epidural-PCA and On-Q

      12:00 - 13:30  |  Presenting Author(s): Joonho Jung  |  Author(s): Seokjin Haam, Jiye Park

      • Abstract

      Background

      Video-Assisted-Thoracic Surgery (VATS) is widely used as a standard surgical treatment in non-small cell lung cancer (NSCLC), the postoperative pain is reduced rather than before, but postoperative pain management is still important because the pain is a problem in itself and can cause other respiratory complications. So we compared the pain control effects and side effects of intravenous (IV) patient-controlled analgesia (PCA), epidural PCA, and continuous local anesthesia infusion (On-Q), the most commonly used pain management modalities after VATs lobectomy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Total 94 patients who underwent VATs lobectomy in this center with NSCLC from January 2014 to August 2015 were analyzed. Of these 94 patients, 28 had epidural PCA, 36 had IV-PCA, and 30 had On-Q for postoperative pain management. The degree of pain was assessed by NPIS (numeric pain intensity scale), and we analyze NPIS from immediate postoperative period to 48 hours after operation by postoperative day. The incidence of side effects associated with pain control devices and early discontinuation due to side effects were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      The mean value of NPIS on the day of surgery was 6.04 ± 2.56 in the epidural PCA group, 4.75 ± 2.35 in the IV-PCA group, and 5.27 ± 1.87 in the On-Q group and there was no statistically significant difference. NPIS values were decreased in all three groups until 48 hours postoperatively, but there was no significant difference between groups. The incidence of side effects related to pain control devices up to 48 hours after operation was the highest in the IV-PCA group (36.1%, 13/36), in the epidural PCA group (35.7%, 10/28) and in the On-Q group (10.0%, 3/30) and there was statistically significance (p=0.032). The rate of early discontinuation of the pain control device due to side effects was 33.3% (12/36) in the IV-PCA group, 25.0% (7/28) in the epidural PCA group, and 6.7% (2/30) in the On-Q group (p = 0.032).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The effects of pain control after VATs lobectomy in NSCLC patients were not significantly different in epidural-PCA, IV-PCA, and On-Q but On-Q was superior in terms of side effects and early discontinuation of pain control device. Continuous extrapleural infusion of local anesthetic via On-Q has less systemic side effects and higher procedural stability than PCA. Therefore, On-Q may be sufficient to replace PCA in pain control after VATs lobectomy in NSCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-19 - Risk Factors for Osteoporosis in Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Kyung Ho Kang  |  Author(s): Juwhan Choi, Jee Youn Oh, Young Seok Lee, Kyung Hoon Min, Gyu Young Hur, Sung Yong Lee, Jae Jeong Shim

      • Abstract

      Background

      Bone related disease is increasingly a problem as lung cancer patients are usually older and the survival rate is increasing. Also cancer patients with multiple chronic comorbidities are at risk of osteoporosis (T-score of ≤ -2.5). The purpose of the study is to investigated the risk factors that attribute to osteoporosis of patients with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively investigated the incidence of osteoporosis of lung cancer patients from March, 2017 to April 2018. A total of 124 patients who were diagnosed with lung cancer at one tertiary academic hospital underwent bone mineral density test.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 124 patients, 40 (32.3%) showed osteoporosis. Alcohol history, smoking history, lung cancer histology, lung cancer stage, bone metastasis, and comorbidity (hypertension, diabetes, coronary artery disease, cerebrovascular accident, and chronic obstructive pulmonary disease) did not differ significantly among the osteoporosis and normal group . In univariate analysis, age (P = 0.025), BMI (P = 0.028), and female (P < 0.001) were statistically significant. In multivariate logistic regression analysis, age (OR: 1.070, 95% CI:1.016-1.126, p = 0.01), BMI (OR: 0.840, 95% CI:0.738-0.956, p = 0.008), and female (OR: 0.142, 95% CI:0.055-0.366, p < 0.001) were also statistically significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      One-third of lung cancer patients were diagnosed with osteoporosis at a high rate. Old age, low BMI and female sex were the risk factors affecting osteoporosis of lung cancer patients. Physicians should be aware to of screening bone marrow density of lung cancer patients with old age, low BMI and female group. Studies on the effect of calcium supply and bisphosphonate treatment on bone metastasis and fracture in these osteoporosis patients are underway.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-20 - Palliative Sedation in Lung Cancer Patients Whom Needs Immediate or Elective Intractable Symptom Control  

      12:00 - 13:30  |  Presenting Author(s): Fatih Kose  |  Author(s): Ali Ayberk Besen

      • Abstract

      Background

      Advanced cancer patients frequently experience high-distressing symptoms which could not be relieved with standard oncological treatment even can be refractory to intensive palliative care. For these cases, palliative sedation or decrease patient’s consciousness below certain level (ramsay score 4 or more) is well defined but not well standardized procedure for intractable symptoms of cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The patients included into this study in consecutive way without any exception from November 2014 to August 2017. There were 82 patients (90.0%) and 9 patients (10.0%) with NSCLC and SCLC, respectively. Palliative sedation protocol is consisted of midazolam /morphine (30 mg/24 hr). For the effectiveness of the palliative sedation, we accept taregt RSS score of 4 for the immediate and elective patients.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 62 and 29 patients electively or urgently sedated. Median age of patients in elective and immediate sedation were 61.5 and 63, respectively.

      Additionally, main etiologies for the refractory symptoms were dyspnea, delirium and intractable pain in 44 (71.0%) vs 3 (4.8%), 15 (24.2%) vs 16 (55.2%), and 6 (20.7%) vs 7 (24.1) patients for the elective and immediate sedation groups. There was no statistically significant difference between two groups with regard to sex, age and main reasons for the palliative sedation. Duration of palliative sedation were 0.59 days in immediate group whereas this time significantly longer in elective group with 4.7 days (p<0.01). Time between last chemotherapy and start of the palliative sedation were 82.3 vs 119.0 days in elective and immediate group, respectively. In elective sedation group, target score of R4 was achieved in 32 (51.6%) patients whereas in immediate sedation group score of R4 was significantly lower than elective group and achieved in only 3 (10.3%) patients, respectively (p<0.01). Dose of 30-30 mg/24-hour IV MaM infusion was perfectly enough for the immediate sedation group , 60-60 mg and 90-90 MaM infusions were required in 10 (16.1%) and 5 (8.1%) patients for target RS. Adverse events were seen in 18 (29%) and 7 (24.1%) patients in elective and immediate group, respectively. Hypotension was the most prominent adverse event in both groups.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Palliative sedation is effective way of controlling intractable symptoms. Most common reason for palliative sedation was progressive dyspnea in lung cancer for both groups. 30-30 mg/24-hour IV MaM starting dose well tolerated and highly effective dose, 15/15 mg dose increment can be done if needed.

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      P3.15-21 - Real-World Experience of First-Line Afatinib Treatment in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Chong-Kin Liam  |  Author(s): Gwo-Fuang Ho, Chee-Shee Chai, Adlinda Bt Alip, Yong-Kek Pang

      • Abstract

      Background

      Published reports of first-line afatinib treatment efficacy, side-effects and resistance mechanism in the real-world setting are lacking.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective observational study of patients with EGFR mutant advanced non-small cell lung cancer (NSCLC) receiving first-line afatinib in University Malaya Medical Center from 1st December 2014 to 30th April 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-two of 33 patients on first-line afatinib were eligible for analysis. The patients’ demographic and clinical characteristics are as shown in Table 1. The mPFS was 14.3 months, overall response rate was 86.3% (19/22) and disease control rate was 95.5% (21/22). The median time-to-treatment failure was 16.2 months. The median overall survival has not been reached but 12-month survival rate was 81.8% (18/22).

      A patient with exon 18 G719X and exon 20 S768I mutation had received treatment for 23.3 months without disease progression (PD). The PFS of a patient with exon 20 insertion was 9 months and of another patient with exon 18 G719X and exon 20 T790M mutations was 4.4 months. Of patients with brain metastases, the PFS of 2 patients treated with stereotactic radiosurgery (SRS) was 15.9 months and 9 months, respectively while that of a patient who had whole brain radiotherapy (WBRT) and a patient who underwent debulking surgery only was 16.5 months and 2.6 months, respectively.

      The incidence of side-effects was rash 90.1% (20/22), stomatitis 63.3% (14/22), paronychia 72.7% (16/22), and diarrhea 77.3% (17/22). One (4.5%) patient each had grade 3 diarrhea and cutaneous lesions. Of 17 patients with PD, 2 (11.8%) had PD in the brain. T790M mutation was detected in 62.2% (8/13) patients who underwent repeat biopsy.

      table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Afatinib is an effective treatment of EGFR-mutant advanced NSCLC. When combined with SRS or WBRT, afatinib conferred good PFS in patients with symptomatic brain metastases. Severe side effects are uncommon and T790M mutation was the commonest resistance mechanism.

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      P3.15-22 - Validation of Eurolung Risk Models in a Japanese Population: A Retrospective Single-Center Analysis of 612 Cases

      12:00 - 13:30  |  Presenting Author(s): Akihiro Nagoya  |  Author(s): Ryu Kanzaki, Naoko Ose, Takashi Kanou, Soichiro Funaki, Masato Minami, Yasushi Shintani, Meinoshin Okumura

      • Abstract

      Background

      The analysis of risk-adjusted outcome is beneficial for quality assessment in surgery as well as preoperative risk stratification. Eurolung risk models are recently reported, large population-based prediction tools of cardiopulmonary morbidity and mortality in patients who underwent anatomic lung resection. This study is aimed to evaluate validity of the models in a Japanese population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 2007 to 2014, 637 anatomic lung resections were performed in our institution. Patients who had induction therapy (n=23) and with missing data (n=2) were excluded from the analysis, and requisite variables (age, sex, body mass index, predicted postoperative forced expiratory volume in 1 s, coronary artery disease, cerebrovascular disease, chronic kidney disease, thoracotomy approach, extended resections, operation of pneumonectomy) were examined. Cardiopulmonary morbidity and 30-day mortality rates were estimated by Eurolung risk models according to the formula for computation (Brunelli A, et al. European risk models for morbidity (EuroLung1) and mortality (EuroLung2) to predict outcome following anatomic lung resections: an analysis from the European Society of Thoracic Surgeons database. Eur J Cardiothorac Surg, 2017; 51: 490-497). Aggregated Eurolung risk scores were also calculated, and patients with similar risk were classified into plural groups. These results were compared with observed outcomes. In addition, we analyzed long term outcomes of the groups using the Kaplan-Meier method.

      4c3880bb027f159e801041b1021e88e8 Result

      Surgical procedures included 9 pneumonectomies, 15 bilobectomies, 483 lobectomies, and 105 segmentectomies. Cardiopulmonary complications of any grade were occurred in 137 cases; this rate was lower than predicted by Eurolung1 (22.4% vs. 28.4%). Within 30 days after operation, 4 fatal cases were experienced, which was significantly lower than expected by Eurolung2 (0.7% vs. 6.9%). Morbidity rate was clearly stratified by Eurolung1 aggregate score as 0% (n=0, score 0-1), 14.7% (n=11, score 2-4), 18.6% (n=30, score 5-7), 21.3% (n=46, score 8-11), 34.5% (n=49, score 12-16), and 33.3% (n=1, score 17-19). Stratification of mortality rate by Eurolung2 aggregate score also developed apparent trend, although the observed number of death was quite small: 0% (score 0-3), 0% (score 4-6), 1.2% (score 7-8), 1.5% (score 9-11), 4.8% (score 12-14), and 0% (score 15-17). The Higher (8-19) Eurolung1 aggregate score group showed poor 5-year overall survival compared with the lower (0-7) score group (72.3% vs. 90.4%, P<0.01).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Eurolung risk models did not completely match with the morbidity and mortality in our institution. On the other hand, Eurolung1 aggregate score was useful to predict not only morbidity, but also long term outcomes.

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      P3.15-23 - Data Mining the Internet and Crowdsourcing in Guiding Patient Decision-Making.

      12:00 - 13:30  |  Presenting Author(s): Shaneel Pathak  |  Author(s): Christina Sit

      • Abstract

      Background

      The internet, through social media, blogs and forums, has enabled patients to share experiences and outcomes. Data mining and crowdsourcing is a methodological approach to gather the individual experiences within these platforms and convert them into Real World Evidence (RWE) that can help patients make decisions, especially in the case of new treatments or treatments in trial. This abstract is a case study of how this methodology was used to inform the decision between Whole Brain Radiation (WBR) vs. osimertinb in treating brain metastasis in EGFR+, t790M, NSCLC – at a time when the results to an open label trial were pending.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The methodology identified trusted sources and similar profiled patients. The steps:

      1. Identify reputable on-line sources by referrals.

      2. Crowdsource peers with same tumour group, staging, gene sequence and treatment path.

      3. Analyze results and patient feedback of treatments

      A search identified 46 lung cancer blogs and 4 cancer forums. Inspire.com was then chosen as the crowdsourcing target as it had over 39,000 lung cancer patients registered.

      4c3880bb027f159e801041b1021e88e8 Result

      The search found 470 posts on osimertinib in clinical trial; 66 discussions on brain lesions and osimertinib were accessible from the search. Conversations with patients of the same genetic profiles, metastasis and treatments were selected. The user profiles detailed clinical histories, which increased the trust factor of the data. Information was obtained from April to June 2016 with data points beginning in 2014.

