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  • WCLC 2018

    19th World Conference on Lung Cancer

    Access to all presentations that occur during the 19th World Conference on Lung Cancer in Toronto, ON

    Presentation Date(s):  
    • Sept 23 - 26, 2018
    • Total Presentations: 2384

    To review abstracts of the presentations below, narrow down your search by using the Filter options below, and then select the session listing of your choice. Click the "+" for a presentation to expand & view the corresponding Abstract details.

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 36
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-01 - Impact of Chromatin Remodeling Genes Including SMARCA2 and PBRM1 on Neoantigen and Immune Landscape of NSCLC (ID 12593)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae  |  Author(s): Lee Chun Park, Sangmin Chang, Taeyoung Ko, Kyunghoon Rhee, Jonathan Anker, Manali Bhave, Andrew A. Davis, Marcelo Cruz, Wade Thomas Iams, Lihua Zou, Victor Wang, Jeffrey H Chuang

      • Abstract
      • Slides

      Background

      Epigenetic changes in tumors and their microenvironment immune cells have been the recent focus of cancer research. Aberrations in SWI/SNF complexes within the chromatin remodeling machine may play a major role in carcinogenesis. However, little is known about their impact on neoantigen and the immune landscape of NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were divided into two groups; Mut group (at least one mutation in 27 SWI/SNF complex subunit genes including SMARCA2 and PBRM1) and NoMut group (no SWI/SNF mutations). We analyzed genomic, transcriptomic data from the TCGA database including patients with adenocarcinoma (ADC, n=515) and squamous cell carcinoma (SQCC, n=501) of lung cancer. The tumor immune landscape was analyzed using the signatures derived from 812 ‘immune metagenes’ (Angelova, M. et al, 2015). We analyzed neoantigen burden and immune landscape between two groups. RNA expression of the above genes were compared. Patients were also divided by the expression levels of the above genes (1st quartile vs 4th quartile).

      4c3880bb027f159e801041b1021e88e8 Result

      figure1.jpg

      Mut group (142 samples, 14%) showed significant higher neoantigen burden compared with NoMut group in ADC and SQCC (mean 32.17/15.22 and 34.75/19.83 mutation/mbp, respectively, both P<0.01). In addition, the Mut group demonstrated higher infiltration of activated CD8 T cells compared with the NoMut group in ADC (39%/25%, P<0.01). However, there was no significant difference between two groups in SQCC (32%/27%, P=0.42).

      For two representative genes (SMARCA2 and PBRM1), lower expression of the two genes were associated with higher infiltration of activate CD8 T-cells in ADC (60%/6% and 37%/17%, respectively, both P<0.01) and SQCC (40%/21% and 43%/17%, respectively, both P<0.01). However, there was no difference in neoantigen burden with respect to gene expression in either ADC or SQCC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Mutation or low expression of chromatin remodeling genes including SMARCA2 and PBRM1 were associated with higher neoantigen burden and higher tumor infiltration of activated CD8 T-cells in human NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.04-02 - Targeting Established Lung Cancer Through Combination of DNT Cellular Therapy with PD1 Checkpoint Blockade (ID 13046)

      16:45 - 18:00  |  Presenting Author(s): Linan Fang  |  Author(s): Dalam Ly, Wei Liu, Sisi Wang, Jong Lee, Heidi Kang, Li Zhang

      • Abstract

      Background

      Lung cancer is the leading cause of cancer-related deaths worldwide. Immune-checkpoint blockade such as anti-PD1 therapies achieved clinical benefit which correlated with presence of immune cells in tumors. Adoptive T cell therapies is another form of immunotherapy with therapeutic-potentials, but obtaining sufficient tumor-antigen specific T cells and discovery of high-expressing tumor-specific antigens remain as challenge. Recently, we have demonstrated that a population of cytotoxic T cells (CD3+CD4-CD8-), termed double negative T (DNT) cells, has potent anti-cancer effect in vitro and in patient-derived xenograft models, can be expanded ex vivo to a therapeutic quantity and quality. In this study, whether DNT cell can target established lung cancer either alone or in combination with anti-PD1 is investigated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Infiltrating T cell populations from 12 resected lung tumors were characterized and compared to resected adjacent and normal tissues using Flow-cytomtery. To determine the efficacy of ex vivo DNT cell therapy on lung cancer, NSG mice subcutaneously engrafted with H460 were systemically infused with DNT cells or DNT cell with Nivolumab in three doses when tumor size reached 100mm3, the tumor size and DNT cell infiltration level were monitored.

      4c3880bb027f159e801041b1021e88e8 Result

      The frequency of DNT cell was reduced in lung tumor when compared to the adjacent and non-tumoral tissues of the same patient. Like conventional CD4 and CD8 T cells, 36%-52% of DNT cells within tumor expressed elevated levels of PD1, suggesting that DNT cells function may be suppressed by PD-1 pathway in patients. Using xenograft mice, we show that treatment with DNT cell alone reduced tumor growth by 14%-38%. A greater reduction (30%-68%) was observed when DNT cell treatment was combined with PD1 blockade, where PD1 blockade alone had no significant effect. Compared to DNT cell transfer alone, DNT cells with PD1 blockade led to a greater infiltration of cells with higher expression of cytotoxicity markers NKG2D and IFN-y and reduced inhibitory markers TIM3 and LAG3.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These studies indicate the potential of DNT cell for the treatment of established lung cancer and that combination of DNT cell with PD1 blockade may further enhance the treatment efficacy by increasing DNT cell infiltrating to solid tumor.

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      P1.04-03 - Suppressive Immune Cell Profiling in Patients with Non-Small Cell Lung Cancer. (ID 12878)

      16:45 - 18:00  |  Presenting Author(s): Jiae Koh  |  Author(s): Kyoung Young Lee, Boram Kim, Mi Soon Kim, Hee Jin Cho, Yeon Hee Bae, Bo Mi Ku, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn

      • Abstract

      Background

      The factors in tumor microenvironment hinder T cell activities against tumor cells. The major immunosuppressive cells in tumor sites are myeloid derived suppressor cell (MDSC), tumor associated macrophage (TAM), and regulatory T (Treg) cell, and the effector molecules released by those immunosuppressive cells also regulate T cell activities. Therefore, in this study we examined the pattern of immunosuppressive cells in patients with non-small cell lung cancer depending on their stages and we compared those immunosuppressive cells in healthy donor blood PBMC as well. Then, we tested T cell activities to verify whether suppressive immune cell populations can influence T cell activity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Granulocytic-MDSC, Monocytic-MDSC, TAM, and Treg population from patients’ PBMC (n=59) and healthy donors’ PBMC (n=20) were analyzed by FACS Verse with appropriate antibodies. For suppressive assay, isolated T cells were activated with anti-CD3 and anti-CD28 for an hour and then MDSC was co-cultured with T cells for a week followed by Ki-67 level analysis by FACS Verse. T cell activity and suppression were tested by FACS analysis with identified cell surface markers.

      4c3880bb027f159e801041b1021e88e8 Result

      G-MDSC (p-value=0.0023) and M-MDSC (p-value=0.0032) population were higher in advanced non-small cell lung cancer patients (stage III&IV) compared with stage I&II patients or healthy donor. G-MDSC isolated from patient’s blood was co-cultured with activated T cells from the same patient. After one week, T cell activity was dramatically inhibited compared with T cell alone (p < 0.001, E:T = 5:1, 10:1) confirming suppressive activity of MDSC against T cells. TAM population was increased as disease progressed (p<0.001), and Treg also slightly increased (p-value=0.0373) in stage III&IV. Activated T cells were higher in stage III&IV, but suppressed T cells were also higher in stage III&IV compared with stage I&II.

      8eea62084ca7e541d918e823422bd82e Conclusion

      G-MDSC and M-MDSC population increased as disease progressed and G-MDSC effectively suppressed T cell activities. TAM population increased in advanced non-small cell lung cancer patients, and Treg population also slightly increased in stage III&IV. Both activated and suppressed T cells were higher in stage III&IV compared with stage I&II.

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      P1.04-04 - Efficient Uptake of Recombinant Lipidated Survivin by Antigen-Presenting Cells Initiates Antigen Cross-Presentation and Antitumor Immunity (ID 11963)

      16:45 - 18:00  |  Presenting Author(s): Chih-Hsiang Leng  |  Author(s): Chen-Yi Chiang, Chiao-Chieh Wu, Shih-Jen Liu, Hsin-Wei Chen

      • Abstract
      • Slides

      Background

      Survivin is over-expressed in various types of human cancer, but rarely expressed in terminally differentiated adult tissues. Thus, survivin is a potential target antigen for a cancer vaccine. However, self-tumor associated antigens are not highly immunogenic. Bacteria derived lipoproteins can activate antigen-presenting cells through their toll-like receptors to enhance immune responses. In this context, lipidated survivin is an attractive candidate for cancer immunotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the present study, recombinant lipidated human survivin (LSur) was prepared from an Escherichia coli-based system. We investigated whether LSur is efficiently captured by antigen presenting cells then facilitating effective induction of survivin cross-presentation and generation of immunity against cancer cells.

      4c3880bb027f159e801041b1021e88e8 Result

      Our results demonstrate that LSur, but not its non-lipidated counterpart, can activate mouse bone marrow derived-dendritic cells (BMDCs) to enhance cytokine (IL-6, TNF-α, and IL-12) secretion and co-stimulatory molecules (CD40, CD80, CD86 and MHC II) expression. However, the pathways involved in the capture of the recombinant lipidated antigen by antigen-presenting cells have not yet been elucidated. To this end, we employ various endocytosis inhibitors to study the effect on LSur internalization. We show that the internalization of LSur is suppressed by the inhibition of various routes of endocytosis. These results suggest that endocytosis of LSur by BMDCs can be mediated by multiple mechanisms. Furthermore, LSur is trafficked to the early endosome after internalization by BMDCs. These features of LSur are advantageous for cross-presentation and the induction of antitumor immunity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrate that immunization of C57BL/6 mice with LSur under treatment with exogenous adjuvant-free formulation induce survivin-specific CD8+ T-cell responses and suppress tumor growth. The antitumor responses are mediated by CD8+ cells. Our findings indicate that LSur is a potential candidate for stimulating protective antitumor immunity. This study suggests that lipidated tumor antigens may be a promising approach for raising a robust antitumor response in cancer immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.04-05 - Elucidating the Role of Leukocyte-Associated Immunoglobin-Like Receptor 2 (LAIR2) in Lung Cancer Development (ID 13859)

      16:45 - 18:00  |  Presenting Author(s): Dalam Ly  |  Author(s): Michael Cabanero, Chang-Qi Zhu, Ming Sound Tsao, Li Zhang

      • Abstract

      Background

      The tumor microenvironment play an important role in shaping cancer development. The contexture of stromal infiltrates have been shown promote or inhibit tumor growth and patient prognosis. In attempts to gain insight into the immune networks that regulate tumorigenesis, we used genome wide expression datasets from patients with resected early stage non-small cell lung cancer (NSCLC) to identify immune-related genes associated with patient survival.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Gene expression analysis was conducted on microarray datasets from 128 early-stage NSCLC adenocarcinoma resected tumor samples. Limiting analysis to immune-related genes, we identified a minimum gene set containing LAIR2 that was prognostic for lung adenocarcinoma. Immunohistochemistry and gene ontology analysis were used to determine the function of LAIR2.

      4c3880bb027f159e801041b1021e88e8 Result

      From the gene signature, the gene encoding the immune collagen receptor LAIR2, was highly expressed within the high-risk patient subgroup (HR = 2.71, 95% CI = 1.49 to 4.90, P = 0.001). Gene ontology analysis revealed that LAIR2 expression correlated with negative immune regulation and associated immune signatures. Immunohistochemistry of resected lung adenocarcinoma revealed heterogeneous expression of LAIR2 within tumor epithelium and stromal immune cells, suggesting specificity and localization. ELISA for LAIR2 suggest that CD4+ Th2 cells maybe a major source of LAIR2 secretion and that recombinant LAIR2 may promote T cell exhaustion by activation of CD8+ T cells and upregulation of PD1 and LAG3.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that expression of LAIR2 result in poor patient prognosis and is associated with negative immune regulation. An understanding of LAIR2 function will provide insight into factors required during lung cancer progression and targets for intervention.

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      P1.04-06 - Clinicopathological Analysis of Pulmonary Pleomorphic Carcinoma (ID 12488)

      16:45 - 18:00  |  Presenting Author(s): Misa Noguchi

      • Abstract
      • Slides

      Background

      Pulmonary pleomorphic carcinoma (PC) is a histological type of poorly differentiated non-small cell lung carcinoma (NSCLC) which consists of both sarcomatous and carcinomatous components. Except for its aggressive behavior and resistance to chemoradiotherapy, clinicopathological characteristics remain elusive due to its rarity. Recently, immunotherapy targeting the programmed death-1 (PD-1)/PD ligand 1 (PD-L1) pathway has demonstrated favorable clinical outcomes in NSCLC. However, the expression patterns of PD-L1 in pulmonary PC are still unknown. We reviewed the results of clinicopathological characteristics and PD-L1 expression of 46 cases of pulmonary PC resected in our institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Forty-six patients with pulmonary PC consecutively underwent lung resections for the treatment in our institution between 2002 and 2017. Various clinical and pathological data were reviewed retrospectively to analyze prognostic factors for overall survival (OS) after surgery. OS was compared among patient groups by log-rank tests. For multivariate analyses, Cox hazard models were applied. P-value less than 0.05 was considered significant. Tissue samples were collected from the paraffine-embedded tumor blocks of these patients. Then, PD-L1 expression levels of the tumor were examined by immunohistochemical staining method using anti PD-L1 antibody (clone 28-8).

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were 40 male and 6 female, and their median age was 68 years (range: 36 to 83 years). The majority of patients with pulmonary PC were smokers (87.0%, 40/46). Forty-five tumors contained identifiable carcinomatous components, and the other 1 consisted of only spindle cell component. An adenocarcinoma component was found in 27 cases, a squamous cell carcinoma component in 5, and the other components in 14. OS rate was 50.8% at 5 years. Univariate analysis revealed that tumor size over 3 cm, the presence of necrosis and pathological T factor were significantly associated with poorer overall survival. Lymphatic invasion was not statistically significant, but tended to be associated with poorer overall survival. Multivariate analysis showed that lymphatic invasion tended to be associated with poorer overall survival.