      When reviewing the 66 self-reported cases, it was found that osimertinib was effective in patients with brain metastases in 36% of patients while 4% had no response. Quality of life and side effects were other fields that were explored. This evidence influenced the patient to choose osimertinib instead of WBR to treat her lung cancer.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The Internet offers opportunities to source evidence and help patients to make informed treatment decisions. There is a risk that misinformation may lead patients in the wrong direction, which will then be a burden on the practitioner and negatively influence treatment outcomes.

      Datamining and crowdsourcing is a methodological system that gathers individual self-reported results from the Internet and converts it into credible RWE. For this patient, it increased the trustworthiness of the information and helped decrease anxiety about the treatment decision. Used appropriately, it has the potential to inform treatment decisions, help predict outcomes, and be a tool for post marketing surveillance that can be used to inform health technology assessment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      Technologies for investigation, diagnosis, and treatment for lung cancer are advance to improve patients’ survival. Many investigations will be performed once the patients were suspected to have lung cancer. All processes sometime take a long time to complete investigations before starting the treatment which may affect treatment outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ramathibodi Lung Cancer Consortium (RLC) was established in October 2014, aims to help the patients accessing all investigations and treatments faster by multidisciplinary team (MDT) approach and patient-center with one-stop service system. We conduct RLC meeting every 1st and 3rd Tuesday of the month. As of May 2017, 200 new lung cancer patients were solved all problems by RLC team. We collected and analyzed the data of lung cancer patients between 2 groups. The first group was the patient whom underwent RLC model (160 cases) and the second group was control group which was the patient whom diagnosed before establishing RLC (72 cases). Our primary endpoint was time from first visit to first treatment. Secondary endpoints were time from first visit to first interventions, number visits from first visit to first treatment, and overall survival (OS). We also did subgroups analysis for time from first visit to first biopsy, to first imaging study, to surgery, to chemotherapy, and to radiation.

      4c3880bb027f159e801041b1021e88e8 Result

      Median time from first visit to first treatment was significantly decreased in RLC group (14 days) compared to 57 days in control group with HR of 2.86 (95% CI; 2.11-3.87, P<0.001). Median time from first visit to first intervention was also significantly decreased in RLC group (2 days) compared to 11 days in control group with HR of 2.01 (95% CI; 1.53-2.62, P<0.001). Median number of hospital visits was significantly lower in RLC group (1 visits) compared to control group (8 visits). All subgroup analyses showed significantly decreased duration of each investigation and each treatment in RLC group. In survival analysis, lung cancer patients whom underwent RLC model had significantly longer mOS compared to control group, especially in stage 3 and 4 disease [mOS = 2.4 vs 0.8 years, HR=0.42 (95% CI; 0.3-0.7, P<0.001)].

      8eea62084ca7e541d918e823422bd82e Conclusion

      RLC model is a very useful model helping lung cancer patients to access treatment and investigations in short period of time and translate to have significantly longer survival. RLC model also provides the cooperation in lung cancer research. This model should be applied for all cancers treatment. Working as MDT is the utmost importance for cancer treatment.

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      P3.15-26 - Safety of Nivolumab in Thoracic Malignancies: Results from a Single Institution in Bangladesh

      12:00 - 13:30  |  Presenting Author(s): Md Shuayb  |  Author(s): Arunangshu Das, Md. Salim Reza

      • Abstract

      Background

      Nivolumab, an anti-PD-1 monoclonal antibody (IgG4), has emerged as a promising drug in the era of immunotherapy of today. Recent trials have demonstrated encouraging activity with favorable safety profile of nivolumab in patients with treatment-refractory lung cancer as well as esophageal cancer. However, experience of using immunotherapy is still quite new in a developing country like Bangladesh owing to its excessive cost and unavailability.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 3 patients have been treated with nivolumab at a dose of 3mg/kg every 2 weeks to date at our centre. Evidence of PD-L1 expression was not present in either of the patients. All were within the ECOG performance status ≤2, and none of them were on systemic corticosteroids or immunosuppressive therapy. First case: a 48-year old male, adenocarcinoma lung with brain metastases, TTF-1 positive and EGFR negative, was treated initially with craniotomy followed by whole brain irradiation. 4 cycles of pemetrexed/carboplatin followed by 6 cycles of maintenance pemetrexed were given but the disease progressed. Then he completed 4 cycles of docetaxel which again resulted with progressive disease (PD). Now he is on nivolumab, 6 cycles completed to date. Second case: A 62-year old female, adenocarcinoma lung with contralateral lung metastases, EGFR and ALK negative, was treated initially with concurrent chemoradiation with 3 cycles of pemetrexed/cisplatin. As the disease progressed, 4 cycles of docetaxel/carboplatin were given which again showed PD. Now he is on nivolumab, cycle-6 completed to date. Third case: A 75-year old male, squamous cell esophageal cancer at lower 3rd, was non-surgical and non-chemo candidate because of uncontrolled diabetes and significant cardiac comorbidity. Nivolumab was started, and received 2 cycles.

      4c3880bb027f159e801041b1021e88e8 Result

      In the first and second cases, ‘stable disease’ was achieved with no serious immune-mediated reactions over the period of nivolumab therapy. When evaluated with Common Terminology Criteria for Adverse Events (CTCAE version 4.03), only grade-1 elevated creatinine was seen in both patients. There was no reported toxicity of endocrinopathy, enterocolitis, intestinal perforation, hemorrhage, neuropathy, pneumonitis, hepatitis or dermatitis. In the third case, patient developed, 7 days after cycle-2, grade-3 diarrhea along with hematemesis and hematochezia. On arrival at our emergency department, he was found to be life-threatening grade-4 enterolcolitis and he died before undergoing any intervention.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab may delay disease progression with minimal toxicity but may sometimes be associated with severe immune-related events. Practice should be done with caution and prompt action is warranted once toxicity has developed in order to prevent fatality

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      P3.15-27 - Initial Response to First Line Treatment is the Best Predictor of the Patient Survival in Advanced NSCLC

      12:00 - 13:30  |  Presenting Author(s): Nazim Serdar Turhal  |  Author(s): Simge Orscelik, Gulsah Taktakoglu

      • Abstract

      Background

      Although most of the NSCLC patients are treated according to the standart guidelines, the patients who present in routine clinical practice usually have inferior performance status, in comparison to the patients registered in the clinical trials. Also in comparison, the frequency and thoroughness of the tests and procedures the clinical trial patients subjected are more intense as well. The oncologist practising in community needs simpler ways and means to assess patients' disease course to make timely and reliable judgement on their management.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We searched among 5130 patients treated in our clinic since 2006 to find 678 lung cancer patients of all stages and pathology. Of these, 171 advanced stage NSCLC patients that were treated primarily under our supervision are selected for the calculations. The other histologies and the patients seen once or twice for a second opinion are excluded. The common patients characteristics including age, gender, stage, date of diagnosis, the date of progression, the site and the number of metastasis etc. are all recorded.

      4c3880bb027f159e801041b1021e88e8 Result

      The median age of the patients were 62, 23% were female, the median overall survival was 18 months. The majority did not receive any targeted immunotherapy because either it did not exist back then or they had access problems in more recent times. We did then univariate/moltivariate analysis of survival according to the age, gender, site of metastasis, platin vs non-platin based treatment and response to first line of chemotherapy. Of these, only the response to first line of therapy appeared as a statitically significant variable, 23 vs 14 months with p=0.0001. In over 90% of the patients, the radiological findings were in line with clinical picture.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although more complex and costly measures exist to predict the overall survival of the NSCLC patients, in our experience the clinical responsiveness to first line of chemotherapy most precisely predicted the overall survival. This simple measure may help the healthcare profesionals to understand the disease course of the patients and manage their needs in more proper fashion.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-28 - Prognostic Nutritional Index for Predicting Postoperative Complications After Surgery Thoracic Tumor Involving the Neighboring Structures

      12:00 - 13:30  |  Presenting Author(s): Isamu Watanabe  |  Author(s): Aritoshi Hattori, Kazuya Takamochi, Shiaki Oh, Kenji Suzuki

      • Abstract

      Background

      The prognostic nutritional index (PNI), which is scored based on laboratory data of albumin and lymphocyte count, predicts postoperative complications in various types of malignancies. This study aimed to assess the risk factors of postoperative complications, especially the preoperative immune nutritional condition as estimated with the PNI, after surgical treatment of patients for thoracic tumor involving the neighboring structures.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From July 2008 to December 2015, 159 patients with resected thoracic tumor involving the neighboring structures were retrospectively analyzed and the relationship between the preoperative PNI and postoperative complications was evaluated. There were 119 men and 40 women with a median age of 61 years (range 21–88 years). Invading neighboring structures, including chest wall, superior sulcus, diaphragm, tracheal carina, left atrium, superior vena cava, aorta, and vertebrae were performed when possible in patients with locally advanced disease.

      4c3880bb027f159e801041b1021e88e8 Result

      Multivariate logistic regression analysis revealed that a preoperative PNI was a significant independent predictor of postoperative complications of Clavien-Dindo Grade ≥Ⅱ (odds ratio:3.87, p=0.0489). Using receiver-operating characteristics curve analysis predicting postoperative complications, we established cutoff values 46 (Area Under the Curve; 0.61) for the PNI. Patients were divided into two groups according to the preoperative PNI: high (≥46; n=95 (59.7%)), low (<46, n=64 (40.3%)). The incidence of postoperative complications of Grade ≥ Ⅱ and Grade ≥Ⅲ was higher in the low PNI groups than in the high PNI groups (p=0.019 and p=0.009, respectively). The incidence of pneumonia and the length of postoperative hospital stay were significantly higher in the low PNI groups than in the high PNI groups. However, the 30 day mortality (1.88%) and 90 day mortality (4.40%) were not correlation with PNI.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The preoperative PNI might be a useful marker to predict the risk of postoperative complications after surgery for thoracic tumor involving the neighboring structures. We have to intensive attention to the low PNI patients in the perioperative management.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-29 - Defining the Symptom Burden of Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Meagan Whisenant  |  Author(s): Loretta A Williams, Viralkumar Bharatbhai Vaghani, Qiuling Shi, Araceli Garcia Gonzalez, Shireen Haq, Charles Cleeland, Jianjun Zhang, John V Heymach, George R. Simon

      • Abstract

      Background

      Symptom burden is disease and treatment symptom severity and its impact on daily functioning. Symptom monitoring has demonstrated improved cancer patient outcomes, including quality of life, resource utilization, ability to continue treatment, and survival. The use of disease-specific patient-reported outcomes (PRO) measures facilitates individualized symptom monitoring and management. The purpose of this study was to describe symptom experience from the patient perspective and identify key symptoms for a PRO measure of non-small cell lung cancer (NSCLC) symptom burden.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with NSCLC described their symptom experience in single qualitative interviews. Content analysis was used to define the content for a PRO measure of NSCLC symptom burden.

      4c3880bb027f159e801041b1021e88e8 Result

      Mean age of the 40 patients interviewed was 66.1 years (standard deviation = 10.9); 60.0% were male, 77.5% were white, and 56.4% had stage IV disease. Content analysis found a total of 32 symptoms, 6 reported by ≥ 20% of participants (see Table 1). Symptoms varied based on treatment modality (chemotherapy versus radiation therapy), but not stage of disease. Numbness or tingling and sore mouth were described only by patients who had received chemotherapy. Patients volunteered ways in which symptoms impacted daily activities and relationships.

      Table 1. Patient quotes from qualitative interviews describing the 6 most common symptoms (reported by ≥ 20% of participants)
      Symptom Participant Quote
      Shortness of breath

      “The heaviness, it’s like a—wow, I don’t know how to explain it—like a rock and hard to breathe sometimes, just shortness of breath. Of course, the more I try to walk, or whatever, I’m more short of breath.”

      ‒ 67-year-old female
      Cough

      “I had a real bad cough. I think I actually even broke a couple of ribs coughing so much.”

      ‒ 52-year-old male

      Distress

      “Terrifying. There’s no ways about it. You know, it’s a terrifying experience, especially when it’s dropped in your lap and you have to deal with it. You go through a lot physically and mentally.”

      ‒ 67-year-old male
      Fatigue

      “I'm more tired. I take a lot of naps where I never had been a nap person. Before I had all my energy, and I was doing lots of things, and now I'm wore out. I wake up, and I'm wore out.”

      ‒ 53-year-old male
      Pain

      “You keep trying to move it to make it feel better and no matter where you put it, it doesn’t feel any better … most of the time it will bother me after I get out of bed in the morning for a while. And then if I go try to take a nap, I’ll go ahead and take something for pain because I can’t lay there and—I just keep moving it and moving it and nothing helps.”

      - 68-year-old male
      Constipation

      “I didn’t have a bowel movement. I had always taken the stool softeners because they told me to do that. And I kept thinking, “Well, it’s going to work. It’s going to work.” Finally, I was in so much pain that I couldn’t stand anymore, so I went to the hospital … and they ended up physically removing, which was horrible.”

      ‒ 68-year-old female

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients with NSCLC experience numerous symptoms related to disease and treatment. Shortness of breath, cough, distress, fatigue, pain, and constipation were commonly reported symptoms, suggesting that clinicians should routinely and proactively monitor the presence and severity of these symptoms in NSCLC clinical care. In patients receiving chemotherapy, attention to specific treatment-related symptoms, including symptoms of neuropathy and sore mouth, is needed. While stage of disease does not produce unique symptoms, the severity of the symptoms may possibly vary by stage of disease. Clinicians should also be aware that symptoms result in interference with daily activities, relationships, life plans, treatment adherence, and mood.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-30 - Treatment Patterns and Survival of Patients with Stage IV Non-Small Cell Lung Cancer (NSCLC) in the Era of Novel Therapies

      12:00 - 13:30  |  Presenting Author(s): Dimas Yusuf  |  Author(s): Manjusha Hurry, Ryan N. Walton, Winson Y Cheung

      • Abstract

      Background

      Treatment strategies for metastatic non-small cell lung cancer (NSCLC) are evolving rapidly. Real–world evidence (RWE) of treatment patterns and outcomes can further our understanding of the impact of novel therapies. In this population-based study, we investigated treatments and outcomes for stage IV NSCLC in a large Canadian province.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients diagnosed with de novostage IV NSCLC from April 1st2010 to March 31st2015 were identified. Baseline characteristics, treatments, and outcomes were analyzed. We classified treatments targeting EGFR, EML4–ALK, and ROS1 as targeted therapy and intravenous checkpoint inhibitors as immunotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 6,438 patients were identified with NSCLC, of whom 3,606 (56%) had de novostage IV disease. The median age of diagnosis was 69 years (range 20–100) and 52.4% were male. The median age among those who received targeted therapy and immunotherapy were 63 (27–90) and 61 (37–72) years, respectively, and 41.8% and 61.8% were male, respectively. First line treatments were: 5.7% targeted agents (n= 204), 1% immunotherapy (n = 1), 19.5% palliative chemotherapy (n= 703), 6.8% palliative radiotherapy (n= 246), and 74.8% received supportive care only (n= 2,698). Most frequent subsequent treatments in 2L included: 30.7% targeted agents (n= 125), 1.7% immunotherapies (n= 7), 67.6% palliative chemotherapy (n= 275), 32.2% palliative radiotherapy (n= 131). Median overall survival (mOS) for the whole cohort was 3.8 months (0–not reached [NR]). MOS with targeted therapies was 18 months (1.4–NR), chemotherapy was 9.4 months (1.1–NR) and supportive care only had a mOS of 2.5 months (0–NR) (Figure 1). About 1.0% of patients (n= 34) received immunotherapy at any line.

      wclc stage iv abstract figure 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Survival benefit was dependent on type of treatment received, with a trend towards improved survival with newer agents.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.15-31 - Better Clinical Outcomes and Resistance Mechanisms of Crizotinib in ALK-Positive Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yongchang Zhang  |  Author(s): Zeng Liang, Yizhi Li, Nong Yang

      • Abstract

      Background

      Advanced anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes and acquired resistance were unclear. This study was to show the clinical outcomes and resistance mechanisms of crizotinib in ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From Fab 2, 2013 to Mar 10, 2018, 2360 patients in Hunan Cancer Hospital were enrolled in this project. We identified 90 ALK-positive NSCLC patients which were detected by Ventana (Roche) and Nex-generation sequencing with known ALK variants were selected for target patients. ALK resistance mutations and clinical outcomes on Crizotinib were retrospectively evaluated according to ALK variant and detection methods. Subgroups of brain metastasis, multiple gene mutation, uncommon rearrangement and concomitant mutation and dual rearrangement were also been evaluated. Nomograms for predicting survival in ALK-Positive NSCLC was also been built.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Moderators:
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      P3.16-01 - A Multi-Omic Study Reveals BTG2 as a Reliable Prognostic Marker for Early-Stage Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): David C Christiani  |  Author(s): Li Su, Ruyang Zhang, Elizabeth Anne Loehrer, Michael Lanuti, Nancy Diao, Feng Chen

      • Abstract

      Background

      Background: B-cell translocation gene 2 (BTG2), which functions as a tumor suppress gene, has been reported to be involved in several cancers. However, no study has focused on its role in lung cancer progression or prognosis. We aimed to investigate the role of BTG2 in early-stage non-small cell lung cancer (NSCLC) survival

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients and Methods: This study included 1,230 early-stage (I, II) surgically treated NSCLC patients with methylation and expression data from five international cohorts. We built a prognostic model based on BTG2 methylation. Then, we explored BTG2 expression and NSCLC survival in 3,038 cases, including the above-mentioned cohorts as well as 17 extended public datasets by meta-analysis. Further, we integrated the clinical information, expression, and methylation to build an integration model and evaluated its prediction ability using C-index.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: Three risk CpG probes (cg01798157, cg06373167, cg23371584) were associated with overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51 to 2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 acted as a tumor-suppress gene in each cohort (HR range, 0.28 to 0.68). A meta-analysis showed high BTG2 expression was associated with better survival (HR = 0.61, 95%CI: 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Further, the integration model based on BTG2 methylation, expression and clinical information showed a better prediction ability in the training set and validation set.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions: The methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-02 - Phase III Study of Canakinumab (ACZ885) as Adjuvant Therapy in Patients with Surgically Resected NSCLC

      12:00 - 13:30  |  Presenting Author(s): Edward B Garon  |  Author(s): Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Shun Lu, Luis Paz-Ares, David R. Spigel, Michael Thomas, Pilar Cazorla Arratia, Jason Baum, Yvonne Y Lau, Cheng Zheng, James Chih-Hsin Yang

      • Abstract

      Background

      Preclinical and clinical data suggest that cytokines such as interleukin (IL)-1β can promote angiogenesis and tumor growth, and are essential to tumor invasiveness. Canakinumab (ACZ885) is a high-affinity human IgGκ anti-IL-1β monoclonal antibody approved for patients with various IL-1–driven auto-inflammatory diseases. In the Phase III Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) in patients with atherosclerosis, canakinumab was associated with a significant reduction in the incidence of fatal and non-fatal lung cancer in patients with increased high-sensitivity C-reactive protein levels. ACZ885T2301 (NCT03447769) is evaluating the efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This Phase III, randomized, double-blind, placebo-controlled study is enrolling patients (≥18 years, Eastern Cooperative Oncology Group Performance Status ≤1) with completely resected (R0) American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) v.8 stages II−IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg every 3 weeks [Q3W], subcutaneous [s.c.]) or placebo (Q3W, s.c.) on Day 1 of 21-day cycles for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Following baseline screening, imaging assessment will be performed every 12 weeks for the first year (treatment phase) following Cycle 1 Day 1, then every 26 weeks during Years 2 and 3, and annually during Years 4 and 5 (post-treatment surveillance phase). Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region.

      The primary objective is to compare disease-free survival (DFS) in the canakinumab versus placebo arms, as determined by local investigator assessment. Secondary objectives include a comparison of the two treatment groups with respect to overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Exploratory objectives include assessment of the relationship between pharmacokinetics, pharmacodynamics, safety, and efficacy, and evaluation of correlation between cytokines/soluble markers and efficacy endpoints. Enrollment is ongoing.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-03 - Uncommon EGFR Mutations as a Worse Prognostic Factor for Surgically Resected Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Kazuki Hayasaka  |  Author(s): Satoshi Shiono, Yuki Matsumura, Hiroyuki Suzuki, Naoki Yanagawa, Jiro Abe, Motoyasu Sagawa, Akira Sakurada, Masato Katahira, Satomi Takahashi, Makoto Endoh, Yoshinori Okada

      • Abstract

      Background

      The characteristics and prognosis of patients with lung adenocarcinoma harboring uncommon epidermal growth factor receptor (EGFR) mutations have not been clarified. Here, we examined whether the presence of uncommon EGFR mutations is a prognostic factor for patients treated surgically.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this multi-institutional retrospective cohort study, clinicopathological data were collected from 1,463 patients who underwent complete surgical resection for lung adenocarcinoma between 2005 and 2012 at five institutions and were examined for EGFR mutation status. Differences in postoperative overall survival (OS) and recurrence-free survival (RFS) according to EGFR mutation status were evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 1,031 eligible patients, 500 (48.5%), 497 (48.2%), and 34 (3.3%) had wild-type EGFR (WT), common EGFR mutations (CMs), and uncommon EGFR mutations (UCMs), respectively. In the UCM group, 19 patients had a single mutation, including exon 18 G719X (n = 7), exon 20 T790M (n = 6), or exon 21 L861Q (n = 5), and 15 patients had compound mutations. The clinicopathological characteristics were not significantly different between the CM and UCM groups. The 5-year OS rates in the WT, CM, and UCM groups were 76.3%, 88.6%, and 68.4%, respectively. OS was significantly shorter in the UCM than CM group (p = 0.011), although no significant difference was observed between the UCM and WT groups (p = 0.83). The 5-year RFS rates in the WT, CM, and UCM groups were 63.7%, 75.4%, and 58.1%, respectively. RFS was significantly shorter in the UCM than CM group (p = 0.006), although no significant difference was observed between the UCM and WT groups (p = 0.41). The use of EGFR–tyrosine kinase inhibitors after recurrence did not affect the prognosis with respect to EGFR mutation type. Among those with single mutations in the UCM group, patients harboring T790M were younger, more likely to be males and smokers, and more likely to have a larger tumor size, lymph node metastasis, pleural invasion, and lymphovascular invasion, compared with those harboring G719X or L861Q. T790M was also associated with shorter OS and RFS; the 3-year OS rates were 50.0%, 83.3%, and 100% and the 3-year RFS rates were 16.7%, 71.4%, and 80.0% for patients harboring T790M, G719X, and L861Q, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among patients with surgically resected lung adenocarcinoma, OS and RFS were significantly shorter in those with UCMs compared with CMs, implying that UCMs may be a worse prognostic factor.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-04 - Comparison of 2D and 3D Consolidation to Tumor Ratios to Predict Less Invasive Lung Adenocarcinoma

      12:00 - 13:30  |  Presenting Author(s): Toshihiro Ikeda  |  Author(s): Jun Nakano

      • Abstract

      Background

      Increases in lung cancer screening with computed tomography have led to more frequent detection of lesions like early stage lung adenocarcinomas. Patients with a ground-glass nodules(GGN) dominant small lesion have an excellent prognosis after complete resection. The consolidation to tumor diameter ratio(d-CTR) is a widely utilized 2D radiological parameter, and lesions with d-CTR<0.5 are candidates for segmentectomy instead of lobectomy. However, the radiological and pathological features of an adenocarcinoma can be contradictory. Some lesions diagnosed as a pure GGN may actually be invasive adenocarcinomas.

      The purpose of this study was to compare 2D and 3D parameters of lesions to identify less invasive pathological Stage I adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated 42 lesions from 41 patients who underwent curative resection for pathological Stage I adenocarcinoma from May 2016 to December 2017 at Sakaide citizen hospital. We defined Adenocarcinoma in situ and minimally invasive adenocarcinoma as less invasive histological subtypes. Besides, we defined lesions exhibiting lymphatic or vascular invasion as invasive lesions. The 2D parameter was the d-CTR. The 3D parameter was the volume ratio of the solid part to the whole tumor(v-CTR). We used a cut-off value of 0.5 for the 2D parameter, and then cubed that value to obtain a cut-off of 0.125 for the 3D parameter.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 29(69.1%) invasive histological subtypes lesions, 8(19.0%) lymphatic invasion lesions and 11(26.2%) vascular invasion lesions. There were 20(47.6%) lesions d-CTR<0.5, and 12(28.6%) lesions v-CTR<0.125. The 20 lesions with d-CTR<0.5, compared to the 22 with d-CTR>0.5, were significantly more likely to be less invasive histological subtypes(p<0.0001), exhibit no lymphatic invasion(p=0.0009), or exhibit no vascular invasion(p=0.0005). In multivariate analysis, having a d-CTR<0.5 was a significant predictive factor for less invasive lesions. Similarly, the 12 lesions with v-CTR<0.125, compared to the 30 with v-CTR>0.125, were more likely to be less invasive histological subtypes(p<0.0001), exhibit no lymphatic invasion(p<0.0001), or exhibit no vascular invasion(p=0.0014). However, the 8 lesions with v-CTR>0.125, despite having d-CTR<0.5, all had invasive histological subtypes(p=0.0009).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The values d-CTR<0.5 and v-CTR<0.125 could be predicted factor of less invasive lesions in early-stage lung adenocarcinomas. Furthermore, the study suggested that the 3D CTR parameter is more accurate than the 2D CTR parameter for making these predictions.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-05 - A Nanotechnology-Enabled Strategy for Image-Guided Transbronchial and Transpleural Photothermal Therapy of Peripheral Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Tomonari Kinoshita  |  Author(s): Hideki Ujiie, Juan Chen, Lili Ding, Harley Chan, Alexander Gregor, Nicholas Bernards, Patrick Z McVeigh, Kosuke Fujino, Chang Young Lee, Yamato Motooka, Terunaga Inage, Michael Valic, Robert Weersink, Brian C Wilson, Gang Zheng, Hisao Asamura, Kazuhiro Yasufuku

      • Abstract

      Background

      Surgical resection has been established as standard of care for early-stage peripheral non-small cell lung cancer (NSCLC). However, the development of non-surgical treatment and minimally invasive therapeutics is urgently needed due to the known morbidity of surgery, particularly in high-risk patients. We have previously demonstrated the potential of porphysome nanoparticle-enabled fluorescence-guided photothermal therapy (PTT) of peripheral lung cancer in preclinical animal models. In an effort to prepare this technology for clinical application, we developed a porphysome-specific fiberscope (scanning fiber endoscope [SFE]) and porphysome-specific thoracoscope (P-PINPOINT), both capable of operating in fluorescence mode, for image-guided transbronchial and transpleural PTT to treat endo-/peribronchial and subpleural tumors respectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In our study, we used three animal models: an in vivo human lung cancer xenograft (A549) in mice, another in vivo orthotopic VX2 tumor in rabbits, and an ex vivo pig lung into which A549 tumor tissue was transplanted. Forty-eight hours after intravenous injection of the porphysomes, the animals were used for imaging evaluation by SFE and P-PINPOINT, followed by photothermal ablation.