      PD-L1 was highly expressed in pulmonary PC (62.5%, 10/16). The proportion of PD-L1 expression was significantly higher in the sarcomatous component than in the carcinomatous component.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We found that lymphatic invasion suggested a worse prognosis for resection of pulmonary PC. Moreover, our study demonstrates that pulmonary PCs very frequently express PD-L1. Thus, targeting the PD-1/PD-L1 pathway may represent a potential therapeutic candidate for this aggressive tumor especially in its sarcomatous component.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.04-07 - Pemetrexed Enhances Anti-Tumor Efficacy of PD-L1 blockade by Promoting Intra-Tumor Immune Response via Tumor and T Cell-Intrinsic Mechanisms (ID 14269)

      16:45 - 18:00  |  Presenting Author(s): Nelusha Amaladas  |  Author(s): David Schaer, Sandaruwan Geeganage, Zhao Hai Lu, Erik R. Rasmussen, Andreas Sonyi, Darin Chin, Andrew Capen, Yanxia Li, Catalina Maria Meyer, Bonita D Jones, Xiaodong Huang, Shuang Luo, Carmine Carpenito, Kenneth D Roth, Alexander Nikolayev, Bo Tan, Manisha Brahmachary, Krishna Chodavarapu, Frank Charles Dorsey, Jason R Manro, Thompson N. Doman, Gregory P Donoho, Gerald E Hall, Michael Kalos, Ruslan Novosiadly

      • Abstract
      • Slides

      Background

      The combination of pemetrexed/carboplatin with the PD-1 antibody pembrolizumab demonstrates a substantial increase in overall survival in NSCLC patients (hazard ratio 0.49) based on KEYNOTE-189 Phase III data (Gandhi et al., 2018), and represents the first chemoimmunotherapy combination ever approved in Oncology. However, the mechanisms underlying the efficacy of this combination remain largely unknown. Many chemotherapies in general and antifolates in particular have detrimental effects on immune homeostasis, and differ in their ability to induce immunogenic tumor cell death. Nevertheless, KEYNOTE-189 results suggest a positive interaction between pemetrexed-based chemotherapy and immunotherapy highlighting the importance to understand the role of pemetrexed in modulating antitumor immune response to assure rational application of this therapy to the appropriate patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To characterize the effects of pemetrexed on intra-tumor immune response, murine syngeneic tumor models (MC38 and Colon 26) were treated with pemetrexed, paclitaxel with or without carboplatin, or anti-mouse PD-L1. Immune cell subsets and immune-related changes in tumor tissue and T cells were assessed by flow cytometry and gene expression analysis. Tumor and T cell-intrinsic effects of pemetrexed including ability to induce immunogenic cell death of tumor cells and enhance immune function through changes in mitochondrial respiration and gene expression in T cells were also evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      In MC38 syngeneic mouse tumor model, pemetrexed increases frequency of intratumor leukocytes and cycling (Ki67+) T cells accompanied by gene expression changes indicative of T cell inflamed phenotype. In contrast, paclitaxel exerts quantitatively and qualitatively different immune effects mainly associated with modest upregulation of myeloid cell-related genes whereas carboplatin barely exhibits any immune-related changes in monotherapy and appears to attenuate immunomodulatory effects induced by pemetrexed in MC38 tumors. Pemetrexed in combination with PD-L1 antibody demonstrates enhanced antitumor efficacy and pronounced inflamed/immune activation phenotype in Colon26 syngeneic mouse tumor model. In vitro data indicate that pemetrexed is a potent inducer of immunogenic tumor cell death as exemplified by marked release of HMGB1 in MC38 and Colon26 tumor cells and suggest T cell-intrinsic effects exemplified by enhanced mitochondrial content, oxidative respiration and increased expression of cell surface molecules and immune-related genes indicative of T cell activation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pemetrexed promotes intra-tumor T cell-mediated immune response through immunogenic tumor cell death and increased activation and metabolic fitness of T cells leading to an enhanced anti-tumor efficacy in combination with PD-L1 antibody.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.04-08 - Co-Residence of Patient-Derived Immune Cells in Patient-Derived Xenografts from Lung Cancer Patients (ID 11161)

      16:45 - 18:00  |  Presenting Author(s): Xingxiang Pu  |  Author(s): Ran Zhang, Li Wang, Apar Pataer, Ismail M Meraz, Xiaoshan Zhang, Shuhong Wu, Yungchang Chen, Lin Wu, Dan Su, Weimin Mao, John V Heymach, Jack A Jack A. Roth, Stephen Swisher, Bingliang Fang

      • Abstract

      Background

      Patient-derived xenograft (PDX) models have been shown to recapitulate many characteristics of human tumors and have been increasingly used for anticancer drug development, molecular characterization of cancer biology, and development of precision therapies. However, because PDXs are grown in immunodeficient mouse strains, they are regarded as inappropriate for preclinical evaluation of anticancer immunotherapy. Here we evaluated whether patient-derived immune cells co-exist in PDXs derived from lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      First-generation PDX (F1) was established by subcutaneously implanting human tumor tissue into non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mice with a null mutation of the gene encoding for interleukin-2 receptor g (NSG). When the resulting tumors in these mice grew to about 1.5 cm in diameter, we passaged the tumors in NSG or nude mice for subsequent generations. A small piece of these PDX tissues (about 2-3 mm3) were minced into fragments and cultured in media containing human interleukin-2 (IL-2) (2000 -6000 units/ml) for up to 6 weeks. The proliferated lymphocytes for analyzed by fluorescence-activated cell sorting (FACS) with antibodies specific for human immune cell surface markers. The provenance of cultured cells was determined by DNA fingerprinting assay together with patients’ DNA samples from primary tumors and/or peripheral blood mononuclear cells (PBMC).

      4c3880bb027f159e801041b1021e88e8 Result

      The mean time of PDX growth in NSG mice before harvesting for culturing tumor-infiltrating lymphocytes (TILs) was 120 days (ranging from 63-292 days). TILs were successfully cultured from 8 of 25 PDXs samples (about 32%), with one from F2 PDXs and 7 from F1 PDXs. TILs from five of those PDXs were predominantly human CD3+CD8+ T cells (72% -99%), while the remaining three were predominantly human CD19+ B cells (77% - 95%). DNA fingerprint analysis showed that genotypes of TILs were identical to patients’ primary tumors and/or PBMC, demonstrating that the TILs were from the same patients as the PDXs. Further analysis showed that CD8+ T cells from PDXs were CD45RO+, with either CD62L+ or CD62L-.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patient-derived immune cells co-exist with PDXs in some lung cancer PDX models. Most of those immune cells were CD3+CD8+ and could be memory T cells. These results suggest that some PDXs might be used for evaluating functions of tumor resident immune cells and/or for evaluating anticancer immunotherapies.

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      P1.04-09 - Immunomodulatory Effects of Afatinib and Pembrolizumab in EGFR-Mutant NSCLC with Progression on Prior EGFR-TKI (ID 12185)

      16:45 - 18:00  |  Presenting Author(s): Jonathan W Riess  |  Author(s): Karen Kelly, Kurt Alex Schalper, Michiko Shimoda, Steffany Lim, Arta M Monjazeb, Kathleen Danenberg, Elizabeth H Moore, Laurel Beckett, Philip Christopher Mack, Emanual M Maverakis, David R. Gandara

      • Abstract

      Background

      EGFR-mutant NSCLC is less responsive to single agent PD-1 blockade than smoking associated NSCLC. Preclinical models suggest EGFR-TKI can render a more immunocompetent tumor microenvironment. This study examined the immunomodulatory effects of combination second generation EGFR-TKI and PD-1 antibody.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this phase 1 dose de-escalation study, patients were treated with afatinib 40 mg oral daily and pembrolizumab 200 mg IV q21day. Key Eligibility: advanced EGFR-mutant NSCLC with progression (PD) on prior EGFR-TKI, age≥18, ECOG PS≤1, acceptable organ function, no significant autoimmune diseases, measurable disease and controlled brain metastases. Tissue biopsy performed baseline and week 5-6 on treatment for PD-L1 IHC (22C3) and quantitative immunofluorescence for immune cell subsets and next-generation sequencing. Blood at baseline and at serial on-treatment timepoints were collected for ctRNA of PD-L1, EGFR, HER2 and MET; changes in circulating immune cell subsets, T-Cell repertoire and cytokine levels were evaluated by flow cytometry and Luminex.

      4c3880bb027f159e801041b1021e88e8 Result

      No DLTs were observed in the first 6 patients and the 10 patient expansion cohort proceeded at afatinib 40 mg daily and pembrolizumab 200 mg IV q21day. Eleven patients enrolled to date. Key molecular and pathologic characteristics: adenocarcinoma 9, neuroendocrine 1, squamous 1. EGFR-TKI resistance mechanism: EGFR-T790M 4, EGFR-T790M/C797S 1, HER2 amp 1, MET 2, Her2 amp+neuroendocrine differentiation 1, unknown 2. Five patients had prior second line osimertinib. Three (27%) patients had immune related AEs (G2 adrenal insufficiency, G2 nephritis, G3 colitis). Nine patients were evaluable for response: (1 PR, 7 SD ((6/7) with tumor reduction <30%)). The responding patient had squamous histology tumor, prior PD on erlotinib, and PFS of 11 months with PD-L1 (22C3) TPS 40% and PD-L1 and PD-L2 amplification. Treatment with afatinib and pembrolizumab induced systemic immune changes including trend for increased soluble IDO, MIG, TIM3, IP-10, LAG3, PD-L1 and PD-L2 and decreased IFN-gamma. ctRNA for EGFR and PD-L1 were detected in 7/7 and 6/7 patients, respectively, with dynamic changes in allele frequency of EGFR and PD-L1 observed. Baseline PD-L1 (22C3) TPS ranged from 0% to 75% expression. Four patients had repeat biopsy and in paired samples analyzed PD-L1 (22C3) expression decreased in the stroma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immunomodulatory effects of afatinib with pembrolizumab were noted in the tumor microenvironment and peripheral blood. Only modest clinical activity has been observed thus far in patients with PD on prior EGFR-TKI. Genomic and immune-profiling is feasible in EGFR-mutant NSCLC and may identify EGFR-mutant NSCLC patients who may respond or lack benefit to PD-1 blockade.

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      P1.04-10 - The Importance of Suppressor and Cytotoxic T Lymphocyte Subsets and Cytotoxic Mechanisms in Non-Small Cell Lung Cancer (ID 14413)

      16:45 - 18:00  |  Presenting Author(s): Akif Turna  |  Author(s): Esin Aktas, Ayşe Engin, Duygu İlke Çıkman, Gizem Ayan, Günnur Deniz

      • Abstract
      • Slides

      Background

      Lung cancer represents the second most frequent cause of death worldwide, and most common subtype of lung cancer is non-small cell lung cancer (NSCLC). Recent trials showed that deficiencies in anti-tumor immunity play a major role in carcinogenesis of NSCLC. CD8+CD28 cytotoxic T (Tc) cells and CD4+CD25+FoxP3+ regulatory T (Treg) cells known as suppresor CD4+ T cells, have been shown to exist in tumor tissues and inhibits the anti-tumoral immune responses. Natural killer (NK) cells are cytokine producing innate lymphoid cells having cytotoxic capacity to kill tumor cells. In this study the prevalence of Treg cells and CD28 expressing Tc cells and cytotoxic functions were analyzed.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study groups comprised patients with newly-diagnosed non-small cell lung cancer (NSCLC) (n=46) with T1-3N0M0 NSCLC, none of whom had received preoperative chemotherapy and/or radiotherapy, and healthy subjects (n=46). The prevalence of CD3-CD16+CD56+ NK cells, CD4+CD25+Foxp3+ regulatory (Treg) and CD8+CD28T cells were analyzed by flow cytometry. Cytotoxic capacity of NK and CD8+ T cells were analyzed by CD107a degranulation assay.

      4c3880bb027f159e801041b1021e88e8 Result

      NK and CD8+CD28- suppressor T cells were increased however percentage of activator CD8+CD28+T lymphocytes were significantly decreased in patients with NSCLC compared to healthy subjects (p=0.002, p=0.005, p=0.000, p=0.001, p=0.001, p=0.02 and p=0.02, respectively). Although the cytotoxic activity of NK cells did not differ between the groups, CD107a expression was found increased in total CD8+ T cells in unstimulated and K562 stimulation (p=0.001). Although the number of Treg cells are decreased in the NSCLC group but this is not statistically significant. No statistically signficant difference was found in terms of lymphocyte subsets and NK cells between the patients with early(T1) and late stages(T2-3).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings showed that suppressor CD8+CD28- T cell subset as well as NK cells were increased in patients with operable NSCLC. Increased CD8+CD28- T cells might cause supression of antitumour immunity and their prevalence might be useful to assess immunotherapy outcomes in patients. Although the number of NK cells increased significantly, the activity of NK cells did not show difference. Functional evaluation of cells has been found to be more important than cell populations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.04-11 - Exploring the Germ-Line Contribution to Exceptional Response to PD-1/PD-L1 Inhibition in Patients with NSCLC by Whole Genome Sequencing (ID 12646)

      16:45 - 18:00  |  Presenting Author(s): Megan Babette Barnet  |  Author(s): Katherine J L Jackson, Bo Gao, Adnan Nagrial, Michael Boyer, Wendy Cooper, Rina Hui, Anthony Linton, Martin Henry Norman Tattersall, Amanda Russell, Greg Gibson, Jonathan Cebon, Georgina V Long, Alexander M Menzies, Richard A Scolyer, Paul Lacaze, Robert Brink, Timothy J Peters, Mark Cowley, Velimir Gayevskiy, David Thomas, Mark Pinese, Prunella Blinman, Steven Chuan-Hao Kao, Christopher Carl Goodnow

      • Abstract
      • Slides

      Background

      Responses to immune checkpoint inhibitors (CPI) may vary between individuals because of somatic mutation differences in the tumour and/or germ-line differences in immunological tolerance. To explore the latter, this ongoing study evaluates patients with metastatic non-small cell lung cancer (NSCLC) treated with single agent PD-1 or PD-L1 inhibitors recruited from a treatment pool of 420 patients (total) / 137 (active since 1 August 2017).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Rare and common germ-line DNA variants are analysed in exceptional responders and non-responders by whole genome sequencing (WGS) (Illumina HiSeqX Ten). Exceptional responders are defined as patients with complete or partial response of more than 12 months or stable disease of more than 24 months (per RECIST), and a concurrent immune-related adverse event of any grade. Non-responders are defined as patients with best response of progressive disease, having received at least 4 cycles or 2 months of treatment.

      In these individuals, the burden of rare and common variants in immune tolerance genes is analysed and compared to the Medical Genome Reference Bank (MGRB), comprising WGS of 1144 well-elderly individuals. Comparisons are made with Fisher Exact test. Genetic risk scores for auto-immune conditions are calculated for these cohorts, MGRB and NSCLC patients included in The Cancer Genome Atlas. Scores are calculated using curated risk alleles and OR weightings derived from the NHGRI-EBI GWAS catalogue.

      4c3880bb027f159e801041b1021e88e8 Result

      Recurrent rare variants (Exome Aggregation Consortium (ExAC) frequency < 1%) were found within responders sequenced to date (n=20), including variant A, a frameshift mutation in a protein kinase not present in ExAC, with allelic frequency (AF) of 1.27% in MGRB and 17.5% of our cohort (p<0.0001). Multiple common variants (ExAC ≥1%) were more frequent within the cohort compared with population standard. Among these, three functional variants within gene B, encoding a protein involved in modulating immune-responsiveness, (variant B.1, B.2 and B.3, ExAC AF: 1.3%, 0.99% and 2.3%), were found seven times (total) across six individuals (one compound heterozygous B.2/B.3). The exceptional responders cohort was enriched for subjects with higher genetic risk for Disease A, psoriasis and psoriatic arthritis compared with control groups.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preliminary findings suggest individuals harbouring functional variants in genes promoting immune tolerance may be more responsive to PD-1/PD-L1 inhibitors. This may be due to higher basal immune activation, requiring greater reliance on inhibitory checkpoints to maintain homeostasis. Ordinarily, this would be clinically undetectable, however the addition of a pharmacological CPI may more effectively break immune tolerance in this primed environment.

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      P1.04-12 - Mass Spectrometry-Based Serum Proteomic Signature as a Potential Biomarker for Survival in NSCLC Patients with Immunotherapy (ID 13444)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae  |  Author(s): Won Bin Kim, Nicholas I. Simon, Kyunghoon Rhee, Junho Song, Anderson Cho, Michael Oh, Wade Thomas Iams, Andrew A. Davis, Jonathan Anker, Lee Chun Park

      • Abstract
      • Slides

      Background

      The Veristrat test is a serum biomarker using a mass spectrometry (MS)-based proteomic signature derived from machine learning. It is used as a prognostic marker for patients with NSCLC undergoing platinum-based chemotherapy. However, its role in patients undergoing immunotherapy has not been investigated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      47 patients with advanced stage NSCLC and no activating EGFR mutation underwent VeriStrat testing from 2016 to 2017. Patients were grouped into Veristrat ‘Good’ risk group (VS-G) or Veristrat ‘Indeterminate’ & Veristrat ‘Poor’ risk group (VS-IP). Kaplan-Meier survival analyses with log rank test were performed to compare the progression-free survival (PFS) and overall survival (OS) between the two groups. PFS of NSCLC patients treated with immunotherapy was derived from the time of the immunotherapy to disease progression or death.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1_pfs by nsclc population treated with immunotherapy.jpg

      47 patients had a mean age of 65.6 (range: 30 to 91). 26 patients were female (55%). 26 patients had diagnosis of adenocarcinoma (55%), while 18 patients had squamous cell carcinoma (38%). 32 patients (68%) underwent treatment with a PD-1 inhibitor (pembrolizumab or nivolumab), whereas 15 patients (32%) did not. 32 patients (68%) demonstrated VS-G trait while 15 patients (32%) demonstrated VS-IP trait (intermediate: 1, poor: 14). Overall, VS-G demonstrated significantly prolonged PFS compared to VS-IP for all NSCLC patients regardless of treatment (median PFS, 12.0 months vs. 6 months, p<0.05), though there was not a significant different in OS between VS-G and VS-IP. Among NSCLC patients treated with immunotherapy, VS-G classification trended towards increased PFS when compared to VS-IP (Figure 1, median PFS, 12.0 vs 4.2 months, p=0.054), while OS was not statistically different. Multivariate analysis revealed that Veristrat was an independent predictor of PFS in this patients, regardless of various clinical factors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MS-based serum proteomic signature may serve as a biomarker for survival outcome in patients with NSCLC, including patients undergoing immunotherapy.