      4c3880bb027f159e801041b1021e88e8 Result

      The SFE, whose 1.2mm diameter is small enough to pass through the working channel of a conventional bronchoscope, could visualize porphysome-laden tumors located inside or close to the peripheral bronchial wall. The P-PINPOINT system had high sensitivity for porphysome fluorescence and enabled image-guided thoracoscopic resection of porphysome-accumulated tumors close to pleural. Porphysomes also enhanced the efficacy of SFE-guided transbronchial PTT and P-PINPOINT-guided transpleural PTT, resulting in selective and efficient tumor tissue ablation in the rabbit and pig models.

      wclc2018.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      These promising results suggest potential in the clinical translation of this novel platform to impact non-surgical and minimally invasive treatment options for early-stage peripheral lung cancer. This could offer new strategies for the treatment of non-small cell lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-06 - Does Comprehensive Mutation Analysis Add Prognostic Value in Resected Early Stage Lung Adenocarcinoma?

      12:00 - 13:30  |  Presenting Author(s): Peter J. Kneuertz  |  Author(s): David P Carbone, Lanni Luo, Desmond M. D'Souza, Susan D. Moffatt-Bruce, Robert E. Merritt

      • Abstract

      Background

      Recent efforts have been directed to enhance staging of non-small cell lung cancer by including common or targetable mutations. However, the predictive value of isolated mutations has been inconsistent between studies, possibly related to mutation interactions, confounding, and heterogeneous patient cohorts. We sought to determine the prognostic role of common mutations in resected early stage lung adenocarcinoma patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lung cancer mutation panel (PULMOL) using next generation sequencing was routinely obtained on tumors of 317 patients who underwent lobectomy and mediastinal lymphadenectomy for stage I-II adenocarcinoma from 2011-2017. Frequency of mutations was determined, and association with disease-free survival (DFS) and overall survival (OS) following complete resection was tested using Cox regression analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      At total of 248 (78%) patients had at least one mutation, 20% had two or more detected mutations. KRAS and EGFR genes were most frequently affected, in 39% and 24% of patients. EGFR mutations were almost exclusively seen in KRAS-negative patients, except for nine KRAS+/EGFR+ patients. TP53 mutation was the most common co-existing mutation in 59% of cases. Other frequent mutations were MET (6%), BRAF (5%), HRAS (4%), and ALK rearrangement (3%). KRAS mutation, and presence of two or more mutations were the only molecular predictors of decreased DFS and OS on univariate analysis (Figure). In a multivariate model, adjusting for pathologic stage, smoking status, histologic subtype, tumor factors and adjuvant therapy, KRAS and EGFR mutations were independently associated with decreased DFS (KRAS, HR 2.84 [95%CI:1.28-6.30]; EGFR, HR 3.24 [95%CI:1.40-7.48]) and OS (KRAS, HR 2.95 [95%CI:1.35-6.42]; EGFR, HR 2.87 [95%CI:1.25-6.61]).

      abstract figure.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Routine mutation analysis may yield important prognostic information in patients with completely resected early stage lung adenocarcinoma and may enhance staging when accounting for other known prognostic factors. KRAS mutation was the strongest predictor of worse survival. The prognostic value of EGFR should be further explored in KRAS-negative tumors.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-07 - The Impact of Clinical and Molecular Profile of Resected EGFR-Mutant Non-Small Cell Lung Cancer on the Risk of Developing Brain Metastases

      12:00 - 13:30  |  Presenting Author(s): Mor Moskovitz  |  Author(s): Michael Cabanero, Jonathon Torchia, Hadas Sorotsky, Jessica Weiss, Melania Pintilie, Natasha B Leighl, Penelope Bradbury, Geoffrey Liu, Gelareh Zadeh, Mark K. Doherty, Alborz Kia, Dax Torti, Ming Sound Tsao, Trevor J. Pugh, Frances A Shepherd

      • Abstract

      Background

      Brain metastases are common in non-small cell lung cancers (NSCLC) with activating EGFR mutations (EGFRm), occurring in 44%-63% of patients. To date, there are no known clinical or molecular factors to predict the risk of brain metastases in these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this retrospective single-institution study, we identified 106 patients with EGFRm NSCLC who underwent surgery for primary lung tumor. Clinical and demographic data was collected from electronic records. Whole Exome Sequencing (WES) of the primary tumor was performed utilizing the Agilent SureSelect Exome v6+COSMIC baits followed by sequencing on the Illumina HiSeq2500 platform. Development of brain metastases was correlated with clinical/pathologic features, EGFR mutation type, co-mutation of EGFR and other frequently mutated genes; and non-synonymous tumor mutation burden (TMB). Statistical analysis used Fisher exact test for categorical variables, Mann-Whitney test for continuous variables of association with the risk of developing brain metastases, and Gray’s test for the probability of brain metastases over time.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 106 patients who underwent surgical resection of primary EGFRm NSCLC, WES was successful for 73: 51 (70%) females, 52 (71%) never smokers, 38 (52%) stage I, 14 (19%) stage II and 21 (28%) stage III; 42 (57%) EGFR exon 19 mutation, 30 (41%) exon 21, 1(1%) Exon 20 insertion mutation.

      Twenty-five patients (34%) developed brain metastases. Patients with brain metastases were younger (median age 61 vs. 65 years, p=0.021), had more advanced stages (p=0.012), with a trend towards higher rates in females (p=0.066). One patient with brain metastases had de-novo EGFR T790M mutation in the primary tumor. No difference was seen regarding smoking history, EGFR mutation type, TP53 co-mutation, and median TMB. The 5-year probability of brain metastases increased with increasing stage (14% stage I; 43% stage II, [HR=3.00], 44% stage III, [HR=3.13], p=0.03), and a trend towards higher probability among females (33% vs. 19%; HR=0.39 for males, p=0.074), and younger patients (37% <65 years vs. 15% >65, HR=0.37 in older patients, p=0.042). There was no difference in probability of brain metastases based on smoking history, ethnicity, EGFR type (33% exon 19 vs. 22% exon 21, p=0.28), TP53 co-mutation (31% vs. 27% without TP53, p=0.59), or TMB (24% TMB≤2.87 vs. 32% TMB>2.87non-synonymous mutations/Mb, p>0.99).

      8eea62084ca7e541d918e823422bd82e Conclusion

      While our findings suggest that younger age, advanced stage, and female sex may be associated with the development of BM in EGFRm NSCLC, we could identify no molecular predictor of BM based on EGFR subtype, TP53 co-mutation or TMB.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-08 - Baseline Quality of Life is Influenced by the Duration of Abstinence from Smoking in Candidates to Lung Cancer Surgery

      12:00 - 13:30  |  Presenting Author(s): Cecilia Pompili  |  Author(s): Galina Velikova, Kevin Franks, Jonathan Robson, Sandra Dixon, Matthew Eric Callister, Alessandro Brunelli

      • Abstract

      Background

      The optimal interval of smoking cessation before Non-Small Cell Lung Cancer (NSCLC) surgery is still unknown. The objective of this study is to evaluate the influence of smoking cessation on the preoperative quality of life (QoL) of surgical NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      266 consecutive ever smokers (133 females) with a pack year history >=20 undergoing lung resections for NSCLC and with complete preoperative QoL data were analysed. The EORTC QoL summary score was calculated (SumS) as the average of the individual functional and reversed symptom scales (excluding Global-Health and Financial-Impact scales). The following smoking-related variables were tested for a possible association with SumS: age when the patient quit smoking and months elapsed from smoking cessation (for current smokers a value of 0 was used). These variables were entered as independent predictors in a stepwise multivariable regression analysis along with several patient-related baseline factors.

      4c3880bb027f159e801041b1021e88e8 Result

      108 patients were current smokers, 158 were ex smokers (quit at least 1month before surgery). We found no difference of preoperative QoL SumS between current smokers and ex smokers (81.5 vs. 83.0, p=0.66). Amongst the 158 ex-smokers, 69 quit smoking before the age of 60. Their SumS was similar to the one of those who quit older (84.2 vs. 82.0, p=0.30). A linear regression showed a significant association between the duration of abstinence from smoke and their QoL SumS (coefficient 0.02, SE 0.009, p=0.03). When the analysis was adjusted for other confounders using a multivariable regression analysis, the duration of abstinence from smoking (p<0.0001-longer time better QoL)(Fig1) and the age at which the patient quit smoking (p=0.001-older age better QoL)remained independently associated with SumS along with performance score.

      Figure 1: Lowess Curve plotting SumS against the months elapsed from the time quit smoking.

      fig 1.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients should be counselled to stop smoking prior surgery independently as the QoL has expected to increase.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-09 - High Preoperative D-Dimer Level Predicts Early Recurrence After Surgery for Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yuki Shiina  |  Author(s): Takahiro Nakajima, Taisuke Kaiho, Kota Ohashi, Yuki Sata, Atsushi Hata, Takahide Toyoda, Takahiro Yamamoto, Junichi Morimoto, Yuichi Sakairi, Hironobu Wada, Hidemi Suziki, Ichiro Yoshino

      • Abstract

      Background

      Carcinoma cells often affect the coagulation and fibrinolysis among cancer patients. Plasma dimerized plasmin fragment D (D-dimer) has been reported as the prognostic marker of various type of malignancies. For non-small cell lung cancer (NSCLC) patients, significance of D-dimer levels still remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two hundreds and thirty five patients with NSCLC who underwent radical surgery between April 2015 and March 2017 were retrospectively reviewed. We divided two groups including 1) high D-dimer (over 1.0ug/mL) group (hDD group, n=47), and 2) normal D-dimer group (nDD group, n=188). The clinical characteristics, tumor CT findings, pathological findings, and clinical outcomes were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      The mean D-dimer level was 2.49±2.58 among hDD group. The hDD group had the character of 1) male gender, 2) elder patients, 3) larger tumor size (p=0.0011), 4) pure solid appearance (p=0.0203). The hDD group showed worse overall survival (OS), disease free survival (DFS), and disease specific survival (DSS) than nDD group (Figure 1-A, B, C; log-rank test, p<0.0001, =0.0007, =0.0003, retrospectively) and these findings were also observed only for the p-Stage IA cases. Interestingly patients with grand glass attenuation-dominant nodule were not affected by D-dimer level with favor prognosis. Pathology showed more frequent vessel involvement (v+) in hDD group (p=0.033), but there was no significant difference for histology or histological subtypes of adenocarcinoma.os_dfs_dss2.png

      Figure1:

      Kaplan-Meier survival curves of postoperative overall survival (A), disease free survival (B), and disease specific survival (C) by preoperative D-dimer level.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The preoperative D-dimer level predicts the postoperative early recurrence and poor prognosis in the patients with NSCLC with pure solid appearance on chest CT.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-10 - Radiomic Features on CT are Prognostic of Recurrence as well as Predictive of Added Benefit of Adjuvant Chemotherapy in ES-NSCLC

      12:00 - 13:30  |  Presenting Author(s): Pranjal Vaidya  |  Author(s): Kaustav Bera, Pingfu Fu, Shridar Ganesan, Arjun Khunger, Pradnya Dinkar Patil, Vamsidhar Velcheti, Anant Madabhushi

      • Abstract

      Background

      Early-Stage non-small cell lung cancer (ES-NSCLC) accounts for approximately 40% of NSCLC cases, with 5-year survival rates varying between 31-49%. The decision to offer adjuvant chemotherapy for these patients is primarily dependent on several clinical and visual radiographic factors as there is a lack of biomarkers which can accurately stratify and predict disease risk

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective chart review between 2005-14 yielded 315 ES-NSCLC patients who underwent surgery with the primary tumor having relapsed in 75 cases. From the entire cohort, 74 underwent adjuvant chemotherapy. This cohort was randomly divided into a training(N=60) and validation(N=255). A total of 248 intratumoral(IT) and peritumoral(PT) radiomic textural features were extracted for every patient. The most stable, significant and uncorrelated features were selected from training cohort using LASSO Cox-regression model. Performance of imaging features was evaluated using hazard ratio(HR) and concordance index(CI). Linear Discriminant Classifier(LDA) was trained using top imaging features and performance of predicted labels was assessed using Kaplan-Meier survival curves and log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Top nine radiomic textural features (from the Haralick, Collage, Laws, Gabor texture families) included a combination of four IT and five PT from 0-12mm distance outside the nodule. The features were prognostic of recurrence (N=255, CI=0.66, HR =1.8, p<0.05). To evaluate the predictive model, subset analysis was performed on the test set. The imaging feature based classifier was able to identify low and high risk groups in the surgery alone setting (N=181, CI=0.73, HR=4.4, p<0.005), potentially identifying patients who might have benefitted from adjuvant chemotherapy. Meanwhile, in the group of patients who received adjuvant chemotherapy following surgery, the classifier did not identify any difference between high and low risk groups (N=74, CI=0.69, HR=1, p>0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified radiomic features from within and outside lung nodule that were prognostic of recurrence and also predictive of added benefit of adjuvant chemotherapy in ES-NSCLC.

      one.jpg

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-11 - Pattern of Recurrence of Completely Resected Lung Adenocarcinoma Varies According to EGFR Mutation Status

      12:00 - 13:30  |  Presenting Author(s): Katsuya Watanabe  |  Author(s): Kentaro Sakamaki, Hiroyuki Ito, Tomoyuki Yokose, Kozo Yamada, Haruhiko Nakayama, Munetaka Masuda

      • Abstract

      Background

      The prognostic significance of epidermal growth factor receptor (EGFR) mutations in resectable lung adenocarcinoma is not well defined. We evaluated the influence of EGFR mutation status on postoperative recurrence timing with the use of event dynamics.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 644 patients with lung adenocarcinoma who underwent complete resection and examined for EGFR mutation status between 2008 and 2015 were studied. Disease-free survival (DFS) were calculated using the Kaplan-Meier method and compared between EGFR mutation-positive patients (n=322) and EGFR wild-type patients (n=322). Event dynamics, based on the hazard rate, were evaluated and only first events (distant metastases or local recurrence) were considered.

      4c3880bb027f159e801041b1021e88e8 Result

      There was no statistical significance in recurrence rate (9.9% versus 14.6%; p=0.09) between EGFR mutation-positive patients and EGFR wild-type patients. In patients with pathological stage I, DFS was significantly better in the EGFR mutant group than the wild-type group (p=0.009), whereas the EGFR mutant group had an inferior DFS compared with the wild-type group among patients with pathological stage II or higher (p=0.110). The resulting hazard rate curves indicated that the recurrence risk pattern was definitely correlated with EGFR mutation status, with an early highest peak during the first year for EGFR wild-type patients and a late maximum peak in the fifth year for EGFR mutation-positive patients.

      fig.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      The prognostic value of EGFR mutations appears to be different according to pathological stage in completely resected adenocarcinoma. The hazard and the peak times of recurrence differ considerably between EGFR-mutant and wild-type patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-12 - Standard Conventional Lobectomy vs Stereotactic Body Radiotherapy in Patients with Early Stage Non-Small Cell Lung Cancer (NSCLC) – A Review 

      12:00 - 13:30  |  Presenting Author(s): Prakash Balakrishnan

      • Abstract

      Background

      Lobectomy is the standard of care surgical treatment for all operable NSCLC . In most patients who are not operable surgical candidates , lesser minimal invasive pulmonary resections or nonoperative options may be indicated , Stereotactic ablative radiotherapy (SABR) offers a promising alternative to these groups of unhealthy patients . In this review , we look into various published studies & articles in various databases , to evaluate the survival outcomes , cost-effectiveness , complications & evidence-based conceptualizations behind both treatment modalities in these studies via a summarized review .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A extensive literature search was performed using MEDLINE ,OVID & PUBMED search databases in the last 10 years . A retrospective review & meta- analysis of these papers were conducted using matched-pair analyses & propensity matched scoring & standard statistical analysis . A total of 21 papers were reviewed & a meta-analysis of these survival outcomes were compared between the standard conventional Lobectomy with the newer SABR treatment arm in early lung cancer patients .

      4c3880bb027f159e801041b1021e88e8 Result

      Pending - applying for late-breaking abstract

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pending -applying for late breaking abstract

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-14 - SBRT in Early Stages of Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Luis Fernández Fornos  |  Author(s): Sandra Miranda Labajos, Danilo Esposito, Pilar Dorado Rodriguez, Maria Dolores Ruiz Sánchez, Domingo Planes Meseguer, Almudena Pomares Arias, Enrique García Miragall

      • Abstract

      Background

      We present the experience in our department with SBRT in early stages of lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between April 2012 and January 2018, 59 patients with 65 different locations underwent to SBRT in early stages of lung cancer (51 men and 8 woman, with a median age of 76 years).

      44 patients had histological confirmation (22 adenocarcinomas, 13 squamous cell carcinomas, 1 adenosquamous and 1 typical carcinoid).

      There was not histological confirmation in 15 patients. In all patients, PET-CT was used for the diagnosis.

      The T-stage classification (8th Edition of the TNM Classification), was the following: T1a (6), T1b (24), T1c (16), T2a (10), T2b (6), T3 (3).

      The treatment planning was made using vacuum body fixation and abdominal compression to reduce intrafractional organ motion. We made five CTs planning in all patients: 3 free breathing, inhalation and exhalation. The internal target volume (ITV) was delineated based on the fusion of five CTs. The planning target volume (PTV) was determined an adding additional setup margin to ITV.

      We made different fraction schemes, and the most used were 5x1200 cGy and 8x750 cGy.

      4c3880bb027f159e801041b1021e88e8 Result

      The assessment of response was performed with CT and/or PET-CT. With a median follow up of 24 months, the local control was 88%, with an overall survival of 76%.

      The tolerance to treatment was excellent, appearing as acute toxicity, rib pain (G1-G2) in 4 patients, asthenia (G1) in 3 patients, and as chronic toxicity, costal fracture in one patient.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The local control obtained in early stages of lung cancer treated with SBRT in our series is high, with an excellent clinical tolerance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-15 - Kinetic Energy Distribution for Gated Technique at Lung Ablative Body Radiotherapy (SABR)

      12:00 - 13:30  |  Presenting Author(s): Kaile Li

      • Abstract

      Background

      Gated technique could be applied for lowering the dose spillage of motion target stereotactic body radiotherapy. There are three clinical steps in gated therapy. The first is the target delineation with 4DCT, the second is the localization for region of interested based on selected gated window and CBCT images, and the third is the gated delivery. At current clinical scale, radiation and target formed six combinations, which were determined by motion and static state of both radiation and target at the condition of with and without gated approach. In this study, the kinetic energy distribution for phased targets were evaluated based on gated radiotherapy procedure.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Patient with tumor adjoined to the heart was selected to simulate a gated lung SBRT case with 9 co-plane beams. The prescription was 50Gy in 5 fractions. The internal target volume (ITV) based on window size was selected to be 20% to 60% of breathing cycle phase. And this fixed radiation beam aperture was determined by the sum of target from phases at 20%, 30%, 40%, 50% and 60%. The dosimetric characteristics of these individual targets, their sum, and overlap region were described with coverage level, conformity index, homogeneity index, and kinetic energy distribution was defined to be the product of mean dose and prescribed target volumes (PTVs) at different phase window sizes. The ranges of these energy distributions were compared with static target with static radiation beam.

      4c3880bb027f159e801041b1021e88e8 Result

      For image sets at phase 20%, 30%, 40%, 50%, 60%, sum of these phase and overlap region, the ITVs were 12.8cc, 14.2cc, 14.4cc, 16.2cc, 13.7cc, 25cc and 6.5cc; their corresponding prescription dose coverage were 96.6%, 98.2%, 96.1%, 96.3%, 97.9%, 95% and 99.3%; their corresponding conformity indexes were 1.88, 1.55, 1.67, 1.56, 1.73, 1.11, and 2.94; their homogeneity indices were equal to 1.64; and the integral energy were 4.69KGycc, 5.69KGycc, 5.31KGycc, 5.59KGycc, 4.97KGycc, 7.77KGycc and 3.04KGycc.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this static beam with motion target simulation, the overlap region received about 1.9 times of kinetic energy density to that of single phase target. The spillage level to adjoined critical structure could be lower with smaller gated window. The relationship between kinetic energy distribution and clinical dosimetry sufficiency could be further investigated in different physical scale levels.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-16 - Long Term Outcomes of Body Gamma-Ray Stereotactic Ablative Radiotherapy for Patients with Stage I/II Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Hongqi Li  |  Author(s): Yingjie Wang, Xuan Wang, Haifeng Pang, Xiangsheng Xu, Jing Li, Tingyi Xia

      • Abstract

      Background

      The authors evaluated the efficacy, patterns of failure, toxicity and cost of body gamma-ray stereotactic ablative radiotherapy (Body Gamma-ray SABR) for patients with medically inoperable, clinical stage I/II non-small cell lung cancer (NSCLC) with 8 years of follow-up. Clinical staging was performed according to the sixth edition of the American Joint Committee on Cancer TNM staging system.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients who had no previous treatments, with histologically confirmed NSCLC, determined as clinical stage I /II, underwent OUR-QGD type of the body gamma-ray SABR (70 grays in 10 fractions for gross target volume) at the Radiation Oncology Department, People's Liberation Army Airforce General Hospital, Beijing, China from January 2007 to July 2010. All patients were immobilized by vacuum bag, and then a slow CT scan was performed without any respiration gating. The total radiation dose of 50%, 60%, and 70% isodose line were prescribed in 50, 60, and 70 Grey (Gy) correspondingly, covering 100% of the planning target volume (PTV), 90% of the clinical target volume (CTV), and 80% of the gross target volume (GTV) in 10 fractions. The CT scan and/or positron emission tomography/computed tomography were every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually thereafter to evaluate the efficacy of the treatment. The primary endpoint was overall survival.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 29 patients were eligible for analysis. The median age of the patients was 71 years (55-87), and the median follow-up was 8.1 years (6.8-10.3). The 1-year, 3-year, 5-year and 8-year overall survival rates were 93.1%, 72.1%, 59.4% and 44.8%, and the local, regional and distant disease recurrence were 10.3%, 13.8% and 13.8% at 5 years and 10.3%, 17.2% and 20.7% at 8 years. Two patients (6.9%) experienced grade 3 treatment-related adverse events. No patients developed grade 4 or 5 adverse events. The median cost of body gamma-ray SABR is 4838 dollars (4615-4923 dollars).

      8eea62084ca7e541d918e823422bd82e Conclusion

      With long-term follow-up, the results of the current study demonstrated outstanding local control and low toxicity after body gamma-ray SABR in patients with clinical stage I/II NSCLC. The dominant failure included regional and distant disease recurrence. And the body Gamma-ray SABR is pretty cost-effective.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-17 - Cardiac Sparing in Stereotactic Body Radiotherapy of Early Stage NSCLC Patients

      12:00 - 13:30  |  Presenting Author(s): Barbara Stam, Jose Belderbos  |  Author(s): Angela Tijhuis, Maddalena Rossi, Jan-Jakob Sonke

      • Abstract

      Background

      In NSCLC patients who receive radiotherapy, cardiac toxicity was not well established as a possible factor until the results of the RTOG 0617 showed associations between cardiac dose and survival. These associations have been confirmed both in early and in locally advanced stage NSCLC patients. Cardiac sparing is not yet systematically pursued, and there is currently no agreement on cardiac constraints to be used. We investigated the feasibility of cardiac sparing in early stage NSCLC patients who receive SBRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ten patients with early stage NSCLC in a middle or lower lobe, treated to 3x18 Gy between 2015 and 2017 using a dual arc VMAT technique were randomly selected. Retrospectively, clinical plans were adapted to minimize the maximum heart dose, while clinical constraints were respected. Mean Lung Dose (MLD) and cardiac doses Dmax, Dmean and V5Gy were compared between clinical and cardiac spared plans using a paired t-test.

      4c3880bb027f159e801041b1021e88e8 Result

      Median GTV was 3.05cc (range 0.54-23.2cc), 7 left sided tumors, 3 right sided. All cardiac spared plans fulfilled the clinical constraints on tumor coverage, conformity and organs at risk. All cardiac parameters were significantly decreased; a reduction in max heart dose of 8.2 Gy, reduction in mean heart dose of 1.0 Gy, and reduction in heart V5Gy of 10.3%, with p-values <0.001, 0.008 and 0.014 respectively. MLD was increased by a mean of 0.51 Gy (p-value 0.002). Results are shown in table 1.