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      P1.04-13 - Combining Clinical and Genomic Data for Predicting Response to Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer (ID 12278)

      16:45 - 18:00  |  Presenting Author(s): Michelle Chiu  |  Author(s): Mary Beth Lipka, Priyanka Bhateja, Afshin Dowlati

      • Abstract
      • Slides

      Background

      Programmed death receptor (PD-1) inhibitors have emerged as a viable option for several cancers including advanced non-small cell lung cancer (NSCLC) by demonstrating good response rates, increased long-term survival, and a favorable safety profile. Although PD-L1 expression and tumor mutational burden have some role in determining response, these are not always predictive. Therefore identification of other characteristics to predict response to immunotherapy remains of interest and is the focus of this study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Information from patients with NSCLC treated at UH Cleveland Medical Center has been compiled into a large single institution database. From this prospective database, 116 patients treated with PD-1 inhibitors were identified and their pathological, clinical, and genomic characteristics were gathered. Parameters such as sex, race, smoking status (current vs. former vs. never smoker, years smoking and pack years), and tumor mutational status were statistically analyzed to determine association with response to immunotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      In this study, 116 patients were treated with PD-1 inhibitors. Overall the response rate to therapy was 22%. Among the 116 patients, 78 had genomic data, which was analyzed and yielded four tumor mutations associated with a clinical response. Of the 6 patients with an NF1 mutation and 6 with an RB1 mutation, none showed a response to treatment (p=0.178). Conversely our analysis showed a positive response to immunotherapy with KRAS and MYC mutations at p-values of 0.098 and 0.018, respectively. MYC mutation remains statistically significant at predicting response when controlling for the effects of age and smoking history.

      Of significant interest we found that a positive response to immunotherapy is associated with positive smoking history and current smoking status. The response rate to immunotherapy was 0% for never smokers, 21.6% for former smokers, and 29.4% for current smokers (p=0.193). Both years smoking and pack years are positively associated with response to immunotherapy with a response increase of 3% per each year smoking (p=0.062).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study found a positive correlation between response to immunotherapy in patients with NSCLC and ongoing smoking habits as well as overall pack years smoked. It also demonstrated that positive response to therapy is associated with tumor mutations in KRAS and MYC while a lack of response is associated with tumor mutations in NF1 and RB1.

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      P1.04-14 - HLA B44 Supertype Associated with Less Favorable Neoantigen Binding in Non-Small Cell Lung Cancer Treated with Immunotherapy (ID 12285)

      16:45 - 18:00  |  Presenting Author(s): Amy Cummings  |  Author(s): Henry Lu, Jaklin Gukasyan, John Madrigal, James Carroll, Krikor Bornazyan, Benjamin Jones, Zorawar Noor, Aaron Lisberg, Jonathan W. Goldman, Siwen Hu-Lieskovan, Steven M Dubinett, Edward B Garon

      • Abstract
      • Slides

      Background

      Human leukocyte antigen (HLA) supertypes may influence immunotherapy efficacy, particularly HLA class 1 B44 supertype (B44), which is found in 35-55% of the population irrespective of race (Sidney, BMC Immunol). In melanoma patients treated with immune checkpoint inhibitors, presence of B44 correlated with improved survival (Chowell, Science), but in a cohort of 58 non-small cell lung cancer (NSCLC) patients treated with single-agent pembrolizumab, B44 was associated with poorer outcomes (Lu, ASCO 2018). Given B44’s small electropositive binding pocket, it was hypothesized that the transversions that predominate in NSCLC result in more positive tumor variant amino acids (vAAs) and that these neoantigens would have decreased binding affinity and/or HLA B44:peptide stability.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      58 advanced NSCLC patients treated with pembrolizumab had germline and tumor multiplexed paired-end Illumina WES performed. HLA typing used BWA-ALN and Athlates software; supertype was determined by 2008 criteria (Sidney, BMC Immunol). Six subjects with at least one strong HLA B44 supertype allele had nonsynonymous coding mutations identified with Genome Toolkit Analysis (GATK) best practices utilizing the Hg38 genome reference. PvacSeq software used NetMHC algorithms to identify tumor neoantigens 9 base pairs in length matched to their corresponding HLA B44 allele (B44-specific neoantigens, BSNs). Missense BSNs were classified by transition (Ti) transversion (Tv) ratios and vAA charge change. TiTv was compared with matched pairs analysis. Predicted NetMHC IC50 binding affinities were compared with student’s t-tests. All statistical analyses were performed with SAS JMP, Version 13.0 (Cary, NC).

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 6 subjects, 3073 BSNs were identified; 1090 were unique. There were no common BSNs among subjects. Subject tumor TiTv median was 1.58 (95% CI 1.09-1.94), mean difference compared to germline was -0.62 (95% CI -1.11 to -0.12, p=0.02). BSNs with vAAs that changed charge represented 13.5% of all BSNs. Positive vAA charge changes were as expected based on theoretical distribution (12.5% Tv vs 6.3% Ti, p=0.02). In aggregate, there were 205 BSNs with negative charge change (-BSN) and 204 with positive charge change (+BSN). The anticipated HLA B44 binding affinity was lower for +BSN, with median NetMHC IC50 binding 176.2 (95% CI 178.0-217.9) vs 258.6 (95% CI 216.9-257.7) for -BSN, p<0.01.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A potential mechanism for decreased survival in B44 NSCLC subjects treated with immunotherapy is unfavorable neoantigen binding related to increased transversions leading to tumor vAAs with positive charge changes and poorer HLA B44 binding. All subjects from this cohort will be evaluated for BSNs 8-12 base-pairs long to confirm these findings.

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      P1.04-15 - Computerized Tomography Texture Analysis as Biomarker of Benefit from Nivolumab in Advanced Non-Small Cell Lung Cancer (ID 13040)

      16:45 - 18:00  |  Presenting Author(s): Carlo Genova  |  Author(s): Emanuele Barabino, Gianluca Ficarra, Marta Verda, Erika Rijavec, Giovanni Rossi, Marco Tagliamento, Federica Biello, Giulia Barletta, Maria Giovanna Dal Bello, Giuseppe Cittadini, Francesco Grossi

      • Abstract

      Background

      While immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), response assessment is a challenging task. Indeed, due to the peculiar mechanism of action of ICIs, the currently employed response evaluation criteria based on dimensional assessment might underestimate their activity. Computerized tomography texture analysis (CTTA) is an emerging approach belonging to the field of “radiomics” and based on the analysis of quantitative data extracted from imaging features; recently, correlations between CTTA and histopathologic as well as molecular characteristics of solid tumors were observed. Our aim is to determine whether parameters derived from CTTA might be used to assess the benefit from ICIs in advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Among 74 patients (Pts) treated with nivolumab for advanced NSCLC, 35 had CT scans evaluable for CTTA and had undergone at least two assessments (at baseline and after 4 cycles). Each pulmonary lesion was evaluated by a radiologist experienced in CTTA, blinded to clinical and temporal data; 295 texture analysis parameters were obtained from each image using an open source software (MaZda, version 4.6). The variations of parameters derived from pre-set gray-level co-occurrence matrices (GLCM) before and after 4 cycles of nivolumab were determined and compared with clinical outcomes. Statistical analyses were performed using MedCalc Statistical Software (version 18).

      4c3880bb027f159e801041b1021e88e8 Result

      After a median follow up of 9.9 months, variations of GLCM features describing entropy were directly associated with overall survival (OS). Most notably, Pts with increase of entropy above the median value between baseline and the subsequent CT scan identified with a specific GLCM combination had longer OS (15.3 vs. 6.2 months; p= 0.044). This finding suggests that increased tissue heterogeneity during treatment, possibly caused by immune cells infiltration, might be associated with improved outcomes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CTTA might have a prognostic/predictive role during treatment with ICIs for NSCLC. Further analyses including clinical and histopathologic features are currently ongoing, in order to enlighten the biological mechanisms at the basis of our observations.

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      P1.04-16 - Comparison of Clinical Response to Checkpoint Inhibitors in Advanced NSCLC with High PD-L1 Expression Tested on Cytology Versus Biopsy Samples (ID 12525)

      16:45 - 18:00  |  Presenting Author(s): Katie Guo  |  Author(s): Goulnar Kasymjanova, Hangjun Wang, Lama Sakr, David Small, Victor Cohen, Carmela Pepe, Alan Spatz, Jason S Agulnik

      • Abstract
      • Slides

      Background

      PD-L1 immunohistochemistry (IHC) expression correlates with clinical response to checkpoint inhibitors in advanced-stage NSCLC. PD-L1 IHC testing is usually performed on tissue blocks from core needle biopsy or surgical resection, but appears to be feasible on cytology cell blocks as well. In this retrospective study, we assessed the clinical response to checkpoint inhibitors in patients with NSCLC and high PDL1 IHC expression on cytology specimens in comparison with tissue biopsy specimens.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between August 2015 and April 2018, 116 patients with NSCLC received immunotherapy at our institution. Only cases with known PD-L1 expression from IHC testing performed on small biopsies or cytology cell blocks were included. A total of 65 consecutive cases were reviewed, including 40 small biopsies and 25 cytology samples. A Tumor Proportion Score (TPS) was categorized as high (≥ 50% tumor cell staining) or low (<50%). Response to treatment was categorized as disease control (DC, including complete and partial response and stable disease) or progression (PD). The primary outcome was the rate of disease control.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were mostly current or ex-smokers (91%), Caucasians (82%) and non-squamous carcinomas (85 %). High TPS was seen in 44 (68%) cases. Immunotherapy was given in the first line setting in 20 (31%) patients, the second line in 36 (55%), and the third line in 9 (14%). 50 (77%) patients received Pembrolizumab, 10 (15%) Nivolumab and 5 (8%) others received immunotherapies on RCTs. Overall, there was DC in 40 (62%) patients and PD in 17 (26%). There was no significant difference in DC rate between the cytology and the small biopsy groups in high TPS group.

      table 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      PD-L1 expression on cytology cell blocks and on small biopsies appears to have similar clinical significance. Further prospective trials are needed to confirm these findings.

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      P1.04-17 - Tumour Burden as a Predictive Tool of Response to Immune Checkpoint Inhibitors (ICI) in Patients with Metastatic Non-Small-Cell Lung Cancer (ID 12467)

      16:45 - 18:00  |  Presenting Author(s): Oded Icht  |  Author(s): Liran Domachevsky, David Groshar, Elizabeth Dudnik, Ofer Rotem, Nir Peled, Daniel Reinhorn, Oded Jacobi, Tzippy Shochat, Hanna Bernstine, Alona Zer

      • Abstract
      • Slides

      Background

      ICI are a novel class of agents that have revolutionized treatment for patients with metastatic non-small-cell lung cancer (NSCLC). Still, most patients do not benefit from PD-1 axis inhibitors, emphasizing the need for additional markers beyond PDL-1 expression for better selection of patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This retrospective, single centre study included all consecutive patients with advanced NSCLC who were evaluated with a FDG-PET scan prior to first administration of an ICI (nivolumab or pembrolizumab) between 1/2016 and 6/2017. Tumour burden was calculated using the total body Metabolic Tumour Volume (MTV) and the sum of all measurable lesions (SOML) with accordance to the RECIST criteria. This study received IRB approval.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 58 patients with histologically proven NSCLC were included. Patients had a median age of 65 years (43-84), 59% were male, 62% had adenocarcinoma and 83% were previously treated with chemotherapy. The median PFS for the entire cohort was 5.7 (1-15.8) months, and the ORR for ICI was 44.8%.

      The median MTV was 12.95 (0-236) millimeter³ and was significantly and inversely associated with longer PFS (p=0.036, 95%CI 1-1.015). The median SOML was 88 (13-305) centimetres, and was significantly and inversely associated with a longer PFS and higher ORR (PFS: P=0.004, 95% CI 1.002-1.011, ORR: OR 0.993 p=0.0067(.

      Additionally, patients with a SOML under 56 CM (first quartile) had a longer PFS compared to patients with a higher disease volume (Table1).

      SOML

      (CM)

      Median PFS

      (months)
      P value
      (compared to 1st quartile)
      1st quartile 56 12.1 -
      2nd quartile 88 5.1 0.017
      3rd quartile 115 4.23 0.036
      4th quartile 305 3.15 0.01

      table 1: some of measurable lesions (in centimeters) and PFS in metastatic NSCLC pateints recieving ICI

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our study, a high tumour burden in patients with advanced NSCLC treated with ICI was associated with a shorter PFS and a lower ORR. This association warrants further prospective evaluation in order to optimize treatment.

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      P1.04-18 - PD-L1 Expression and its Correlation with Tumor TNM Stage in Patients with Non-Small Cell Lung Cancer   (ID 13121)

      16:45 - 18:00  |  Presenting Author(s): Taewon Jang  |  Author(s): Jehun Kim

      • Abstract

      Background

      Immunotherapy has now become a standard therapy of lung cancer treatment. Programmed death ligand (PD-L) 1 expression has provided a predictive biomarker for anti-PD-1/PD-L1 therapy. However, the relationship between the expression of PD-L1 and the clinical and pathologic features were still unclear. The purpose of this study was to investigate the clinical factors affecting the expression of PD-L1 and the concordance of the DAKO assay with the Ventana assay.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We evaluated in 178 non-small-cell lung cancer patients and assessed PD-L1 expression by immunohistochemistry after staining them with antibody 22C3 (Dako) or SP263 (Ventana). Clinical features were acquired from the electrical medical records, retrospectively. We analyzed the relationship between PD-L1 expression and clinicopathological characteristics.

      4c3880bb027f159e801041b1021e88e8 Result

      One hundred fifty four patients were available for analysis. There were 130 cases which both tests were performed. Mean age was 66.7 years-old. Male patients were 70%, and adenocarcinoma was 68%. Stages were stage I 15.6%, II 7.1%, III 28.6%, and IV 48.7% respectively. In using the 22C3 antibody, PD-L1 expression in Tumor proportion score (TPS) ≥ 50% was 27.7%, and 52.3% in TPS ≥ 1%. PD-L1 expression rate in man was higher than woman (37,6 % vs 16,7%, P=0.028). In the sp263 antibody, PD-L1 expression rate (TPS ≥10%) was 52.9%, and 68.8% in TPS ≥ 1%. Age, primary tumor, regional lymph node, distant metastasis and stage grouping were not statistical different between patients with and without PD-L1 expression. All patients (n=36) with TPS ≥ 50% in the 22c3 test were found to have TPS ≥ 10% in the sp263 test.

      8eea62084ca7e541d918e823422bd82e Conclusion

      There were no specific predictable factor in PD-L1 expression except male factor. But, we suggest that further study will be needed by adding other factors and more patients.