      Difference in cardiac and lung doses between clinical plans and cardiac spared plans.
      Patient Difference Heart_Dmax (Gy) Difference Heart_Dmean (Gy) Difference Heart_V5 (%) Difference MLD (Gy)

      1

      -6.1

      -0.2

      -2.5

      0.2

      2

      -6.6

      -0.9

      -6.8

      0.5

      3

      -2.8

      0

      -0.1

      0.1

      4

      -8

      -0.5

      -3.7

      0.8

      5

      -8

      -0.2

      -1.9

      0.7

      6

      -8.6

      -1.8

      -13.4

      0.2

      7

      -12.8

      -2.9

      -34.9

      1.3

      8

      -12.4

      -0.4

      -5.6

      0.2

      9

      -7.4

      -1.4

      -14.8

      0.6

      10

      -9.4

      -1.9

      -19.5

      1

      Average

      -8.21

      -1.02

      -10.32

      0.56

      8eea62084ca7e541d918e823422bd82e Conclusion

      Cardiac sparing is feasible for early stage NSCLC patients treated with SBRT, without compromising target coverage, and with minimal increase in mean lung dose. As cardiac exposure is associated with increased mortality, cardiac sparing has the potential to increase survival, and should be considered for all early stage NSCLC patients treated with radiotherapy. These data will need to be confirmed in a larger, prospective cohort.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-18 - Modern Radiotherapy Increases Patient Access to Curative Intent Radiotherapy in Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Karen Tumelty  |  Author(s): Jonathan McAleese, Claire Mary Rooney, Gerard M Walls, Ruth L Eakin, Jacqueline Harney, Linda Young, Gerard G Hanna

      • Abstract

      Background

      Technical developments in the delivery of radiotherapy such as image-guided radiotherapy (IGRT) and intensity modulated radiotherapy (IMRT) have permitted the introduction of advanced radiation techniques such stereotactic ablative radiotherapy (SABR). These new techniques have the advantage of more accurate localisation of the tumour and reduced irradiation of normal tissues. In our centre, we have implemented a range of new techniques to deliver IGRT (such as PET/CT and 4-dimensional CT planning, and cone beam CT during treatment delivery). We postulate that using the advanced techniques increases the access to curative intent radiotherapy treatment of lung cancer. We seek to assess the access rates to curative intent thoracic radiotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using our institutional lung radiotherapy database we analysed the data recording intent of treatment with reference to the stage and performance status (PS) of all patients with stage 1-3 non-small cell lung cancer (NSCLC) in 2007 and compared this to the same population receiving radiotherapy during 2017 and up to April 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      In 2007, 217 patients with stages 1-3 NSCLC received any radiotherapy compared to 218 patients for the 2017/2018 cohort. Within the 2017/2018 cohort 96% of patients (n=94) received radical radiotherapy compared to 28% of patients in 2007 (n=26). Of the 94 patients receiving radical treatment in 2017/2018, 61% received SABR. This increase was largely due to in the introduction of SABR. In those patients with stage 3 disease, overall fewer patients received any radiotherapy in 2017/2018 compared to 2007, however the number of patients receiving curative intent radiotherapy increased from 20 (13% of all stage 3 patients) to 44 (37%). Of note in those patients receiving curative intent radiotherapy there was an increase in access for patients with poorer PS, with only 7% of patients with a PS ≥2 in 2007 receiving curative intent radiotherapy compared with 42% of patients in 2017/2018.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our series, we report an increase in the proportion of patients with NSCLC receiving curative intent radiotherapy. Furthermore, more patients with a poorer performance status received curative intent radiotherapy. We suggest that the introduction of advanced radiotherapy techniques has permitted the curative intent treatment of patients who were previously treated with a palliative approach to management.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-19 - Clinical Outcomes of Stereotactic Body Radiation Therapy for T2N0M0 Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Yaping Xu  |  Author(s): Yaoyao Zhu, Chenxue Jiang, Wucheng Chen, Qingren Lin, Xiaojiang Sun, Kainan Shao, Hongyu Wu

      • Abstract

      Background

      For patients with inoperable stage I non-small cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) is considered standard. However, the effectiveness and safety of SBRT specifically for T2N0M0 NSCLC remains controversial. This retrospective study investigated the safety and efficacy of SBRT in T2N0M0 NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The medical records of 29 patients with T2N0M0 NSCLC treated by SBRT were reviewed. The overall, progression-free, and cause-specific survival rates were determined.

      4c3880bb027f159e801041b1021e88e8 Result

      The mean follow-up was 20.1 months. At years 1, 2, and 3, the overall survival rates were 93.1, 93.1, and 89.7%, respectively; the corresponding cause-specific survivals were 96.6, 96.6, and 93.1%; the progression-free survivals were 75.9, 65.5, and 62.1%; the local control rates were 100, 96.6, and 96.6%; the regional control was 86.2, 79.3, and 75.9%; and distant control was 89.7, 82.8, and 79.3%. Twenty patients (69.0%) developed symptoms of grade 1 toxicity: dyspnea, chest pain, fatigue, cough, esophagitis, or pneumonia. Among these, 5 patients suffered grade ≥2 therapy-associated pneumonitis, and one patient experienced grade 4 adverse pulmonary effects.

      8eea62084ca7e541d918e823422bd82e Conclusion

      SBRT was efficient and safe for patients with inoperable T2N0M0 NSCLC, imposing tolerable toxicities. These results warrant a prospective study to develop the multidisciplinary criteria for SBRT in T2N0M0 NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-20 - Feasibility of Limited Resection for Peripheral Small-Sized Non-Small Cell Lung Cancer According to FDG Accumulation and Imaging Findings

      12:00 - 13:30  |  Presenting Author(s): Masato Aragaki  |  Author(s): Kichizo Kaga, Yasuhiro Hida, Tatsuya Kato, Ryohei Chiba, Yusuke Motohashi, Yoshiro Matsui

      • Abstract

      Background

      With the progress of diagnostic imaging modalities, such as CT and FDG-PET, the number of resectable lung cancer, particularly small peripheral lung cancer, is increasing. We focused on the SUVmax of FDG-PET as a prognostic factor for lung cancer and established criteria for limited resection on the basis of CT findings and SUVmax. Since 2007, we continuously monitored the recurrence and prognosis of non-small cell lung cancers (NSCLCs) resected using our criteria. Here, we report the results of this study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between December 2007 and December 2015, 611 consecutive patients underwent surgery for NSCLC at our institution. Of these, 73patients with cT1aN0M0 who underwent limited resection (partial resection or segmentectomy) were enrolled. The criteria for undergoing limited resection were as follows: ①tumor GGO ratio of ≥0.75and ② tumor SUVmax of ≤1.5. GGO ratio was calculated using the following equation: GGO ratio=[(maximum diameter of the tumor) – (maximum diameter of tumor consolidation)] / (maximum diameter of the tumor). The group that met our criteria and underwent limited resection was designated as intended limited resection group (ILR group), and the group subjected to limited surgery without meeting the criteria treated as control group.

      4c3880bb027f159e801041b1021e88e8 Result

      The study included 35 men and 38 women with a median age of 65 (range, 36–84) years. In total, 51 patients who met our criteria were included in the ILR group, and 21 patients who did not meet the criteria were included in the control group. The control group was selected for limited resection in terms of complications, pulmonary hypofunction, and heart failure. Regarding surgical approach, in the ILR group, 19 patients underwent partial resection and 32 underwent segmentectomy; in the control group, 13 patients underwent partial resection and 8 underwent segmentectomy. According to our criteria, no relapsed cases were reported in the ILR group. Moreover, the 5-year overall survival rates of the ILR and control groups were 100% and 60.5%, respectively, and the disease-free survival rates were 100% and 56.0%, respectively, indicating a significant difference (P < 0.0001). In the control group, 6 patients showed the recurrence of lung cancer.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, we analyzed the feasibility of our criteria for performing limited resection on the basis of CT findings and SUVmax. In the ILR group, no relapsed cases were reported, suggesting that our criteria may be useful in determining patient’s eligibility for undergoing reduction surgery.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-21 - Robotic Thoracic Surgery in Lung Cancer Resection – A Comprehensive Review 

      12:00 - 13:30  |  Presenting Author(s): Prakash Balakrishnan

      • Abstract

      Background

      Minimally invasive VATS thoracic surgery is currently the gold standard approach for most thoracic procedures . It has come along way since major maximally invasive thoracotomy approaches . Minimally invasive thoracic procedures indefinitely has its distinctive positive outcomes & other secondary benefits to patients & surgeons . Introduction of robotic technique into thoracic surgery has brought huge advantage to patients & surgeons as well as maximised treatment modalities more efficiently . In the review , we will look into the state of art robotic thoracic surgeries available , feasibility , outcomes , accessibility & costs and the pitfalls .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A extensive literature search was performed using MEDLINE ,OVID & PUBMED search databases in the last 10 years . A retrospective review & meta- analysis of these papers were conducted using matched-pair analyses & propensity matched scoring & standard statistical analysis . A total of 43 papers were reviewed & a meta-analysis of these studies in terms of feasibility , outcomes , accessibility & costs and the pitfalls were looked into . A summary review into the current state of robotic thoracic surgery , with the its current limitations and future adaptations were also looked into

      4c3880bb027f159e801041b1021e88e8 Result

      pending data collection & interpretation . Applied late-breaking abstract

      8eea62084ca7e541d918e823422bd82e Conclusion

      pending -applied late-breaking abstract

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-22 - Wedge Resection for Small Pulmonary Lesions with Preoperative Bronchoscopic Barium Marking

      12:00 - 13:30  |  Presenting Author(s): Tatsuo Furuya  |  Author(s): Tsunehiro Ii, Shogo Toda

      • Abstract

      Background

      Barium marking is one of the various types of preoperative marking used with minimal pulmonary lesions. We evaluated the safety and efficacy of wedge resection for small pulmonary lesions after using preoperative bronchoscopic barium marking.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective study was conducted for patients who underwent barium marking before surgery between January 2009 and January 2018. Lesions were localized in advance by chest computed tomography (CT); then, a catheter was inserted into a bronchus close to the lesion under bronchoscopic guidance. Small amounts of barium sulfate ( 0.1–2 ml ) was injected under fluoroscopic guidance. During surgery, the lung surface was observed with a thoracoscope to check color change by barium. In case of the absence of clear identification by visual inspection, the lung was palpated to search for the barium marker. Once barium was detected, A grasping forcep was used to hold the lesion and barium en bloc, and a wedge resection was performed with stapling devices.

      4c3880bb027f159e801041b1021e88e8 Result

      We retrospectively investigated 29 lesions in 29 patients who underwent barium marking before surgery. Five lesions were solid nodules with a longest diameter of 0.5–1.4 cm (mean, 0.9 cm). Eight lesions were partially solid nodules with an overall longest diameter of 0.8–2.2 cm (mean, 1.3 cm) and solid longest diameter of 0.3–0.8 cm (mean, 0.5 cm). Sixteen lesions were pure ground-glass nodules (GGNs) with an overall longest diameter of 0.7–1.7 cm (mean, 1.0 cm). The only complication of marking was mild pneumothorax that did not require drainage in 1 patient. On performing CT after barium marking, the distance between marked barium and the lesion was 0.0–3.7 cm (mean, 0.9 cm). The period between marking and surgery was 5–33 days (median, 15 days). We performed wedge resection in all cases, and all lesions were resected completely. Pathological results showed adenocarcinoma in situ in 20 patients, primary lung adenocarcinoma in 4, metastatic pulmonary tumor in 3, an inflammatory pulmonary nodule in 1, and an intrapulmonary lymph nodule in 1. All margins were pathologically negative. The only postoperative complication was arrhythmia that required an anti-arrhythmic drug in 1 patient.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Wedge resection for small pulmonary nodules after using preoperative bronchoscopic barium marking was safely conducted with satisfactory outcomes.

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      P3.16-23 - Soft-Tissue Sarcoma of the Chest Wall, Surgical Resection: Analysis Our Cases Period of Time Decembre 2004-July 2017

      12:00 - 13:30  |  Presenting Author(s): Fadil Gradica  |  Author(s): Dhimitraq Argjiri, Lutfi Lisha, Alma Cani, Fahri Kokici, Ibrahim Avdiu, Helidon Nino, Ylber Vata, Valbona Rexha, Sali Gradica

      • Abstract

      Background

      Soft tissues include muscle, fat, blood vessels, nerves, tendons and joint linings (synovial tissue). Cancerous tumors (sarcomas) of the soft tissue are rare, but there are many types. Because soft tissue sarcomas arise from a number of different kinds of tissue, they can occur anywhere in the body. Outcomes for people with soft tissue sarcomas depend on the type, size, grade, stage and location of the tumor, as well as a person's age and general health. Clasification from grade are :low ,midle ,high diferenciations..Aim of Study: Our objective was to introduce a patient diagnosed with neglectetd giant soft tissue chest wall liposarcoma .

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Records of 32 patients admitted to our institution from January 2004 to July 2017 were treated in our clinic’ A patient with the initials K.B bored 17/06/1950 .He was admitted to our hospital in thoracal surgery at 19.09.2012 with diagnosis : soft tissue tumor left chest wall .Pacienti without other diseases . We did all necessary examinations , CT , MRI and determined the extent of tissue tumor.

      4c3880bb027f159e801041b1021e88e8 Result

      Ages ranged from 13 to 86 years (median, 38 years); the ratio of male to female patients was 3:1. The initial complaint was mass or pain in 98% of the cases. Histologic types were as follows: desmoid tumor (n = 5), 15 %; liposarcoma (n = 7), 21%; rhabdomyosarcoma (n = 6), 18%); fibrosarcoma (n =4 , 12%); malignant peripheral nerve tumor (n = 3, 9%); malignant fibrous histiocytoma (n = 1, 3%); tenosynovial sarcoma (n = 1),3 %; hemangiopericytoma (n = 2) ,6%%); alveolar soft part sarcoma (n = 2),6%); and other types(lymphoma) (n = 2),6%). Resection was the primary treatment in 28 cases (87%).All patients were treated by multimodal treatment ,chemoradition therapy and surgery. Local recurrence developed in 25%. Metastases occurred in 15 (46%) of the cases (metachronous in 12, synchronous in 3) and were more common in patients with high-grade disease than in those with low-grade disease Overall 5-year survival was 60%. Five-year survival rate for those with high-grade sarcomas was significantly lower than that for low-grade sarcomas .Tumor size and age of patient were not prognostic.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Surgery is important in the treatment of most sarcomas.[Additional treatments, including chemotherapy and radiation therapy, may be administered before and/or after surgery. Thoracic wall soft-tissue sarcomas are best controlled by wide surgical resection.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-24 - Prognostic Value of Positive Lymph Node Ratio in Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Jiaxi He  |  Author(s): Hui Pan

      • Abstract

      Background

      Previous studies had shown the importance of lymph node (LN) resection in T1 NSCLC and recommended no less than 16 LN examination. Few of them reported the role of positive lymph node ratio (PLR). This study was performed to elucidate the prognostic value of PLR in T1 LN positive NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with T1N1-2M0 NSCLC who underwent complete tumor and LN resection in the SEER database from 2009 to 2014 were identified. PLR was defined as positive LN/examined LN. The cut-off value wad determined by ROC. The overall survival of patients was evaluated using Kaplan-Meier and Cox regression analysis. Those whose LN examination number was less than 16 were excluded.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 362 cases were included in the primary cohort. Among them, female accounted for 51.7%. The median number of examined and positive LN were 21 and 2, respectively. Patients with lower PLR had better OS in N2 but no significant result was observed in N1.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PLR has significant prognostic value in N2 group. Greater PLR predicts worse prognosis. More cases and clinical data are warranted to verify the effect of PLR in the contemporary staging system.

      wx20180505-030359@2x.png

      wechatimg1748.jpeg

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-25 - Impact of Diabetes Mellitus on Survival Outcome in Patients with Pathological Stage IA Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Shunki Hirayama  |  Author(s): Mariko Fukui, Aritoshi Hattori, Kazuya Takamochi, Shiaki Oh, Kenji Suzuki

      • Abstract

      Background

      The aim of this study was to investigate the impact of diabetes mellitus (DM) on prognosis of non-small cell lung cancer (NSCLC) patients with pathological stage IA.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective study was performed on 506 patients with pathological stage IA in NSCLC, who underwent complete resection between 2008 and 2012. We investigated the clinicopathological features and prognosis of patients with DM (DM group; N = 62) and those without (non-DM group; N = 444) retrospectively. Median follow-up period was 5.2 years.

      4c3880bb027f159e801041b1021e88e8 Result

      The DM group consisted of more males, high serum CEA level, history of smoking and heart disease, vascular invasion and lymphatic permeation than the non-DM group. 5-year overall survival (OS), recurrence free survival (RFS) and disease specific survival (DSS) rate in the DM group (5-year OS rate, 80.6%; 5-year RFS rate, 77.4%; 5-year DSS rate, 91.6%) were significantly worse than those in the non-DM group (5-year OS rate, 92.0%; 5-year RFS rate, 90.6%; 5-year DSS rate 97.6%) (p = 0.001, p = 0.001 and p = 0.014; respectively). The univariate and multivariate analyses revealed that DM was an independent prognostic factor for RFS and OS (P = 0.027 and P = 0.020, respectively). Relapse in the DM group was higher than that in the non-DM group (p = 0.036). Distant metastases in the DM group (10%) were significantly more common than in the non-DM group (3%) (p = 0.015).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pathological stage IA in NSCLC patients having diabetes mellitus have a decreased survival compared with those without.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-26 - Anatomic Segmentectomy in Stage I Non-Small-Cell Lung Cancer Reveals Equivalent Long-Term Outcomes Compared to Lobectomy

      12:00 - 13:30  |  Presenting Author(s): Alireza Hoda  |  Author(s): Katharina Sinn, Theresa Stork, Ariane Steindl, Gyoergi Lang, Shahrokh Taghavi, Thomas Klikovits, Walter Klepetko

      • Abstract

      Background

      Lobectomy represents the prefered surgical procedure for patients with early stage non-small cell lung cancer (NSCLC). The choice for the right surgical procedure for stage I patients remains controversial. Aim of our study is to analyze short term and long term outcome of patients undergoing anatomic segmentectomy compared to lobectomy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this retrospective cohort study we included all patients with stage I NSCLC undergoing anatomic segmentectomy or lobectomy from 2006 until 2013 at your institution. A Propensity Score analysis was carried out with respect to age, gender, cardiovascular comorbidities, lung function (FEV1 >60%) and histology (adenocarcinoma vs squamous cell carcinoma). Overall survival and disease free survival as well as morbidity were endpoints of the study

      4c3880bb027f159e801041b1021e88e8 Result

      In total, 385 patients with peripheral located stage I NSCLC who neither underwent neoadjuvant nor adjuvant treatment were identified in our database. After applying propensity core matching, 47 patients underwent anatomic segmentectomy and lobectomy was performed in 47 patients. Of these 94 patients, 76 (81%), were in stage IA and 18 (19%) in stage IB. Adenocarcinoma was the histology in 67 (71%) patients and 27 (29%) patients had squamous cell lung cancer. 25 (27%) patients were operated by VATS and 69 (73%) patients underwent thoracotomy. In all patients, the postoperative complication rate was 11,7% and mean hospital stay was 9 days. There were no significant differences with regard to postopertative morbidity, 30- and 90-day mortality between the anatomic segmentectomy group and lobectomy group. 3- and 5-year overall survival (OS) were 79% vs. 84% and 69% vs. 76%., respectively. There was no significant difference between both groups regarding overall survival (p=0.302) and disease free survival (p=0.603). Interestingly , there was no significant difference in OS und disease free survival in both groups when tumor size was bigger than 2 cm( p=0.728 and p=0.432).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The benefit of lobectomy over anatomic segmentectomy in patients with stage I NSCLC is still not clear. In our cohort, oncologic short- and long-term outcome of anatomic segmentectomy was comparable to outcome after lobectomy. However, the results of prospective randomized studies are warranted to clarify the value of sublobar resections for stage I NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-27 - Clinical Outcome of Preoperative Intervention Bronchoscopy Followed by Surgery

      12:00 - 13:30  |  Presenting Author(s): Yasufumi Kato  |  Author(s): Kinya Furukawa, Ryosuke Amemiya, Hidetoshi Furumoto, Shunsuke Shigefuku, Norihiko Ikeda

      • Abstract

      Background

      The report of patients with respiratory disease who could receive surgery after bronchial intervention (IVB) is relatively rare. We still experience patients with advanced lung cancer that develops with severe dysplasia and bleeding. To assess the usefulness intervention bronchoscopy combined with surgery.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We experienced a total of 5 lung cancer patients treated by surgery after IVB at Tokyo Medical University Ibaraki Medical Center. Chief complain were severe dysplasia in 4 cases and bronchial bleeding in one case. The lesions were located at central bronchus in 4 cases. Histological types were 2 squamous cell carcinomas, 1 adenocarcinoma, 1 large cell carcinoma, and 1 pleomorphic carcinoma. Endobronchial snare & argon plasma coagulation (APC) were firstly performed in 2 cases, airway stentings using Dumon stent or Dumon-Y stent in 2 cases, and endobronchial Watanabe spigot (EWS) in 1 case. We evaluated the clinical outcome retrospectively.

      4c3880bb027f159e801041b1021e88e8 Result

      4 cases with obstructive lesions were treated by endobronchial snare and APC, and the other 2 cases were used bronchial stent. EWS was used to occlude the bronchi in the purpose of stopping blood aspiration in advanced adenocarcinoma case. After reducing the massive bleeding using EWS, we could perform salvage surgery. Performance status improved from 2 and 3 to 1 in all patients. All cases showed their symptom improvements after IVB, and were examined full staging (cT4N0M0) and checked operative risk. Thereafter, we could undergo salvage surgery (lobectomy: 2, bi-lobectomy: 1, pneumonectomy: 1, tracheoplasty: 1, carinoplasty: 1). Mean time of IVB followed by surgery was 115.7 days. Overall survival was 22.5 months (1-107.2 months), 5 years survival was 50%, and recurrent rate was 40% (2/5), respectively.

      .

      8eea62084ca7e541d918e823422bd82e Conclusion

      IVB followed by surgery is useful modality, and we should realize that there are some patients who can be treated by surgery after IVB because of improvements of their conditions. Also, IVB can be effective for reducing performance status.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-28 - Surgery of Stage I Non-Small Cell Lung Cancer in Patients Aged 70 Years or Older

      12:00 - 13:30  |  Presenting Author(s): Osamu Kawamata

      • Abstract

      Background

      Non-small cell lung cancer (NSCLC) is a typical disease of the elderly patients, and is becoming increasingly. Surgical resection is standard treatment for early-stage NSCLC. The strong predictor of long-term survival for lung cancer is reported to be age. We evaluate the influence of age for stage I non- small cell lung cancer in elderly patients 70 years or older.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      156 cases with stage I (UICC 8th) non-small cell lung cancer aged 70 years or more who underwent surgery at our hospital between 2007 and 2016 were studied. The patients’ medical records were reviewed with age, gender, type of operation, postoperative morbidity, postoperative mortality and survival results.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 89 male and 67 female. The average ages were 78.2years (range, 70-90 years). The 5-year survival of all patients was 75.7%. Two groups were compared: patients aged 70 to 79 years, patients aged 80 years or more. At pathologic analysis, 74.5% and 70.7% were stage IA, 25.5% and 29.3% were stage IB. Procedure performed was lobectomy in 52.1% and 39.7%, segmentectomy in 40.8% and 39.7%, and wedge resection in 7.1% and 20.7%. Postoperative complications were documented in 12 patients (12.2%) and 11patients (19.0%) without any difference in two groups. The 30-day mortality was 0.6% , and the 90-day mortality was 0.6% . No case died for lung cancer and 14 cases (male 11) died for other disease within 5 years after lung resection in 70-79 years. The 5-year survival was 81.3%. 3 cases died for lung cancer and 12 cases (male 8) died for other disease within 5 years after lung resection in 80 years or more. The 5-year survival was 66.3%. Comparing the 5-year survival by male and female at 5 year interval were 90.0% and 90.2% in 70-74 years, 68.5% and 90.5% in 75-79 years, 61.1% and 88.9% in 80-84 years, and 82.5% and 25.0% in 85 years or more. The reason for the poor prognosis of patients in 75-79 years, 80-84 years male and 85 years or more female was that many deaths by other disease occur.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung resection for stage I NSCLC patients in 70 years or more expected long-term survival. However, the cause of death was found to be more death from other disease than lung cancer after lung resection. We thought that the management of other disease improved the prognosis after lung resection for stage I NSCLC in elderly patients aged 70 years or older.

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      P3.16-29 - Prediction of Lymph Node Metastases in Clinical T1aN0M0 Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Tung-Ming Tsai  |  Author(s): Chao-Yu Liu

      • Abstract

      Background

      Lung cancer with smaller tumor size is now frequently being detected because of prevalent use of computed tomography (CT) as a screening tool for pulmonary lesions. A small group of cT1N0M0 NSCLC have a worse prognosis than what they are expected to be, and nodal upstaging after surgery is a main reason. Prediction of the pathologic nodal upstaging is important. In our study, we aim to reappraise the prediction factors of lymph node metastases in cT1aN0M0 (AJCC 7th edition for lung cancer) NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Cases of cT1aN0M0 NSCLC after surgical resections in National Taiwan University Hospital from 2011 to 2015 were retrospectively reviewed. The prediction factors of interest are tumor size, tumor ground glass opacity (GGO) percentage in chest CT, and preoperative serum carcinoembryonic antigen (CEA) level. Logistic regression model was done to find predictive factors for nodal upstaging.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 770 patients were included for study, 14 (1.8%) were found to have pN+ (nodal upstaging) after pulmonary resection. Larger tumor size, less tumor GGO percentage, and higher preoperative serum CEA level are significant predictors for nodal upstaging. In patholoy, less lepidic component of tumor, presence of visceral pleural invasion, and presence of lymphovascular invasion were also significantly correlated with nodal upstaging. With preoperative variables grouped into categorical data, tumor size ≥ 1.5 cm, CEA ≥ 3 ng/mL, and GGO< 25% have a strong predictive value for lymph node metastases.

      table (2).tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      For patients with clinical stage T1aN0M0 NSCLC, tumor size, serum CEA level, and GGO percentage in CT are significant predictive factors for lymph node metastases after surgery. For patients with tumor size less than 1.5 cm, serum CEA level less than 3 ng/mL, and GGO predominant tumor, avoiding lymph node dissection can be justified. Sublobar resection, instead of standard lobectomy, may be a good alternative for this group of patients.