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      P1.04-19 - Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Predict Survival After Immunotherapy in Non-Small Cell Lung Cancer (ID 13650)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae  |  Author(s): Michael Oh, Diana Saravia, Sarita Agte, Ashkon Alexander Rahbari, Wungki Park, Gilberto de Lima Lopes

      • Abstract
      • Slides

      Background

      Effective use of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) may be improved by identifying biomarkers that are easily measured and predictive of clinical outcomes. Peripheral complete blood counts are commonly obtained and can be indicative of systemic inflammatory response, which has been associated with poor prognosis in multiple cancer types. Here, we investigated the ability of peripheral cell counts to predict patient survival after treatment with immunotherapy for NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Complete blood counts were retrospectively collected for 274 patients and analyzed for absolute neutrophil count (ANC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). Values were obtained immediately prior to treatment initiation. Overall survival (OS) and progression-free survival (PFS) was assessed using Kaplan-Meier analyses with log-rank test and Cox regression analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      OS was significantly associated with ANC (HR 1.63, p<0.0001) and NLR>5 (HR 1.62, p<0.0001), as was PFS (HR 1.48, p=0.0008 and HR 1.48, p=0.0012, respectively). PLR>400 was not associated with OS but did have a significant association with PFS (HR 1.39, p=0.0388). Baseline elevation of both NLR and PLR identified a particularly high-risk population, with worse OS (HR 1.69, p=0.0020) and PFS (HR 1.58, p=0.0069) when compared to the patient group with low baseline NLR and PLR (Figure 1). High NLR and PLR as a combined marker remained an independent predictor of OS in multivariate analysis after adjusting for multiple clinical variables (HR 1.91, p=0.008).

      figure 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Increased baseline ANC, NLR, and PLR were associated with worse overall and progression-free survival, and the combination of both high NLR and PLR denoted a subgroup with especially poor outcomes. These findings will need to be validated in larger prospective studies to further assess their clinical utility.

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      P1.04-20 - Computational Biological Model Prediction of PD-L1 Expression and Immunotherapy Response for KRAS Mutated Lung Cancer Based on Co-Mutations (ID 13049)

      16:45 - 18:00  |  Presenting Author(s): Sukhmani Kaur Padda  |  Author(s): Jacqueline Virginia Aredo, Shireen Vali, Neeraj Kumar Singh, Sumanth M Vasista, Upasana Mitra, Taher Abbasi, Heather A Wakelee

      • Abstract
      • Slides

      Background

      Emerging data suggest that KRAS mutated non-small cell lung cancer (NSCLC) is a heterogeneous disease based on the presence of co-mutations. These co-mutations may impact PD-L1 expression, a predictive biomarker for PD-1/PD-L1 immunotherapy, and may result in differential responses to immunotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Genomic information of NSCLC patients, including 2888 from publically available datasets and 86 from Stanford University, was input into computational biological model (CBM) software (Cellworks Group, San Jose, CA). Customized computational protein network maps of disease characteristics were generated for each patient. CBM was used to predict PD-L1 protein expression and also response to PD-1/PD-L1 immunotherapy in KRAS co-mutation subsets using 3 key metrics: PD-L1 expression; Dendritic Cell Infiltration Index (9 chemokine markers); and Immunosuppressive Biomarker Expression (14 markers).

      4c3880bb027f159e801041b1021e88e8 Result

      The major co-mutations observed with the KRAS mutation were in tumor suppressor genes (TP53, STK11, CDKN2A, KEAP1) and a downstream effector (PIK3CA). Using the CBM approach, KRAS mutated NSCLC tumors with TP53 co-mutations had the highest prevalence of PD-L1 protein expression whereas tumors with KRAS/KEAP1 and KRAS/STK11/KEAP1 co-mutations were associated with the lowest expression. Expression of PD-L1 in tumors with KRAS/STK11, KRAS/CDKN2A, KRAS/PIK3CA co-mutations, and KRAS without co-mutations was higher than in tumors with KRAS/STK11/KEAP1 and KRAS/KEAP1 co-mutations. Of the 30 NSCLC tumors in the Stanford dataset with available PD-L1 immunohistochemistry results, including 19 with KRAS/TP53 and 11 with KRAS/KEAP1 or KRAS/STK11/KEAP1, CBM accurately predicted PD-L1 expression in these two groups at rates of 79% and 72%, respectively. In regards to prediction of response to PD-1/PD-L1 immunotherapy, CBM predicted the majority of patients with KRAS/KEAP1 and KRAS/STK11/KEAP1 to be non-responders, whereas CBM predicted the majority of patients with KRAS/TP53, KRAS/PI3KCA, and KRAS without co-mutations to be responders. The proposed mechanism for KRAS co-mutations’ impact on PD-L1 expression from the CBM model integrates differential activation of (i) downstream pathways of KRAS (PI3K/AKT, RAF/ERK, and RAL) and (ii) transcription factors involved in PD-L1 expression (i.e., MYC, HIF1α, NFKβ, AP1, and STAT1/3).

      8eea62084ca7e541d918e823422bd82e Conclusion

      KRAS mutated NSCLC is emerging as a diverse disease based on co-mutations. The CBM approach demonstrates that PD-L1 expression varies among KRAS co-mutation subtypes along with likelihood of response to PD-1/PD-L1 immunotherapy. CBM provides proposed mechanisms underlying these differences and therefore, provides further rationale to examine more precise delivery of immunotherapy.

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      P1.04-21 - The Utility of PD-L1/CD8 Dual Immunohistochemistry for Prediction of Response to Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) (ID 13815)

      16:45 - 18:00  |  Presenting Author(s): Mari Mino-Kenudson  |  Author(s): Matthew Rosenbaum, Sara Khosrowjerdi, Vashine Kamesan, Subba Digumarthy, Justin F Gainor

      • Abstract

      Background

      PD-L1 immunohistochemistry (IHC) is an important predictive biomarker for PD-(L)1 blockade in advanced non-small cell lung cancer (NSCLC); however, this assay is imperfect. The presence of CD8+ tumor infiltrating lymphocytes (TILs) may be a complimentary biomarker for response to immunotherapy. Thus, we examined the performance of PD-L1/CD8 dual IHC (dIHC) in two cohorts of NSCLC patients receiving immunotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were identified through retrospective review of medical oncology and pathology databases. The first cohort predominantly received nivolumab as a 2nd or later line treatment; tissue samples were mainly obtained at initial diagnosis. The second cohort received pembrolizumab as a first line therapy, and tissue samples were procured immediately before the initiation of immunotherapy. PD-L1/CD8 dIHC was performed on those tissue samples. Percentage of tumor cells with membranous PD-L1 expression and CD8+ stromal cells were measured, and CD8+ TILs were semi-quantitatively evaluated. The quantities of CD8+ T cells were dichotomized with appropriate cut-offs.

      4c3880bb027f159e801041b1021e88e8 Result

      Eighty-four patients were identified, including 60 in the Nivolumab cohort (NC) and 24 in the Pembrolizumab cohort (PC). In the NC, PD-L1 expression ≥1% was marginally associated with improved progression-free survival (PFS, p=0.09), and an increased rate of response (p=0.08). CD8+ TILs and stromal cells did not correlate with outcome. However, a subset of PD-L1-positive patients who showed abundant CD8+ TILs and stromal cells had significantly reduced PFS (p=0.04). In the PC cohort, all cases chosen exhibited PD-L1 expression in ≥50% of tumor cells. Increased CD8+ TILs were correlated with improved PFS, (p=0.0194), and an increase in both CD8+ TILs and stromal cells was also associated with improved PFS (p= 0.0238).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although limited by small sample size, this study suggests that PD-L1/CD8 dIHC improves the prediction of response to the PD-1/PD-L1 blockade in advanced NSCLC patients when it is performed on tissue samples obtained immediately before the initiation of the blockade as first-line therapy . However, for the 2nd or later line of treatment, dIHC on archival tissue samples obtained before initial therapy provides a useful but less clear picture of the tumor immune microenvironment. Reduced PFS seen in patients with PD-L1 expression and abundant CD8+ TILs and stromal cells may be due to T-cell exhaustion after the chemotherapy before the PD-1/PD-L1 blockade. These findings suggest that PD-L1/CD8 dIHC may be useful for treatment response stratification in advanced lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.04-22 - CD73 Immunohistochemical Expression in Malignant Cells and Correlation with Immune Infiltrate in Non-Small Cell Lung Carcinoma (NSCLC). (ID 11859)

      16:45 - 18:00  |  Presenting Author(s): Ignacio I. Wistuba  |  Author(s): Ruth Salazar, Jose Luis Solorzano, Luisa Solis, Carmen Behrens, Barbara Mino, Edwin Roger Parra, Jianjun Zhang, Ara A Vaporciyan, David Rice, Neda Kalhor, Cesar Moran, Don Lynn Gibbons, Annikka Weissferdt, Boris Sepesi

      • Abstract
      • Slides

      Background

      CD73 is potential novel target for lung cancer immunotherapy involved in the adenosine pathway that induces tumor microenvironment immunosuppression. We investigated the immunohistochemical (IHC) expression of CD73 in a large cohort of NSCLC and correlated with tumor’s clinical, pathological, molecular and immune cells infiltration data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We examined 175 surgically resected stages I-III formalin-fixed and paraffin-embedded NSCLC tumors tissue microarrays, including 107 adenocarcinomas (ADC) and 68 squamous cell carcinomas (SqCC). For IHC, we used the anti-CD73 antibody (clone D7F9A, Cell Signaling Technology) and evaluated membrane (basolateral and luminal) expression in malignant cells. In a subset of cases, CD73 IHC expression was correlated with data available on: a) CD73 gene mRNA expression (Illumina arrays; n=91); b) EGFR and KRAS mutation status and mutational load (whole exome sequencing; n=104); and, c) density of tumor associated immune cells infiltration (CD3, CD4, CD8, CD68, CD45RO, CD57, FOXP3, and granzyme B) and immune checkpoints expression (PD-L1, PD-1, ICOS, TIM-3, IDO-1, B7-H3, B7-H4, VISTA and OX40) assessed by IHC and image analysis (n=172).

      4c3880bb027f159e801041b1021e88e8 Result

      ADC showed higher CD73 IHC expression than SqCC (P<0.0001). Pathological stage I ADCs showed higher CD73 expression than higher tumor stages (P=0.0419). Using any level of CD73 expression (>1%) CD73 was expressed in 73% and 40% of ADCs and SqCs, respectively. High expression (>50% of malignant cells) was detected in 35% of ADCs and 20% of SqCC. No other significant correlations with clinical-pathological variables, including patients’ outcome were found. Interestingly, ADCs with EGFR (P=0.04) and KRAS (P=0.02) mutation expressed higher CD73 levels than wild-type tumors. In ADC, CD73 IHC expression correlated significantly with the density of immune T CD3+, CD4+, CD8+, CD45RO+ and FOXP3+ cells, as well as macrophages CD68+ cells in tumors (r values range: 0.22-0.45; P values range: 0.001-0.02). Overall, we did not find significant correlations between CD73 immunostaining and the IHC expression of the immune checkpoints examined. CD73 IHC expression correlated positively with mRNA CD73 gene expression levels in all NSCLCs (r=0.6; P<0.0001), ADCs (r=0.6; P<0.0001), and SqCCs (r=0.49, P<0.0001) histology

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified that CD73 protein expresses in a subset of resected NSCLCs, being significantly higher in adenocarcinoma histology. In this histology type, CD73 correlates with immune T cells and macrophages infiltration, and notably, with tumor’s EGFR and KRAS mutation. Our data suggest that CD73 is a potential target for NSCLC, particularly for adenocarcinoma histology (Supported by grants CPRIT RP160668 and UT Lung SPORE).

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      P1.04-23 - Expression of Emerging Immunotherapy Targets in Early-Stage Squamous Lung Carcinoma (ID 13520)

      16:45 - 18:00  |  Presenting Author(s): Hui Yu  |  Author(s): Zhengming Chen, Karla Ballman, Mark Watson, Ramaswamy Govindan, David Beer, Raphael Bueno, Michael Herman, Wilbur A. Franklin, David R. Gandara, Mary-Beth Moore Joshi, Daniel T Merrick, William G Richards, Christopher J. Rivard, Frances A Shepherd, Ming Sound Tsao, Adrian van Bokhoven, David Harpole, Fred R. Hirsch

      • Abstract
      • Slides

      Background

      Anti-PD1/PD-L1 immunotherapy has demonstrated response in approximately 20% of unselected advanced non-small cell lung cancer (NSCLC) patients. Strategies involving combination immunotherapies are under investigation to improve the overall response to immunotherapy. The objective of this study was to identify the expression of emerging immune targets in a cohort of early-stage squamous lung carcinoma (SqLC), which may be used to design combinatorial immunotherapy approaches.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      202 early stage (I-II) SqLC resected patient tumors and corresponding clinical data were collected from 6 cancer centers as part of the SPECS II program. Fourteen emerging immune targets or targeted axis were selected based on their advanced stage of development in preclinical/clinical studies. The mRNA expression level of these targets and PD-1/PD-L1 were determined by Affymetrix U133A gene expression profiling. The correlations among these targets and the overall survival were evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      The mRNA levels of the immune molecules which were grouped on PD-L1 protein expression in early stage SqLC are shown in Figure 1. No correlation was found between the mRNA level of PD-L1 and the other immune targets expressed on APC/tumor cells, except PD-L2 (r2= 0.41, p<0.00001). We found that the immune cell receptor, CD226, correlated with CD96 and CD112R respectively (r2= 0.514, p<0.00001; r2= 0.476, p<0.00001), and CD96 correlated with CD112R (r2= 0.644, p<0.00001) as well. In addition, higher expression of GAL-9, CD48 and ICOS were associated with better prognosis [p= 0.0358, HR=0.249 (0.068, 0.912); p= 0.0309, HR=1.61 (1.04, 2.49); p= 0.0429, HR=2.47 (1.03, 5.93)].

      figure 1.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      Several emerging immune targets were expressed at higher levels than PD-L1 in this early stage SqLC cohort. The mRNA levels of all immune targets evaluated were independent of PD-L1 expression, except PD-L2. The expression of GAL-9, CD48 and ICOS were identified as prognostic. These results may provide important information in the design of future combination immunotherapies for early-stage SqLC.

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      P1.04-24 - Digital Core Needle-Biopsy to Assess PD-L1 Expression in Non-Small Cell Lung Cancer: Optimal Sampling and Need for Re-Biopsy (ID 12059)

      16:45 - 18:00  |  Presenting Author(s): Alexander Haragan  |  Author(s): John Kirkpatrick Field, Michael P A Davies, Carles Escriu, Aaron Gruver, John Roy Gosney

      • Abstract
      • Slides

      Background

      Assessing expression of PD-L1 on tumour cell membranes by immunochemistry is an important complementary or crucial companion diagnostic test to guide the use of immune modulating checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, the known temporal and spatial heterogeneity of PD-L1 expression raises the important question of how to ensure that the small biopsy specimens with which this assessment is usually made are adequately representative of PD-L1 expression by the whole tumour.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Expression of PD-L1 was assessed in sections of 94 tissue blocks from 50 primary pulmonary adenocarcinomas using the Ventana SP263 antibody and a validated protocol. Scoring was performed by two appropriately-trained pathologists with extensive experience in its interpretation. After conventional assessment, slides were digitally scanned and divided into squares of 1mm² area to form a digital database (mean of 150 data-points per tumour), which were assigned co-ordinates and re-scored. By these means, multiple, “digital core biopsies” (DCBx) approximating a 17 gauge needle were simulated in sequential fashion, and expression in these was compared to that in the whole tumour and categorised by current UK prescribing guidelines*

      4c3880bb027f159e801041b1021e88e8 Result

      PD-L1 score (%)

      Total number of cases

      Cases where PD-L1% from single DCBx changed scoring category vs whole tumour*

      Cases where PD-L1% from two DCBx changed scoring category vs whole tumour*

      Cases where PD-L1% from three DCBx changed scoring category vs whole tumour*

      Cases where PD-L1% from four DCBx changed scoring category vs whole tumour*

      Cases where PD-L1% from five DCBx changed scoring category vs whole tumour*

      Focal expression primary pattern in non-correlative cases

      <1

      14

      2

      2

      2

      2

      2

      Y

      1-10

      13

      6

      3

      1

      1

      0

      Y

      11-49

      10

      1

      1

      0

      0

      0

      Y

      50-100

      13

      0

      0

      0

      0

      0

      n/a

      All

      50

      9 (18%)

      6 (12%)

      3 (6%)

      3 (6%)

      2 (4%)

      PD-L1, programmed death ligand 1; DCBx, Digital Core Biopsy

      *Based on pembrolizumab categories as: 1st line ≥50%, 2nd line 1-49%; nivolumab categories as: ≥1% (for adenocarcinoma)

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the majority of cases, three digital core biopsies achieved closest correlation with the whole tumour, with little greater accuracy achieved by assessing four cores or more. Correlation was weakest when expression was low and very focal, an important consideration in view of the importance of the ‘1% cut-off’ used commonly to guide immune checkpoint therapy. Using this model as a guide, a single good quality biopsy (2x10mm² area) is sufficient for most tumours scoring 11% or greater PD-L1 expression. However, in the lower range of expression, re-biopsy might be routinely considered if there is doubt about specimen adequacy.

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      P1.04-25 - The Implication of Frameshift Mutation Burden in Neoantigen and Immune Cell Landscape in Non-Small Cell Lung Cancer (NSCLC) (ID 11995)

      16:45 - 18:00  |  Presenting Author(s): Young Kwang Chae  |  Author(s): Sangmin Chang, Taeyoung Ko, Kyunghoon Rhee, Marcelo Cruz, Manali Bhave, Jonathan Anker, Andrew A. Davis, Wade Thomas Iams, Victor Wang, Jeffrey H Chuang, Lee Chun Park

      • Abstract
      • Slides

      Background

      Recent research has shown an association between enrichment of insertion and deletion (indel) mutations and tumor-specific neoantigens, which in turn correlated with T-cell activation in renal cell carcinomas. Furthermore, frameshift indel (fsindel) mutation counts were significantly associated with clinical response to immune checkpoint inhibitors (ICIs) in melanoma patients. However, little is currently known about such associations in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Neoantigen counts were based on CloudNeo, a cloud pipeline used for identifying patient-specific neoantigens. The immune cell signatures of 31 distinct immune cell types of samples were derived from RNA-sequencing of 812 immune metagenes obtained from The Cancer Genome Atlas. 511 lung adenocarcinoma (ADC) and 471 squamous cell carcinoma (SqCC) patient samples were divided into 4 quartiles (Q1-Q4) according to number of fsindel mutations in order to compare neoantigen counts and immune cell infiltration. Fsindel mutations were identified from mutation annotations generated by the Genomic Data Commons’ MuTect2 somatic variation calling workflow.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1_final.pngThe range of fsindel count of ADC and SqCC were 0-139 and 0-150, respectively, while the median fsindel count was 7 and 8, respectively. Neoantigen count showed a significant positive association with fsindel in both ADC and SqCC (p<0.0001, p<0.01 respectively). Furthermore, a higher number of fsindels was associated with significantly increased activated CD4 and CD8 T-cell infiltration in ADC (Figure 1. p<0.001, p<0.01, respectively), while a similar trend was observed in SqCC for CD4 and CD8 T-cells, although not significant (Figure 1. p=0.056, p=0.341, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We report for the first time the association between fsindels and higher neoantigen burden and infiltration of activated CD4 and CD8 T-cells in human NSCLC. As the presence of immune cells has been shown to be an important factor in determining response to ICIs, our findings suggest that fsindels could potentially be used as a predictive marker for immunotherapy.

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      P1.04-26 - Prospective Immuno-Biobank in NSCLC (ID 13831)

      16:45 - 18:00  |  Presenting Author(s): Alfredo Addeo  |  Author(s): Celine Py, Garance Gutknecht, Alex Friedlander, Aurelie Vuilleumier, Pierre-Yves Dietrich

      • Abstract
      • Slides

      Background

      Immune system could recognize tumor cells and eliminate them. T lymphocytes play an essential role in recognizing and lysing tumor cells. However, the humoral response (antibodies) seems also important. Recently, therapeutically progresses have been obtained with monoclonal antibodies that target inhibitory molecules expressed by T lymphocytes (anti-CTLA4, anti-PD1). Those antibodies induce reactivation or improvement of T lymphocytes’ lysing capacities. This clinical benefit can last for years and has been observed in several types of tumors. This is the beginning of a therapeutic revolution and hundreds of clinical trials are on-going with the objective of better exploitation of this strategy.

      Several steps are needed in order to increase the proportion of patients who benefit from immunotherapies.We currently do not understand completly the reason why an immune response could be efficient or not (spontaneously or after treatment), the respective role and interactions between humoral and cellular responses and mechanisms involved in the development of side effects observed in patients

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All NSCLC patients who are candidate for Immunotherapy treatment regardless of staging and line of treatment cancer will be identified within our oncology department

      Blood sampling will be performed (50 to 100 ml) at severals time points: before any immunotherapy and repeated every 3 months or, in case of side effects or in case of extra-ordinary evolution.

      We will investigate cellular (T lymphocytes) and humoral (B lymphocytes) immune responses. We will also do a sequencing of the tumor in order to investigate genetic alterations. We will question the correlations between immune response and tumor pathological and molecular characteristic’s, as well as the impact of therapies administered to the patients on their immune response.

      4c3880bb027f159e801041b1021e88e8 Result

      We have recruited 12 patients so far, on treatment with immune check point inhibitor. We are going to perform another sampling 3 months after the beginning of the treatment (9 patients at the present time) Currently, we are continuing to reclute patients. The first analysis will be performed once we have 50 patients within the study and presented and the incoming meeting in November 2018

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is, as far as we know, the first prospectiveand ongoing immune- bio-bank in NSCLC patients that is going to provide valuable information to better understand the immunological changing at serological, tissue and genomic level induced by the immunotherapy in NSCLC and the possible mechanism of resistance or progression.

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      P1.04-27 - Safety of Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) in the Real-Life Setting: A Single-Institution Experience from Argentina. (ID 13553)

      16:45 - 18:00  |  Presenting Author(s): Maria Virginia Bluthgen  |  Author(s): Mercedes Tamburelli, Carlos Calderon, Javier Castillo, Carlos Bas, Gonzalo Gomez Abuin, Susana Sena

      • Abstract
      • Slides

      Background

      Immunotherapy (IO) targeting programmed death-1 receptor (PD-1) has become standard of care in NSCLC treatment. Therefore, many patients will be at risk of developing toxicities from these treatments, representing a new challenge in daily clinical practice. We assessed its safety and activity in advanced NSCLC patients in the real-life setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a retrospective analysis of patients with NSCLC treated with immunotherapy at a single institution between January 2016 and January 2018. Safety and efficacy analyses were made by treating physician according to CTCEAE 4.0 and RECIST 1.1 respectively and retrospectively collected from medical records. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-seven patients were included. Median age was 66 years [range 45 - 79], 67% were male, 89% (n=24) had ECOG performance status (PS) of 0-1; all patients had advanced disease, with up to 2 metastatic sites in 52% (n=14) of the cases; 45% (n=12) had been tested and were positive for PDL-1 (≥ 1%). Almost all patients received immunotherapy as first or second-line treatment (n= 23, 85%). A median of 6 cycles [range 1 – 34] had been administered, with 60% exposed to nivolumab (n=16) and 40% (n=11) to pembrolizumab. Median follow-up since IO was 18 months [range 0.5 - 25.2]. Seven patients achieved partial response and eight had stable disease, giving an overall response rate of 26% and a 56% disease control rate; 44% presented progressive disease. Median PFS was 5.1 months [95%CI 2 – 8.1] and median OS was 19.3 months [95%CI 2.3 – 36.3]. A total of 10 patients (37%) developed high grade toxicity. The most common grade 3-4 related events were asthenia (n=5), adrenal insufficiency (n=2), infection (n=2), hypothyroidism (n=1), hepatitis (n=1), renal insufficiency (n=1) and thrombocytopenia (n=1) among others. Seven patients should discontinue treatment, 5 of them received glucocorticoids and almost all of them had full recovered after corticoid treatment (n=5).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Activity of immunotherapy was comparable to that reported in previous studies. However, high grade toxicity rates in our practice were much higher than those reported in clinical trials, despite the highly similar proportion of patients with good performance status in both settings. Although studies populations are highly selected, this finding must lead us to question our ability in early recognition and prompt management of adverse events in daily practice.

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      P1.04-28 - Baseline Markers of Inflammation and Outcome with Nivolumab in Pretreated Non Small Cell Lung Cancers: A Retrospective Study. (ID 13858)

      16:45 - 18:00  |  Presenting Author(s): Alessandro Russo  |  Author(s): Alessandra Battaglia, Giusy Provazza, Giuseppe Lo Certo, Giuseppina Rosaria Rita Ricciardi, Maria Picciotto, Antonino Scimone, Giuseppe Toscano, Vincenzo Adamo, Tindara Franchina

      • Abstract
      • Slides

      Background

      Nivolumab is a novel therapeutic option in pre-treated Non Small Cell Lung Cancer(NSCLC), independently of tumor histology and PD-L1 status. However, predictive biomarkers are lacking. We aimed to evaluate whether there is a correlation between some baseline markers of inflammation and the outcome of patients (pts) treated with Nivolumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All consecutive NSCLC pts treated with Nivolumab between Aug. 2015-Dec. 2017 at our Institution were analyzed. Baseline characteristics were collected and correlated with the outcome. Derived neutrophil-to-lymphocyte (dNLR) ratio was calculated as: neutrophil count/white blood count – neutrophil count. Platelet-to-lymphocyte (PLR) ratio was defined as platelet count/lymphocyte count. Overall survival (OS) was defined as time from Nivolumab start to death and Progression Free Survival (PFS) as time from Nivolumab start to progression disease or death for any cause. OS and PFS survival were estimated using the Kaplan–Meier method. Survival curves were compared using the log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      We included 45 consecutive NSCLC pts treated with Nivolumab. Baseline characteristics were as follows: median age 69 years (range 46-78), sex male 78%, female 12%, squamous histology in 51% and non-squamous in 49%. After a median follow-up of 16 months (mos), median PFS was 4.0 mos (CI 95%, 2-8) and median OS was 9.0 mos (CI 95%, 4-15). High neutrophil count (≥7500/mmc) and high lymphocyte count (≥1000/mmc) were associated with a shorter PFS (p=0.05 and p=0.01, respectively) and OS (p=0.373 and p<0.001, respectively), as well as low albumin levels (<3 g/dl) (p=0.05 for both PFS and OS). Moreover, a high dNLR (≥3), high PLR (≥160) and high LDH levels (> Upper Limit Normal) correlated with a numerically longer PFS and OS, although these differences were not statistically significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Baseline markers of inflammation correlate with inferior outcome with Nivolumab in unselected, pretreated, NSCLCs. The relative easy estimation of these parameters may be used with other predictive biomarkers in the treatment selection of pts candidate for immunotherapy.

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      P1.04-29 - Second or Third Line Nivolumab Versus First Line Nivolumab in Patients with Previously Treated Advanced Non Small Cell Lung Cancer (NSCLC) (ID 13510)

      16:45 - 18:00  |  Presenting Author(s): Antonio Irigoyen Medina  |  Author(s): Elia Martinez Moreno, Ruth Alvarez Cabellos, Katherin Aly Barroso Martinez, Jesus Andrade Santiago, Miguel Borregon Rivilla, Juan David Cardenas, Carmen Esteban, Blanca Trujillo, Adriana Rosero, Lourdes Fernandez, Irene Ramos, Alba Ramos, Jose Ignacio Chacon

      • Abstract

      Background

      The aim of the study was to report outcomes in advanced NSCLS patients treated with Nivolumab after progression to one versus two or three lines of chemotherapy from our everyday clinical practice. Exploratory assessments include the progression-free survival (PFS) and overall survival (OS) , the rates of chemotherapy retreatment after Nivolumab progression and toxicity profile.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Elegibility criteria included, histologically or citologically confirmed stage IV NSCLC without EGFR mutated or ALK traslocated genes treated with Nivolumab when relapsed after 1 versus 2 or 3 prior lines of chemotherapy from January of 2016 to current date.

      4c3880bb027f159e801041b1021e88e8 Result

      From January of 2016 to January of 2018 , a total of 61 patients were enrolled in the study from our Hospital.

      The patients demographics were: median age 63 years, 4,9% (n=3) female and 95% (n=58) male.

      There were 59% ( n=36 ) non squamous-cell and 41% (n=25 ) squamous-cell carcinoma.

      96% (n=59) have received platinum-based therapy previously to Nivolumab : 57% (n=34) combined with Premetrexed and 41% (n=25 ) with other drugs.

      60.7% % (n=37) received Nivolumab at second line and 39.3% (n=24) at 3 or more line .

      45,9 % ( n=28) received chemotherapy after Nivolumab. .These chemotherapy schemes icludes Bevacizumab in 40% of cases

      Grade 1-2 treatment related adverse events (AEs) occurred in 32% patients and the most common ones were endocrine 16% (n=7) and neumonitis 4% ( n=2) but there were one case isolated of grade 3-4 encephalitis, nephritis and hypophysitis

      The 4% ( n=29 patients need to be admitted to the hospital due Nivolumab toxicity versus 16% due to chemotherapy toxicity.

      The median of PFS with Nivolumab was 3 months for both groups IC 95% (2,09-3.9) and median OS for second line Nivolumab was 6 months IC 95% ( 2,7-9,2) and for Nivolumab at 3rd and sucesive lines of 9 months IC 95% ( 3,7-14,2)

      Median PFS for chemotherapy after Nivolumab was 5,3 months ( 2-12 months)

      Median OS was 18 months for second line Nivolumab and 26 months for the other patients and OS for all populaion was 21 months IC 95% (15.2 y 26.7)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Data suggests that Nivolumab is effective and well tolerated in no selected metastatic NSCLC enabling survival of 21 months for these patients with an aceptable toxicity profile .Chemotherapy and antiangiogenic based treatments after Nivolumab are effective and well tolerated.

      This support benefit in heavily chemotherapy pretrated patients: a crucial question that we can not ignore.

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      P1.04-30 - A Potential Effect of Diabetes Mellitus and Metformin Use on Efficacy of Immune Checkpoint Inhibitors (ICI) (ID 14072)

      16:45 - 18:00  |  Presenting Author(s): Oded Jacobi  |  Author(s): Yosef Landman, Daniel Reinhorn, Oded Icht, Elizabeth Dudnik, Ofer Rotem, Victoria Neiman, Michal Sarfaty, Inbar Finkel, Daniel Hendler, Nir Peled, Alona Zer

      • Abstract
      • Slides

      Background

      Numerous studies have demonstrated metformin use is associated with decreased cancer risk in the general population, as well as improved overall response rate (ORR), progression free survival (PFS) and overall survival (OS) in cancer patients undergoing chemotherapy.Recent in-vitro studies found several new mechanisms which granted metformin the potential to increase cancer patients' response to immune checkpoint inhibitors (ICI).
      In this study we aim to explore the correlation between the daily use of metformin and benefit from ICI in patients with lung cancer and other solid malignancies.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated all consecutive patients with metastatic solid malignancies treated with ICI therapy in a single institution between February 2015 and June 2017. Patients' clinical data was obtained from electronic medical records. Cox proportional hazards model and chi squared test were used to determine the associations between metformin use and ORR, median PFS (mPFS) and median OS.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 218 patients included in the analysis (202 NSCLC, 16 non lung cancers), 49 (22.5%) suffered from type 2 diabetes mellitus (T2DM). Of them 33 (15.1%) were treated with metformin and 16 (7.3%) received other, non-metformin therapy for T2DM. Comparison between non-diabetic and diabetic cancer patient groups demonstrated that mPFS was found to be significantly higher in the non-diabetic patients – 6.0 vs. 4.0 months (HR=1.47 [1.03-2.09], p=0.036). ORR was comparable (35.5% vs. 30.6%, p=0.52).
      In the T2DM subgroup - mPFS and HR suggested increased efficacy in the metformin group compared to non-metformin, but the numbers were too small to reach significance 8.0 vs. 3.2 months (HR=0.63 [0.32-1.23], p=0.17). ORR was also numerically higher (36.4% vs. 18.8%, p=0.21).
      In both comparisons, no significant differences were found in OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This data suggests T2DM might be associated with decreased efficacy of ICI.

      While several studies demonstrated that diabetic cancer patients receiving chemotherapy gained much benefit with metformin use, the trend we observed regarding metformin use with ICI therapy was milder and should be further explored in larger prospective cohorts.