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      P3.16-30 - The Impact of the Surgical Approach on Lymph Node Upstaging in Curative Intent Lung Cancer Surgery

      12:00 - 13:30  |  Presenting Author(s): Khaled Mardanzai  |  Author(s): Danjouma Cheufou, Balazs Hegedus, Till Plönes, Mohamed Zaatar, Dirk Theegarten, Kaid Darwiche, Clemens Aigner

      • Abstract

      Background

      Radical mediastinal lymphadenectomy is an essential part of lung cancer surgery. The purpose of preoperative mediastinal staging is to identify patients who benefit from induction treatment. However, even in early stage lung cancer some patients present with N1 or N2 disease only intra- or even post-operatively. Accordingly, this study aims to evaluate the impact of different surgical approaches and tumor size on the rate of nodal upstaging.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed an analysis of our prospectively collected database from January 2016 (for robotic assisted surgery January 2015) to March 2018 and nodal upstaging with regard to surgical approach and T status in all patients with early stage T1/T2 NSCLC undergoing primary resection with curative intent.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 452 T1 or T2 stage NSCLC patients were operated with curative intention. Upstaging occurred in 65 cases (14.4%), from which 43 (9.5%) patients had pN1 and 22 (4.9%) had pN2 disease. Staging was performed according to ESTS guidelines. 366 patients (81%) were preoperatively evaluated by PET/CT and/or EBUS. 293 patients received PET/CT and 169 of them had an additional EBUS. 73 patients received EBUS based on conventional staging without PET/CT. There was a significant difference (p=0.01) in upstaging between T1 and T2 tumors (10.5% (7%N1/3.5%N2) and 19.4% (12.8%N1/6.6%N2), respectively). A stratification based on the surgical approach is shown in Table 1.

      table1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Irrespective of the surgical approach the rate of N1 upstaging is significantly higher in patients with T2 tumors compared to T1 tumors. The rate of mediastinal upstaging is comparable in both groups. The distribution between T1 and T2 tumors needs to be taken into account when analyzing upstaging rates in primary lung cancer surgery.

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      P3.16-31 - Younger Patients Operated for Lung Cancer Have Better Overall Survival

      12:00 - 13:30  |  Presenting Author(s): Tomasz Marjanski  |  Author(s): Robert Dziedzic, Danush Davoodi, Sofie Josefsson, Witold Rzyman

      • Abstract

      Background

      Median age of patients diagnosed with lung cancer is 63 years. Incidence of lung cancer in population of patients younger than 50 years of age is relatively low. The aim of this study was to compare the clinical outcomes of patients with early lung cancer onset (ELCO, onset before the age of 50) and late lung cancer onset (LLCO, onset after the age of 50).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have retrospectively analyzed the prospectively collected data of 1517 patients with Lung cancer treated in a Thoracic Surgery Department in the years 2007-2015. Patients were divided into two groups, group I - 78 patients with ELCO and group II - 1439 patients with LLCO. We have compared overall survival in unmatched and matched population. In order to reduce potential selection bias being a result of different histology and different rate of concomitant diseases we performed a propensity-score matched analysis (based on exact matching – by sex, pTNM, type of operation, pathological diagnosis and Charlson Comorbidity Index). The latter analysis was performed in 65 ELCO patients with 453 LLCO patients.

      4c3880bb027f159e801041b1021e88e8 Result

      In the unmatched population we found no differences in gender, pTNM and type of surgery performed. Younger patients were also more likely to have typical carcinoid (23.1% vs 2.6%, p<0.05, OR 11.06 95%CI 5.695-21.360) and mucoepidermoid tumours (2.6% vs 0.3%, p<0.05, OR 7.547 95%CI 0.997-44.708), whereas the older patients were more likely to have squamous cell lung carcinoma (39.7% vs 23.1%, p<0.05, OR 0.455 95%CI 0.256-0.799). Older patients were more likely to be smokers (82% vs 59%, p<0.05 OR 0.316, 95%CI 0.192-0.519). Median Charlson Comorbidity Index in younger population was 0 and in the older population was 1 (p<0.05). Five-year survival in EOLC group was 71.9% vs. 58.7% in LLCO (p=0.008).

      The propensity score-matched analysis with exact method, comparing sex, pTNM, type of operation, pathological diagnosis and Charlson Comorbidity Index, showed that younger patients had better survival rates compared to older patients (p<0.001 HR=0.559, 95%CI 0.360-0.865). Five-year survival in patients with ELCO was 77.6% comparing to 61.5% in LLCO patients (p=0.011).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients with early lung cancer onset have higher five-year survival after surgical treatment compared to patients with late lung cancer onset irrespectively of histology.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-32 - A Study of Postoperative Recurrence in Pathological Stage 1 Non-Small Cell Lung Cancer Patients

      12:00 - 13:30  |  Presenting Author(s): Kotaro Mizuno  |  Author(s): Mamiko Kuriyama, Masayoshi Morishita, Yuichiro Araki, Akinori Ishihara, Hiroyoshi Maeda

      • Abstract

      Background

      Even in pathological stage 1 non-small cell lung cancer, there are some cases in which recurrence occurs after surgical treatment. The prognosis of the recurrent cases is poor despite the early stage of their disease. An analysis of the clinicopathological factors of these recurrent cases may help improve the prognosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 199 patients underwent surgical treatment for primary lung cancer from July 2010 to December 2017 in our hospital. We retrospectively analyzed the clinicopathological factors of 131 patients (65.8%) with pathological stage 1 disease. To compare the clinical data, we divided the 131 patients into 2 groups depending on the presence of recurrence. Group A was recurrent cases and group B nonrecurrent cases. For the statistical analysis, the T-test, F-test, and chi-squared test were used.

      4c3880bb027f159e801041b1021e88e8 Result

      Group A included 19 cases and group B 112 cases. The mean age was 71.3±5.4 years in group A and 70.7 ± 8.0 years in group B (p = 0.75). The procedures performed in group A were lobectomy in 14, segmentectomy in 2, and wedge resection in 3, while those performed in group B were lobectomy in 83, segmentectomy in 18, and wedge resection in 11 (p=0.13). The mean tumor size was 2.5±0.9 cm in group A and 2.0±0.9 cm in group B (p<0.05). In group A, pathologic T factor 1a was found in 0 patients, 1b in 3, 1c in 6, and 2a in 10. In group B, 1a was found in 17 patients, 1b in 48, 1c in 23, and 2a in 24 (p<0.05). Pleural invasion (pl) in group A was 0 in 13 patients, 1 in 6, and 2 in 0, while that in group B was 0 in 99 patients, 1 in 11, and 2 in 2 (p=0.56). Positive lymphatic invasion (ly+) and venous invasion (v+) were found in 6 and 10 patients in group A and 14 and 17 patients in group B, respectively (p<0.05, p<0.01). The mean survival time after the operation was 1185.8±557.0 days in group A and 1034.3±736.0 days in group B (p=0.39).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The mean tumor size and pT outcomes showed significant differences between the two groups. Furthermore, ly and v were positive significantly more frequently in the postoperative recurrence group. In conclusion, the tumor size, ly+, and v+ indicate a high malignant potential and may be considered predictors of a poor prognosis in patients with early-stage lung carcinoma.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-33 - Characteristics and Risk Factors of Recurrence After Segmentectomy in Patients With Clinical Stage I Non-Small Cell Lung Cancer

      12:00 - 13:30  |  Presenting Author(s): Akihiro Nakamura  |  Author(s): Yuki Shimizu, Tatsuya Goto, Seijiro Sato, Terumoto Koike, Masanori Tsuchida

      • Abstract

      Background

      Although lobectomy is the standard surgical procedure for operable non–small cell lung cancer (NSCLC), sometimes we performed segmentectomy for compromised patients, and patients with small-sized NSCLC and adequate pulmonary function for curative intent.

      The aim of this study was to investigate first recurrence sites and risk factors of recurrence in NSCLC patients who underwent segmentectomy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed 136 patients with clinical stage I NSCLC (the 7th edition of the TNM classification) who underwent segmentectomy at Niigata University Medical and Dental Hospital between 2000 and 2016. We investigated first recurrence site to classify as intrathoracic or extrathoracic recurrence. The significant demographic, clinical, and pathologic factors identified with the log rank test in univariate analyses were analyzed with the Cox proportional hazards regression model to examine independent predictors for recurrence in multivariate analysis. For the significant predictor, we determined optimal cutoff points by receiver operating characteristic (ROC) analysis and Youden’s Index

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 136 patients in this study, 81 were male and 55 were female, and the median age was 71 years (range, 41 to 86 years). During the median follow-up period of 1568 days (range, 15 to 6584 days), recurrence was developed in 11 patients. Intrathoracic recurrence was developed only in 4 patients, including 2 patients with surgical resection margin recurrence.

      The 5- and 10-year recurrence-free probabilities were 89.7% and 89.7%, respectively. Solid tumor component size on computed tomography (CT) was identified as an independent significant predictor (hazard ratio [HR], 3.459). To illustrate ROC curve and use Youden’s Index, the optimal cutoff points were determined as 1.5 cm for solid component size on CT.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the study, the NSCLC patients with solid component of larger than 1.5 cm on CT had a higher risk for postoperative recurrence after segmentectomy. However it is still unknown whether these patients could be cured by lobectomy, because many of the patients with postoperative recurrence had extrathoracic recurrence.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-34 - The Impact of Preoperative Exercise Therapy on the Surgical Outcomes of Patients with Lung Cancer and COPD: A Systematic Review and Meta-Analysis

      12:00 - 13:30  |  Presenting Author(s): Wu Nan  |  Author(s): Xiang Li, Shaolei Li, Shi Yan, Yaqi Wang, Xing Wang, Alan D L Sihoe, Yue Yang

      • Abstract

      Background

      Although isolated studies have looked at the impact of preoperative exercise on patients with lung cancer and chronic obstructive pulmonary disease (COPD), a comprehensive meta-analysis of the available data has hitherto been lacking.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Articles were searched from PubMed, Embase, and Cochrane library, with the following criteria: lung cancer patients with or without COPD; undergoing resection; receiving preoperative exercise training. Key outcomes were analyzed using meta-analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Seven studies containing 404 participants were included. Patients receiving preoperative exercise training had a lower incidence of postoperative pulmonary complications (PPCs) (Odds Ratio (OR) 0.35, 95% Confidence Interval (CI) 0.21 to 0.59) and shorter length of hospital stay (Standard Mean Difference −1.02 days, 95% CI −1.31 to −0.74 days). Exceptionally, incidence of pneumonia remained unchanged. Patients with COPD could not obviously benefit from exercise training to reduce PPCs(OR 0.44, 95% CI 0.18­ to 1.08)but still might achieve faster recovery. No significant difference in pulmonary function was observed between the two groups. However, 6-minutes walking distance and VO2 peak were significantly improved after exercise training.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preoperative exercise training might not reduce PPCs for COPD patients undergoing lung cancer resection, but still facilitate faster recovery. Muscle capacity was strengthened after rehabilitation, which emphasized the possible mechanism of the protocol design.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.16-35 - Stair Climbing Exercise May Ameliorate Pulmonary Function Impairment in Patients at One Month After Lung Cancer Resection

      12:00 - 13:30  |  Presenting Author(s): Wu Nan  |  Author(s): Yaqi Wang, Shi Yan, Xing Wang, Xiang Li, Shaolei Li, Yue Yang

      • Abstract

      Background

      Surgical resection remains the primary treatment for patients with localized non-small cell lung cancer (NSCLC). Despite the possibility of a cure, lung resection is associated with an immediate pulmonary function impairment.

      Stair-climbing test as a reliable indicator of pulmonary function, is often performed preoperatively to select patients. It also has been reported that stair-climbing yielding greater values of VO2 is a more stressful exercise than cycle ergometry. The benefits of this intervention in postoperative patients remain unclear. Thus, this study aimed to evaluate the effects of performance at the postoperative symptom-limited stair climbing exercise on pulmonary function.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed 36 consecutive NSCLC patients undergoing video-assisted thoracoscopic surgery lobectomy and systematic mediastinal lymphadenectomy from November 2017 to January 2018. In the postoperative pulmonary rehabilitation program, all patients were suggested to perform symptom-limited stair climbing exercise in addition to routine physiotherapy (walking, incentive spirometry, breathing) from the first day after surgery. Patients were encouraged to climb gradually to the maximum number of floors at a pace of their own choice, and to stop in case of exhaustion, insufferable pain, limiting dyspnea or leg fatigue. A nursing professional was indispensable for the management of chest drains and supervision of any symptoms. Heart rate, pulse oxygen saturation were continuously measured using a portable pulse oximeter. Stair climbing exercise was performed at least twice a day during and after hospital stay. According to their performance of the exercise, patients could be divided into two groups. Stair climbing group completed the exercise training as planned, while routine physiotherapy group was reluctant to stair climbing exercise except for routine physiotherapy. Pulmonary functions were performed on all patients preoperatively and at one month postoperatively.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally, 25 patients (15 in stair climbing group and 10 in routine physiotherapy group) were included in the final analysis. The average preoperative and postoperative FEV1 for patients in two groups were 2.69±0.83 L vs. 3.08±0.72 L (p=0.244) and 2.08±0.72 L vs. 2.23±0.60 L (p=0.592), respectively. The difference in FEV1 decline between stair climbing group and routine physiotherapy group was significant (0.61±0.26 L vs. 0.84 ± 0.23 L, p=0.032).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study suggested that symptom-limited stair climbing as a more stressful exercise performed postoperatively in patients may ameliorate pulmonary function impairment at one month after lung resection. Prospective randomized controlled trials are therefore warranted.

      6f8b794f3246b0c1e1780bb4d4d5dc53