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      P1.04-31 - Efficacy and Tolerance of Immune-Checkpoint Inhibitors in EGFR, ALK/ROS 1 Non-Small-Cell-Lung-Cancer (NSCLC): GFPC 03-2016 IMAD Study (ID 11166)

      16:45 - 18:00  |  Presenting Author(s): Olivier Bylicki  |  Author(s): Florian Guisier, Isabelle Monnet, Helene Doubre, Radj Gervais, Henri Janicot, Maurice Pérol, Pierre Fournel, Jacques Le Treut, Regine Lamy, Sabine Vieillot, Herve Le Caer, Jean-Bernard Auliac, Christos Chouaid

      • Abstract
      • Slides

      Background

      Patients with molecular alterations are considered to be poor candidates for immune- checkpoint inhibitors (ICI) on the second-line phase III trials. Here, we analyze the efficacy of ICI in EGFR /ALK/ROS1 NSCLC patients in real world setting

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This retrospective, multicentric study in EGFR, ALK and ROS1 NSCLC treated by ICI, analyzed clinical characteristics and outcomes (progression free survival (PFS), duration of ICI treatment and overall survival (OS), since initiation of ICI .

      4c3880bb027f159e801041b1021e88e8 Result

      51 patients were included from 20 centers in France: 100% adenocarcinoma, 60.7% never smokers, 58.8% female, 58 ± 8.8 years age at diagnosis (36-83), 82.3% EGFR mutated, 15.7 % and 2% ALK and ROS 1 translocated respectively. ICI was a third line treatment in 35,3% of cases, a fourth and more lines treatment in 64,7% of cases. Median PFS was 2.1. [95% CI: 1.5-3.2] months for the whole population, 2.15 [95% CI: 1.4-3;2], for EGFR patients and 2.4 [95% CI: 2.1; NR] for ALK tranlocated patients; 3 months-PFS were 37,3% [95% CI: 26.1; 53.2]; 8 weeks ORR were 19.6% (10 pts with partial response). The median OS for the whole population was 14.7.[95%CI: 12.1-19.2] months, 13.9 [95% CI: 8.8-20] for EGFR patients, 19.2. [95% CI: 13.1-NR] for ALK translocated; 7 (13.7%) patients were treated more than 9 months by ICI; 21.6% (11/51) of patients reported toxicities, all < grade3.

      11.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this real-world setting analysis, efficacy of ICI in EGFR, ALK, ROS1 NSCLC patients appears close to the efficacy observed in pretreated unselected NSCLC patients. Large prospective studies are needed in these populations

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      P1.04-32 - Phase I/II Study of the A2AR Antagonist NIR178 (PBF-509), an Oral Immunotherapy, in Patients (pts) with Advanced NSCLC (ID 12495)

      16:45 - 18:00  |  Presenting Author(s): Alberto A. Chiappori  |  Author(s): Charles C. Williams, Ben C. Creelan, Tawee T Tanvetyanon, Jhanelle Elaine Gray, Eric B. Haura, Dung Tsa Chen, Ram Thapa, Amer Beg, Theresa Boyle, Mansee Sangani, Eric Morris, Aiyang Tao, Felipe Hurtado, Luigi Manenti, Julio Castro, Scott J Antonia

      • Abstract
      • Slides

      Background

      Background: ATP is catabolized to adenosine in the tumor microenvironment, leading to excess adenosine and immunosuppressive effects via immune checkpoint protein adenosine 2A receptor (A2AR). NIR178 is an oral A2AR antagonist that selectively binds and inhibits A2AR, reactivating T cell-mediated antitumor immune response. This Phase I/II study evaluated NIR178 in previously treated pts with advanced NSCLC (NCT02403193).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: Pts (ECOG PS 0─1) had received ≥1 prior line of therapy; EGFR/ALK pts had failed prior TKI therapy. Objectives: primary – determine MTD of single-agent NIR178; secondary – efficacy endpoints, PK, and evaluation of PD-L1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: At 13 Dec 2017 data cut-off, 24 pts had been treated: median age 68 yrs, 46% male; 79% received prior immunotherapy; 22/24 (92%) pts had discontinued (due to progression [n=13], death [n=2], AEs [n=2] or other reasons [n=5]) and 2/24 (8%) pts remained on treatment. Dose levels evaluated: 80 (n=3), 160 (n=3), 320 (n=7), 480 (n=6), 640 mg BID (n=5). There was 1 DLT: Gr 3 nausea (640 mg). The most frequent (≥20%) any-Gr AEs regardless of causality were nausea (67%), fatigue (63%), dyspnea (46%), vomiting (33%), chest pain and other (29%), gastroesophageal reflux disease, anemia, diarrhea (all 25%), anorexia, back pain, generalized muscle weakness and cough (all 21%). Drug-related Gr 3 AEs were pneumonitis (8%) and nausea (4%); no Gr 4 AEs were reported. Potential immune-related any-Gr AEs were rash (8%), pneumonitis (8%), hypothyroidism, increased ALT/AST (all 4%). NIR178 systemic exposure (Cmax, AUC) increased more than proportionally with dose. Efficacy data for 17/24 treated pts demonstrated responses and SD across the dose range, including 1 confirmed CR (480 mg) and 1 PR (80 mg), both in immunotherapy-naïve pts. Durable SD >44 wks with tumor shrinkage was observed in 2 ongoing immunotherapy-exposed pts. Disease control was seen in pts with both high and low baseline PD-L1 expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions: NIR178 was well tolerated; AEs were manageable and there were no Gr 4 drug-related AEs. Immune-related AEs may indicate immune stimulation. Clinical benefit was observed in immunotherapy-exposed and -naïve pts irrespective of PD-L1 status.

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      P1.04-33 - Retrospective Descriptive Analysis of Metformin with Atezolizumab in Advanced Non-Small Cell Lung Cancer in The OAK Trial (ID 12388)

      16:45 - 18:00  |  Presenting Author(s): Richard Pietras  |  Author(s): Hao Xu, Xiaoping Hu, Christina Matheny, Alan Sandler, Manish Patel

      • Abstract
      • Slides

      Background

      The randomized Phase III OAK trial investigated atezolizumab (anti–PD-L1) for treatment of advanced or metastatic previously-treated NSCLC. Atezolizumab significantly improved OS compared with docetaxel. Given that emerging studies have identified an association between metformin use and antitumor activity/immune interactions, we retrospectively explored metformin use in patients in the OAK study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients received atezolizumab (1200 mg IV every 3 weeks [q3w]) until PD or loss of clinical benefit or docetaxel (75 mg/m2 IV q3w) until PD/unacceptable toxicity. Patients who received atezolizumab or docetaxel and did or did not receive metformin as concomitant therapy were retrospectively evaluated for ORR, PFS and OS (data cutoff, July 7, 2016). Unadjusted and adjusted comparisons between metformin users and non-metformin users were done.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 425 patients randomized to atezolizumab, 36 received metformin; of the 425 patients randomized to docetaxel, 35 received metformin. Key baseline characteristics are shown in the table. Most metformin users started metformin before or within 30 days of study start (92% and 7% respectively). There was a numerical improvement in ORR in Atezo-Met patients compared with Atezo-NoMet patients (25% vs 13%; unadjusted P = 0.038 [adjusted = 0.093]), whereas there was no statistically significant improvement in ORR in Doc-Met patients compared with Doc-NoMet patients (17% vs 13%; unadjusted P = 0.499 [adjusted = 0.295]). There were no observable differences in PFS or OS in either the Atezo-Met vs Atezo-NoMet or Doc-Met vs Doc-NoMet groups (median PFS, 2.8 vs 2.8 mo and 4.2 vs 4.0 mo, respectively; median OS, 12.6 vs 14.1 mo and 9.1 vs 9.7 mo, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Encouraging response rates suggest patients may benefit from receiving concomitant metformin treatment with atezolizumab. Lack of difference in PFS and OS may be due to lack of treatment effect or lack of statistical power and requires further prospective investigation.

      Table. Characteristics of Patients Who Received Atezolizumab (Atezo) or Docetaxel (Doc) Combined With Metformin (Met) or No-Metformin (NoMet)

      Atezo-Met, n (%) (n = 36)

      Atezo-NoMet, n (%) (n = 389)

      Doc-Met, n (%)
      (n = 35)

      Doc-NoMet, n (%)
      (n = 390)

      Diabetes mellitus type 2

      33 (91.6)

      28 (7.2)

      33 (94.3)

      26 (6.7)

      Sex

      Male

      28 (77.8)

      233 (59.9)

      28 (80.0)

      231 (59.2)

      Female

      8 (22.2)

      156 (40.1)

      7 (20.0)

      159 (40.8)

      Tobacco use history

      Never smoker

      2 (5.6)

      82 (21.1)

      2 (5.7)

      70 (17.9)

      Current/previous smoker

      34 (94.4)

      307 (78.9)

      33 (94.3)

      320 (82.1)

      Histology

      Nonsquamous

      22 (61.1)

      291 (74.8)

      21 (60.0)

      294 (75.4)

      Squamous

      14 (38.9)

      98 (25.2)

      14 (40.0)

      96 (24.6)

      No. of prior therapies

      1

      30 (83.3)

      290 (74.6)

      24 (68.6)

      296 (75.9)

      ECOG performance status at baseline

      0

      15 (41.7)

      140 (36.0)

      12 (34.3)

      148 (37.9)

      1

      21 (58.3)

      249 (64.0)

      23 (65.7)

      242 (62.1)

      EGFR mutation status

      Positive

      1 (2.8)

      41 (10.5)

      1 (2.9)

      42 (10.8)

      PD-L1 IHC subgroup

      TC3 or IC3
      (PD-L1 ≥ 50% TC or 10% IC)

      11 (30.6)

      61 (15.7)

      5 (14.3)

      60 (15.4)

      TC1/2/3 or IC1/2/3
      (PD-L1 ≥ 1% on TC or IC)

      27 (75.0)

      214 (55.0)

      19 (54.3)

      203 (52.1)

      TC0 and IC0
      (PD-L1 < 1% on TC and IC)

      9 (25.0)

      171 (44.0)

      16 (45.7)

      183 (46.9)

      TC, tumor cell; IC, tumor-infiltrating immune cell.

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      P1.04-34 - Study on Treatment of Stage IV Solid Tumors with Mutant Neoantigen Specific T Cells (ID 12833)

      16:45 - 18:00  |  Presenting Author(s): Song Qi  |  Author(s): Jin Song, Sun Shengjie, Qin Boyu, Zhang Xiaoling, Huaibo Sun, Yuqi Wang, Yanfang Guan, Xuefeng Xia, Yi Xin, Jiao Shunchang

      • Abstract
      • Slides

      Background

      As an important tumor immunotherapy, the specificity and efficiency of PD1 inhibitor is not yet satisfactory. The treatment of solid tumor with mutant neoantigen specific T (Nas-T) cells developed in this study is an adoptive cell therapy which is specific for each patient. The aim is to explore the difference in safety and efficacy between Nas-T cells and PD1 inhibitors, and to evaluate the charateristic of immune repertoire (IR) as predictive biomarker.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total number of 11 patients with advanced solid tumors who failed after multiline treatments were recruited. They were treated with Nas-T cells, PD1 inhibitors and BSC; other 11 patients were treated with PD1 inhibitors and BSC as control. Peripheral blood was collected at baseline and per cycle (21-28d) respectively. Multiple PCR and NGS on TCR beta chain was used to detect IR.

      4c3880bb027f159e801041b1021e88e8 Result

      pfs and indexes of ir.jpg

      PFS of two groups had a statistical significance (P<0.05), suggesting Nas-T cells prolong patients' PFS. The safety was analyzed from routine blood urine stool test, coagulation function, liver and kidney function. There was no significant difference at baseline (P>0.05). Compared with C group, total protein and albumin in T group had a transient decrease in 3rd, 4th and 5th follow-up respectively (P<0.05), however, It can be recovered autonomously before 6th cycle.

      Three indexes were examined to illuminate the diversity and clonality of IR. Compared to baseline, T cell repertoir of non-responders and responders after 1st cycle showed significant changes: Shannon 1.14 vs 0.97, P=0.048; Evenness 3.90 vs 0.85, P=0.004; Clonality 1.20 vs 0.70, P=0.017. Elevated Clonality may indicate amplification of tumor specific T cells which could recognize mutant neoantigen specifically.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combined immunotherapy of Nas-T cells and PD1 inhibitors is more effective than PD1 inhibitor alone in prolonging the PFS, and has a good safety. IR Clonality change shows its potential as a predictive biomarker.

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      P1.04-35 - Quick Progression (QP) in Patients Treated by Nivolumab (IO) in 2nd Line or More for Non-Small Cell Lung Cancer: ERORECI Study (GFPC 2016-04) (ID 11936)

      16:45 - 18:00  |  Presenting Author(s): Alain Vergnenegre  |  Author(s): Margaux Geier, Florian Guisier, Regine Lamy, Bénédicte Comet, Gwenaelle Le Garff, Pascal Do, Henri Janicot, Hugues Morel, Chantal Decroisette, Michel Andre, Lionel Falchero, Nicolas Paleiron, Isabelle Monnet

      • Abstract
      • Slides

      Background

      Nivolumab has been approved in 2nd line for advanced non-small cell lung cancer (NSCLC). However, more than half of the patients had progressive disease at 16 weeks, without any response and sometimes with deleterious progressions. This descriptive prospective study aimed to assess the characteristics of non responders with QP after IO and the following treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From September 1st, 2016 to August 31th, 2017, patients (pts) treated by IO (second line or more) with QP<16 weeks were included by 20 GFPC centers. NSCLC characteristics at the diagnosis, at the IO initiation, treatments (before IO, IO and after IO) and outcomes responses, progression free survival (PFS) according to lines of treatments were recorded.

      4c3880bb027f159e801041b1021e88e8 Result

      The sample included 319 pts: 64,3y± 9,6, smokers/ex-smokers: 48.0%-42.9%, male: 70.8%, PS01/2: 92.8%-7.2%, stage IV at diagnosis: 71.8%; adenocarcinoma: 63.9%. K-Ras mutated: 25.7%. Only 29% of patients had a PDL1 determination. 93% of pts received first line therapy, 32% second line, 10.3% third line before IO. First line PFS (PFS1) was 6.9m [6.43-7.8], PFS2: 9.33m [1.2-19], PFS3: 4.1m [1.56-12.43]. PFS for IO was 1.7m [0.76-4.16]. 229 (71,8%) patients had a IO PFS<2m; 14.7% of these patients stopped the treatment for toxicity. Among the 146 pts evaluable for response, PR was found in 23% of cases, SD in 30%, and PD in 47%.The table describe a comparison between two groups of QP during IO.

      table eroreci.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In real life, QP during IO remains a challenge in NSCLC. Multivariate analyses will be presented to characterize these patients.

      _______________________________________________________________________________________________________________

      In collaboration with the GFPC* team and supported by an academic grant from Pierre-Fabre pharmaceuticals.

      *GFPC: French Lung Cancer Group

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      P1.04-36 - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 12092)

      16:45 - 18:00  |  Presenting Author(s): Jie Wang  |  Author(s): Jun Zhao, Zhijie Wang, Zhiyong Ma, Jiuwei Cui, Yongqian Shu, Zhe Liu, Ying Cheng, Shiang Jiin Leaw, Jian Li, Fan Xia

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors have shown efficacy in patients with NSCLC as monotherapy and in combination with chemotherapy. Tislelizumab is a humanized IgG4 monoclonal antibody to PD‑1 specifically engineered to minimize FcϒR binding on macrophages, possibly minimizing negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity; 200mg IV Q3W was established as the recommended dose.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This multi-arm phase 2 study, consisting of safety run-in and dose-extension phases, assessed tislelizumab in combination with platinum-based chemotherapy (by tumor histology) as a potential first-line treatment for Chinese patients with lung cancer. All patients received tislelizumab at 200mg Q3W in combination with 4–6 cycles of platinum-doublet until disease progression. Nonsquamous (nsq) NSCLC patients received pemetrexed + platinum Q3W for 4 cycles followed by pemetrexed maintenance, while squamous (sq) NSCLC patients received paclitaxel + platinum (A) or gemcitabine + platinum (B) Q3W, and small-cell lung cancer (SCLC) patients received etoposide + platinum Q3W. Tumor response (RECIST v1.1) and safety/tolerability were evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 21 Feb 2018, 48 patients (median age, 62 years [range: 36–75], 71% male, 71% current/former smokers) received tislelizumab treatment (median, 3 cycles [range: 1–7]); 44 patients remain on the study. Across the four cohorts, confirmed and unconfirmed partial responses were observed in 13 and 9 patients, respectively (Table). The most frequent AEs were chemotherapy-related hematologic toxicities. The most commonly reported grade ≥3 treatment-related AEs were neutropenia (20.8%) and anemia (12.5%); the most common grade 3 immune-related AEs were pyrexia (6.3%) and rash (6.3%). One sq‑NSCLC patient experienced a fatal myocarditis/myositis following one cycle of paclitaxel/cisplatin; all other treatment-related AEs were managed/resolved by study-drug interruption (n=15) or discontinuation (n=4) and appropriate treatment.

      Best Overall Response (Patients With ≥1 Post-Baseline Tumor Assessment)

      nsq-NSCLC (n=9)

      sq-NSCLC [A] (n=12 )

      sq-NSCLC [B] (n=5 )

      SCLC (n=8)

      Total

      (N=34)

      PR

      4 (44.4)

      9 (75)

      4 (80)

      5 (62.5)

      22 (64.7)

      Confirmed PR

      1 (11.1)

      4 (33.3)

      4 (80)

      4 (50)

      13 (38.2)

      Unconfirmed PR

      3 (33.3)

      5 (41.7)

      0 (0)

      1 (12.5)

      9 (26.5)

      SD

      3 (33.3)

      2 (16.7)

      1 (20)

      2 (25)

      8 (23.5)

      PD

      1 (11.1)

      0 (0)

      0 (0)

      1 (12.5)

      2 (5.9)

      NE

      1 (11.1)

      1 (8.3)

      0 (0)

      0 (0)

      2 (5.9)

      Data presented as n (%).

      Abbreviations: nsq-NSCLC, non-squamous non-small cell lung cancer; NE, not evaluable; PD, progressive disease; PR, partial response; SCLC, small cell lung cancer; SD, stable disease; sq-NSCLC, squamous non-small cell lung cancer.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tislelizumab, in combination with platinum doublets, demonstrated preliminary antitumor activity and was generally well tolerated in patients with advanced lung cancer.

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    P1.05 - Interventional Diagnostics/Pulmonology (Not CME Accredited Session) (ID 937)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 23
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.05-01 - Incidence and Clinical Relevance of NSCLC Lymph Node Micro-Metastasis Detected by Staging EBUS-TBNA (ID 13829)

      16:45 - 18:00  |  Presenting Author(s): Adam R Belanger  |  Author(s): Johnanthan Hollyfield, Gabriella K Yacovone, Agathe S Seppe, Jason A Akulian, Cole Burks, Patricia Rivera, Leslie G Dodd, Jason M Long, Benjamin E Haithcock, Chad Victor Pecot

      • Abstract

      Background

      Appropriate staging of non-small cell lung cancer (NSCLC) patients is crucial to provide accurate prognostic information and select appropriate treatment. Several publications have reported an approximate 20% incidence of occult micro-metastasis (MM) in surgically resected lymph nodes (LN) pathologically interpreted as negative by hematoxylin and eosin staining (H&E). Detection of MM was associated with worsened survival. The majority of NSCLC lymph node staging is now conducted using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The purpose of this study is to determine the frequency of detection of occult MM in EBUS-TBNA specimens and to evaluate the impact of the presence of MM on progression-free and overall survival.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients undergoing EBUS-TBNA for NSCLC lymph node staging at our institution between September 2013 and October 2017 were eligible for inclusion. Patients were identified using provider-maintained case lists, operating or procedure room electronic schedules, and tumor board patient presentations. Patients were excluded if a definitive diagnosis of NSCLC was not obtained within 3 months of the EBUS-TBNA examination or if distant metastatic disease was present at the time of diagnosis. Patient cell blocks from the EBUS-TBNA procedure were evaluated by a cytopathologist using H&E staining according to standard guidelines. Patients with N2 or N3 disease on routine cytopathology examination were excluded. Cell blocks from the included patients were sectioned into five 5 mm sections spaced at least 10 mm apart and immunohistochemistry for pan-cytokeratin was performed. The resulting slides were then reviewed for evidence of MM by a blinded cytopathologist.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 887 patients screened, 44 patients were identified fitting inclusion criteria with sufficient additional tissue for testing. The mean age and smoking history were 68 ± 10 years and 45 pack-year history, respectively. The patients were majority male (61%) and Caucasian (75%). Fifty-two percent of patients were stage 1 at the time of diagnosis, 34% were stage 2, and 14% were stage 3a. Three patients (6.8%) were found to have pan-cytokeratin positive MMs. All 3 MMs detected were at N2 LN stations. The presence of MMs was associated with significantly decreased progression-free (median 210 vs. 1293 days, p=0.0099) and overall survival (median 238 vs. 1120 days, p=0.0357).

      8eea62084ca7e541d918e823422bd82e Conclusion

      LN micro-metastases can be detected during EBUS-TBNA staging examinations and are associated with poor clinical outcomes. If prospectively confirmed in a larger study, these results have significant implications for EBUS-TBNA specimen analyses and the current NSCLC staging paradigm.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.05-02 - Endobronchial Ultrasound-Transbronchial Needle Aspiration for Lymphoma in Patients With Mediastinal Lymphadenopathy (ID 13168)

      16:45 - 18:00  |  Presenting Author(s): Yu-Deok Choi

      • Abstract

      Background

      Surgical excision and core biopsy are the current preferred sampling techniques for diagnosing lymphoma. However, In patients who present with intrathoracic adenopathy that is suspicious for lymphoma, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an attractive option.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The cases of patients who had undergone EBUS-TBNA for 31 cases of suspected lymphoma were retrospectively reviewed.

      4c3880bb027f159e801041b1021e88e8 Result

      EBUS-TBNA diagnosis was that : 6 cases was diagnostic lymphoma, but not subtyping, 6 cases was specific lymphoma using cell block (2 cases of diffuse large B-cell lymphoma, NOS, 1 case of mantle cell lymphoma, 1 case of NK-T cell lymphoma, 1 case of anaplastic large cell lymphoma, and 1 case Hodgkin lymphoma) , 5 cases was granuloma, 4 cases carcinoma, 6 cases diagnostic lymphoid tissue without specific diagnosis, and 4 cases non-diagnostic. Of 31 cases, 14 (45.2%) were finally diagnosed with lymphoma. In EBUS-TBNA, these cases were diagnosed as lymphoma (12 cases) and non-diagnostic (2cases). Other diagnosis in EBUS-TBNA was not finally diagnosed as lymphoma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EBUS-TBNA is effective at diagnosing suspected lymphoma in patients with mediastinal lymphadenopathy. A specific EBUS-TBNA features, such as granulomas and carcinoma, are associated without a probability of lymphoma.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.05-03 - Significance of Lymph Node SUVmax In Predicting Nodal Metastasis By EBUS in Lung Cancer Patients (ID 12043)

      16:45 - 18:00  |  Presenting Author(s): Michael Alexios Gulak  |  Author(s): Caitlin Anstee, Sebastian Gilbert, Andrew J.E. Seely, Farid M Shamji, Sudhir Sundaresan, Patrick James Villeneuve, Donna E Maziak

      • Abstract
      • Slides

      Background

      Nodal staging of non-small-cell lung cancer (NSCLC) patients begins with imaging such as Positron emission tomography–computed tomography (PET-CT). It provides information about lymph node (LN) location, enlargement, and metabolic activity as measured by the maximum standardized uptake value (SUVmax). However, more definitive information can only be obtained by direct sampling through cervical mediastinoscopy (Med) and/or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS). There remains discrepancy when comparing the diagnostic accuracy of these two methods for detecting nodal metastasis. Further, there is inadequate data on the value of SUVmax magnitude in predicting nodal metastasis by EBUS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was a retrospective analysis of 148 biopsy-confirmed NSCLC patients who underwent Med and/or EBUS for staging purposes from 2010-2015 (2013 excluded). Two groups matched by age, sex, and year of procedure were analyzed to determine if the diagnostic accuracy was comparable between the two methods. Primary tumour and LN SUVmax was correlated with the likelihood of finding LN metastasis by either method. Chi-squared tests and Student's t-tests were used to assess for significance where appropriate.

      4c3880bb027f159e801041b1021e88e8 Result

      The mean SUVmax of true positive LNs was significantly higher than true negative LNs sampled by EBUS (7.77 vs. 4.06, p=0.0047, t-test). Among PET-positive LNs, there was a significant correlation between likelihood of positive findings by EBUS and increased SUVmax>4 (p=0.018, Chi-squared test). There were no significant differences between Med and EBUS in sensitivity, specificity, PPV, or NPV. However, Med had significantly higher diagnostic yield (p<0.0001, Chi-squared test).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that among PET-positive LNs, there is a significant correlation between SUVmax magnitude and likelihood of detecting true LN metastasis by EBUS. Additional studies should aim to further characterize this relationship.

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      P1.05-04 - Cone-Beam CT Confirms the Status of Transbronchial Biopsy Under Virtual Bronchoscopic Navigation for Peripheral Lung Lesions (ID 13788)

      16:45 - 18:00  |  Presenting Author(s): Naoya Kawakita  |  Author(s): Hiromitsu Takizawa, Eman Ali, Mika Takashima, Daisuke Matsumoto, Toru Sawada, Mitsuhiro Tsuboi, Hiroaki Toba, Mitsuteru Yoshida, Yukikiyo Kawakami, Kazuya Kondo, Akira Tangoku

      • Abstract
      • Slides

      Background

      CT guided transbronchial biopsy has been reported to have a high accuracy for the diagnosis of peripheral lung lesion. Recently, C-arm cone-beam CT (CBCT) with a flatpanel detector system has been developed and offers greater flexibility in orientating the detector around the patient than closed CT gantry systems. We have introduced CBCT to the transbronchial lung biopsy and report the usefulness of the method.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with undiagnosed peripheral lung lesions 3 cm or less in size between June 2016 and August 2017 were enrolled.An ultrathin bronchoscope was inserted as far as possible to the target bronchus by comparing the direct vision and virtual bronchoscopic navigation images displayed simultaneously at same monitor. After reaching the target bronchus, the biopsy forceps was introduced to the target bronchus under conventional fluoroscopy. After the biopsy forceps reach the target bronchus, a CBCT scan data was taken. We categorized the CBCT findings into three types according to positions of the target lesion and the forceps as follows: (Type A: The forceps clearly reached within the lesion. Type B: It could not be categorized into neither type A nor C. Type C: The forceps could not reach the lesion.). The diagnosis yields of biopsy or cytology results was examined.

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-two patients (12 males and 10 females) were included in the study and age ranged from 50 to 87 with average age of 72.8 years. Thirteen lesions were located at the upper lobe, seven lesions at lower lobe and one lesion at middle lobe. Size of the lesions ranged from 9 to 29 mm with average of 20 mm. They included 13 solid lesions and 8 mixed GGO lesions. Regarding CBCT type, A was 16 cases, B was 4 cases, and C was 1 case. Bronchoscopic diagnosis was malignant in 11 cases, benign in 10 cases (4 mycobacterium infections and 6 non-specific inflammations) and undiagnostic in 1 case. There was one false negative case whose bronchoscopic diagnosis as non-specific inflammation was finally proved as adenocarcinoma. Overall the diagnostic accuracy was 91%(20/22). Based on the CBCT category, the accuracy was 100% (17/17), 75% (3/4), 0% (0/1) in Type A, B and C respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CBCT guided bronchoscopy is valuable in the diagnosis of peripheral lung lesions and useful for confirming the position of the forceps.

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      P1.05-05 - Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Suspected Malignancy; Current Status and Issues (ID 13209)

      16:45 - 18:00  |  Presenting Author(s): Hidenao Kayawake  |  Author(s): Toyofumi Fengshi Chen-Yoshikawa, Yojiro Yutaka, Daisuke Nakajima, Masatsugu Hamaji, Toshi Menju, Akihiro Ohsumi, Toshihiko Sato, Makoto Sonobe, Hiroshi Date

      • Abstract
      • Slides

      Background

      The number of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is now increasing, since it is less invasive and useful for the pathological diagnosis of lung cancer or thoracic and hilar lymph node enlargement. However, there are some problems to be solved, such as diagnostic accuracy and complications. Here, we retrospectively reviewed our experiences of EBUS-TBNA performed for diagnosis of malignant diseases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between July 2009 and December 2017, 489 patients underwent EBUS-TBNA. Among them, the subject of this study was 424 cases underwent EBUS-TBNA for diagnosis of malignancy. We retrospectively analyzed the completion rate, the complication rate, the adequate sample collection rate and the diagnostic accuracy of EBUS-TBNA among these 424 patients.

      4c3880bb027f159e801041b1021e88e8 Result

      Among all 424 cases, the target lesions of EBUS-TBNA consisted of mediastinal lesions (n=303), hilar lesions (n=69) and both mediastinal and hilar lesions (n=52). Almost all EBUS-TBNAs were performed under conscious anesthesia, while 9 EBUS-TBNAs were performed under general anesthesia. Among 424 cases, EBUS-TBNA was completed in 408 cases (96.2%) and the collection of adequate sample was performed in 382 cases (90.1%). There were four complications (0.94%); they consisted of mediastinal infection (n=2), obstructive pneumonia (n=1) and airway obstruction (n=1). All 4 cases were treated medically and fully recovered. Among 16 incomplete cases, 10 cases were histologically diagnosed with having malignancy; 5 cases were surgically diagnosed, and other 5 cases were diagnosed by EBUS-TBNA under general anesthesia. Other 3 cases were clinically diagnosed with having malignant diseases. Among 26 patients in whom adequate samples were not collected, 14 patients were finally diagnosed with having malignancy. On the other hand, among 382 patients in whom adequate samples were collected, the sensitivity, specificity, positive predictive value and negative predictive value were 90.0%, 100.0%, 100.0% and 76.0%, respectively. Furthermore, the diagnostic accuracy of EBUS-TBNA for hilar lesions was the least among the three lesions (mediastinal: 94.2%, hilar: 83.9%, both mediastinal and hilar: 91.8%, p=0.029).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among the patients in whom adequate samples were collected, the outcome of EBUS-TBNA was favorable. Since complications are rare but can happen, early recognition and treatment for complication are important. When EBUS-TBNA under conscious sedation is not completed, EBUS-TBNA under general anesthesia or other diagnostic approaches such as mediastinoscopy and video-assisted thoracoscopic surgery are to be considered.

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      P1.05-06 - Bronchoscopic Image-Guided Microwave Ablation of Peripheral Lung Tumours – Early Results (ID 14420)

      16:45 - 18:00  |  Presenting Author(s): Kelvin Kar Wing Lau  |  Author(s): Alexander Spiers, Michael A. Pritchett, William Krimsky

      • Abstract
      • Slides

      Background

      Thermal ablation is indicated for the treatment of early lung cancer in medically inoperable patients, and for oligometastatic disease. However, percutaneous ablation is associated with 30-50% pneumothorax, haemothorax, pleural effusion and pain. Peripheral lung tumours can be reached by electromagnetic navigation bronchoscopy (ENB) without breaching the pleura. Intraprocedural cone-beam CT (CBCT) and transbronchial access instruments allow lesions in the lung periphery to be reached with accuracy. Another advantage of the bronchoscopic approach is the ability to concurrently obtain tissue for diagnosis and molecular characterization, and to perform full nodal staging.

      Bronchoscopic radiofrequency ablation (RFA) has been described for tumours with positive bronchus sign, but the effectiveness of RFA is limited by impedence of air and heat-sink effects of vessels. Microwave avoids these limitations.

      We present our early experience of bronchoscopic microwave ablation of tumours with CBCT guidance and transbronchial access.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ENB (Superdimension, Medtronic, Minneapolis) was carried out under general anaesthesia. A CBCT (Philips, Eindhoven) confirms probe position and its relationship to the lesion. Transbronchial access with CrossCountry device (Medtronic, Minneapolis) was used as required to reach extrabronchial lesions. A flexible microwave ablation catheter (Emprint, Medtronic) was advanced to the lesion. Ablation was planned with OncoSuite (Philips, Eindhoven) to ensure the ablation zone encompassed the lesion with a 5mm margin. Ablation was carried out and a fiducial was placed at the ablation site to facilitate follow-up. A control CBCT was carried out post procedure.

      4c3880bb027f159e801041b1021e88e8 Result

      Between February and April 2018, three patients (2F:1M, mean age 70.3) with oligometastatic disease (2 colorectal, 1 endometrial) underwent bronchoscopic microwave ablation to 4 lung lesions (two RLL nodules (in one patient), LUL and LLL, median size 10.5mm (range 7-13mm), 3 without bronchus sign). All lesions were reached, with the LUL nodule requiring transbronchial access. All lesions were treated at 100W for 10 minutes.

      CBCT confirmed ground-glass opacification of the ablation zones encompassing the lesions. There were no procedural complications, pneumothorax or bleeding. Two patients with lesions close to the pleura experienced mild, localised chest discomfort which resolved by 24 hours. All patients were discharged the following day. A CT at 30 days for the first patient showed a 25x32mm area of dense ovoid consolidation representing the ablation zone, with no complications.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our early experience shows bronchoscopic microwave ablation is safe and feasible with low morbidity. The accuracy of the procedure is enhanced by CBCT control. Lesions remote from the bronchial tree could be accessed and safely treated.

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      P1.05-07 - Clinical Significance of Pleural Indentation of Lung Adenocarcinoma Presented as Ground Glass Opacities (ID 11969)

      16:45 - 18:00  |  Presenting Author(s): Choon-Taek Lee  |  Author(s): Hyung Joon Kim

      • Abstract
      • Slides

      Background

      After the emphasis on lung cancer screening, incidental detection of ground glass opacities (GGOs) has increased. Such GGOs commonly have peripheral location and pleural indentation, which may increase the risk of visceral pleural invasion (VPI). Although the impact of pleural indentation among solid lung cancers is well established, such impact among GGO lung cancers is not well known.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients who underwent lung resection with curative intention of GGO lung cancer from April 2007 to January 2016 were retrospectively evaluated. Demographics, radiographic findings, pathological findings, and clinical outcomes including recurrence were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      A total 404 of patients were analyzed, and pleural indentation was observed in 258 patients (63.9%). All cancers turned out to be adenocarcinoma. Older age, worse lung function, longer diameter, and tumor shadow disappearance rate were associated with indentation. VPI was observed in 36 (8.9%) patients, and indentation was independently associated with VPI (odds ratio 9.34, p=0.032) after adjustment of pleural attachment, diameter, and tumor shadow disappearance rate. During a median follow-up duration of 48.3 months, 34 (8.4%) patients recurred. Although indentation was not associated with earlier recurrence (adjusted hazard ratio 2.16, p=0.168), concurrent pleural attachment with indentation was associated with recurrence among those with solid portion≥8mm (adjusted hazard ratio 3.05, p=0.019).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pleural indentation was associated with increased risk of VPI in GGO lung adenocarcinoma. Although indentation itself did not increase the risk of recurrence, concurrent pleural attachment with indentation may increase the risk of recurrence among selected patients.

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      P1.05-08 - Spread Through Air Spaces (STAS) in Invasive Mucinous Adenocarcinoma of the Lung: Incidence, Prognostic Impact, and Predictive Factors (ID 13767)

      16:45 - 18:00  |  Presenting Author(s): Min A Lee  |  Author(s): Ho Yun Lee

      • Abstract
      • Slides

      Background

      Spread through air spaces (STAS) is a recently recognized as a novel negative impact on prognosis in lung adenocarcinoma, however was almost investigated non-mucinous adenocarcinoma. We investigated the incidence of STAS in invasive mucinous adenocarcinoma (IMA) of the lung and whether tumor STAS was a risk factor of disease recurrence even in IMA, and determined clinico-radiologic factors in patients with IMA harboring STAS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed pathologic specimens and imaging characteristics of primary tumors from 132 consecutive patients who underwent surgical resection for IMA. On pathology, the presence of aerogenous spread (AS), mucin, and STAS were evaluated. Two groups determined by STAS were compared with respect to clinical characteristics as well as CT imaging using the Pearson χ2 test or the Fisher exact test. Multivariate logistic regression was used to explore the clinico-radiologic features that facilitate the detection of STAS in IMA, for which receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance. The relationships between all variables including STAS and survival (overall survival [OS] and disease-free survival [DFS]) were analyzed by using Kaplan–Meier curves and Cox regression analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 119 patients with full pathologic specimens, STAS was observed in 86 patients (72.3%). On multivariate analysis, IMA patients with STAS were significantly tended to be lobectomy (odds ratio [OR] = 7.120, 95% confidence interval [CI] = 1.184 to 42.825, P value = 0.032), older (OR = 2.979, 95% CI = 1.109 to 8.001, P value = 0.030) and the absence of peripheral GGO on CT (OR =0.376, CI=0.141 to 0.999 , P value = 0.049), where the predictive model for presence of STAS showed discrimination performance with an area under the receiver operating characteristic curve (AUC) of 0.798 (95% CI = 0.711 to 0.884, P value < 0.005). The DFS was lower in patients with STAS compared with in those without STAS, whereas there was no statistically significant difference (P value =0.091). On multivariate analysis for DFS, STAS failed to be an independent predictor, but lymph node metastasis (hazard ratio [HR], 2.505; 95% CI 1.288–11.089, absence of mucin on pathologic specimen (HR, 0.46; 95% CI 0.194–0.985) and CT angiogram sign (HR, 2.872; 95% CI 1.036–7.963) remained independent predictors for disease recurrence.

      8eea62084ca7e541d918e823422bd82e Conclusion

      IMA with STAS represented older age, absence of peripheral GGO on CT, more frequent lobectomy than limited resection. STAS was associated with reduced DFS, but failed to be a significant prognostic factor.

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      P1.05-09 - Dielectric Property Test for the Rapid Differential Diagnosis of Lung Nodules/Mass (ID 13075)

      16:45 - 18:00  |  Presenting Author(s): Di Lu  |  Author(s): Xiaoying Dong, Siyang Feng, Xiguang Liu, Xiaoshun Shi, Hua Wu, Dingwei Diao, Pengfei Ren, Ruijun Cai, Zhiyong Huang, Haofei Wang, Kaican Cai, Xuegang Xin, Hongli Ji, Zhizhi Wang, Chang Hong, Ying Sun, Xuefei Yu

      • Abstract
      • Slides

      Background

      Developing new methods for rapid diagnosis for lung nodules/mass has always been one of the most attractive topics. And it has been found that the dielectric property, including permittivity and conductivity, varies from benign tissues to malignancies. However, no studies comparing the dielectric property between lung benign tumors to malignancies has been reported and whether dielectric property test could be used for differential diagnosis remains uncertain.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with lung nodules/mass who received surgical resection were included for permittivity and conductivity test right after the occupying lesions were removed and before sent for pathological examination. The informed consents were obtained before surgery. Independent-samples T Test and multiple variables for ROC curve analysis were used.

      4c3880bb027f159e801041b1021e88e8 Result

      More than 250 lesions were expected to be tested for calculating the differential diagnosing cutoff value. For each lesion, 4000 datasets of permittivity and conductivity at different frequencies from 1MHz to 4000MHz were collected. By far, 73 patients with 74 lung occupying lesions were enrolled for dielectric property test, including 19 lung benign tumors and 55 malignancies. Though the differences of mean permittivity and conductivity between the 2 groups were not statistically significant (p>0.05), there might be a tendency to distinguish the 2 groups. And the mean values of permittivity and conductivity and their independent values at frequency 1MHz, 500MHz, 1000MHz, 1500MHz, 2000MHz, 2500MHz, 3000MHz, 3500MHz, 4000MHz were chosen as multiple variables for ROC curve analysis. With the false positive rate of 10%, the cutoff value Pcutoff was 0.8588 and the logistic regression formula for differential diagnosis were shown as followed, of which the area under the ROC curve was 0.905.

      捕获.jpg

      Funding

      The study was supported by the Presidential Foundation of Nanfang Hospital, Southern Medical University (2016B018).

      8eea62084ca7e541d918e823422bd82e Conclusion

      With more data collected, dielectric property test might become another rapid way of distinguishing lung malignancies from benign tumors.

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      P1.05-10 - Usefulness of Respiratory Dilatation Balloon in Tracheobronchial Stenosis Requiring Silicone Y-Stent Treatment (ID 12685)

      16:45 - 18:00  |  Presenting Author(s): Shinjiro Mizuguchi  |  Author(s): Makoto Takahama, Ryu Nakajima, Hidetoshi Inoue, Ryuichi Ito, Nao Nomura, Ryoji Yamamoto

      • Abstract
      • Slides

      Background

      The Dumon silicone Y-stent (Novatech SA, La Ciotat, France) is useful for releasing tracheobronchial stenosis but requires sufficient predilation because of the weak expansion force of silicone Y-stents. We have performed mechanical expansion (debulking or coreout) by rigid bronchoscopy, microwave coagulation, and balloon expansion (Fogarty catheter). In recent years, however, we have used a respiratory dilatation balloon (CRE Pulmonary Balloon Dilator; Boston Scientific, Marlborough, MA). We investigated the feasibility, efficacy, and safety of stenting using a silicone Y-stent or additional self-expanding metallic stent (SEMS), focusing especially on the usefulness of a pulmonary balloon dilator, in patients with malignant tracheobronchial stenosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From May 2012 to November 2017, 75 patients (54 male, 21 female; mean age, 64 years; range, 30–91 years) who underwent Dumon silicone Y-stent placement for malignant tracheobronchial stenosis in our department were retrospectively examined. Forty-six patients had lung cancer, 20 had esophageal cancer, 5 had tracheal carcinoma, and 4 had other carcinomas. All procedures were performed in the operating room under general anesthesia, and the stents were implanted via rigid bronchoscopy. The patients were divided into three groups according to the method of predilatation before stenting: no use of balloon expansion (Group N, n=36), use of a Fogarty catheter (Group F, n=22), and use of a respiratory dilatation balloon (Group B, n=17).

      4c3880bb027f159e801041b1021e88e8 Result

      Stents were implanted and symptoms were resolved in all patients. No operative death occurred. The types of indwelling stents were only a Y-stent in 46 patients and a Y-stent with additional SEMS in 29. Although the mean number of additional SEMS was significantly higher in Group B (0.7 stents/patient) than in Groups N and F (0.3 stents/patient, respectively), there was no difference in the median (range) operation time among Groups N, F, and B: 55 (32–115), 59 (29–110), and 49 (17–102) minutes, respectively. In the 46 patients who underwent placement of only a Y-stent without a SEMS, the operation time was significantly shorter in Group B [n=6, 39 (17–64) minutes] than in Groups N [n=25, 53 (32–115) minutes] and F [n=15, 59 (29–106) minutes] (p=0.028). There were no differences in the amount of bleeding, postoperative performance status, or hospitalization days.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A respiratory dilatation balloon is useful for predilatation in patients with tracheobronchial stenosis requiring a silicone Y-stent. Such balloons also contribute to a shorter operation time and more efficient procedure for severe stenosis requiring additional stenting.

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      P1.05-11 - Role of EBUS-TBNA in Evaluation of Mediastinal Lymphadenopathy and Masses in Patients with Known or Suspected Extra-Pulmonary Malignancies (ID 11907)

      16:45 - 18:00  |  Presenting Author(s): Deepali Jain  |  Author(s): Aruna Nambirajan, Maonaro Longchar, Saumya Ranjan Mallick, Aanchal Kakkar, Karan Madan, Sandeep Mathur

      • Abstract
      • Slides

      Background

      Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) has recently emerged as a minimally invasive and safe modality for the evaluation of mediastinal lymphadenopathy, particularly in staging of lung carcinoma patients. Our aim was to evaluate its utility in patients with non-pulmonary malignancies presenting with mediastinal lymphadenopathy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A computerized database search was performed for all EBUS-TBNA aspirations performed from 2015 to 2017 on patients with known or suspected extra-pulmonary malignancy and presence of mediastinal lymphadenopathy and/or masses on imaging. All archived cytology material was reviewed and categorized as positive, negative and unsatisfactory. Follow-up histology samples served as comparison standard.

      4c3880bb027f159e801041b1021e88e8 Result

      One-hundred-twenty-one patients were included. In 99 patients with known malignancy, primary sites were in the head and neck (25%), breast (22%), female genital tract (9%), lower gastrointestinal (GI)-tract (8%), genitourinary tract (7%), and upper GI-tract (5%). Six patients had history of hematolymphoid malignancy while primary site or type of malignancy was unknown in the remaining (18%). EBUS-TBNA diagnosed metastases or lymphoma relapse in 48 (40%), identified new malignancy in 18 (15%), granulomatous inflammation in 15 (12%), tuberculosis in 2 (1%), reactive lymphadenitis in 21 (17%) patients and was inadequate in 17 (14%) patients. Cell block was adequate in 43% (23/53) cases and was indispensible for diagnosis in 13% (7/53) cases. Subcarinal and right paratracheal lymphnodes were most commonly aspirated (77%) while hilar and paratracheal masses of non-lymphnode origin were assessed in 10% cases. Follow-up histology samples (available only in 13 cases) showed 100% concordance with EBUS-TBNA results (no false positive or false negative cases). Two cases unsatisfactory on EBUS-TBNA were positive for malignancy on histology.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EBUS-TBNA is a highly efficient modality for the evaluation of mediastinal lymphnodes and masses in patients with extra-pulmonary malignancies with an overall diagnostic yield of 86%.

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      P1.05-12 - 18F-FDG PET/CT Findings May Predict Postoperative Acute Exacerbation of Interstitial Pneumonia in Lung Cancer Patients (ID 11131)

      16:45 - 18:00  |  Presenting Author(s): Hisashi Oishi  |  Author(s): Akira Sakurada, Fumihiko Hoshi, Shunsuke Eba, Yasushi Matsuda, Tetsu Sado, Masafumi Noda, Yoshinori Okada

      • Abstract
      • Slides

      Background

      Acute exacerbation could be life-threatening for idiopathic interstitial pneumonia (IIP) patients. It is often challenging to choose a surgical treatment for a patient with IIP associated with lung cancer because lung resection is one of the risk factors of acute exacerbation. The objective of this present study was to investigate the correlation between preoperative findings of 18F-FDG PET/CT and postoperative acute exacerbation in patients with IIP associated with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the data of 450 patients who underwent lung resection for non-small cell lung cancer between November 2012 and October 2017. We excluded patients who had preoperative radiotherapy (25 patients) from the analysis. All these patients preoperatively underwent 18F-FDG PET/CT for staging lung cancer. The maximum standardized uptake value ( was obtained.world-lc-2018_abst_fig1-tiff.tif

      4c3880bb027f159e801041b1021e88e8 Result

      CT findings of IIPs were found in 31 out of 425 patients (7.1%). Five out of 31 patients (16.1%) developed acute exacerbation after lung resection. These 5 patients had significantly higher SUVmax in the lesions of IIPs compared 26 patients without postoperative acute exacerbation.world-lc-2018_abst_fig2-tiff.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study demonstrated that 18F-FDG PET/CT findings may predict postoperative acute exacerbation of IIP in lung cancer patients.

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      P1.05-13 - The Demonstration of the Possibility of the Pleura Cryo Biopsy – A Preliminary Report (ID 12086)

      16:45 - 18:00  |  Presenting Author(s): Jaroslaw Pierog  |  Author(s): Bartosz Kubisa, Janusz Wójcik, Małgorzata Wojtyś, Michał Bielewicz, Bogumił Maciąg, Norbert Wójcik, Tomasz Grodzki

      • Abstract
      • Slides

      Background

      The demonstration of the possibility of diagnosing changes located in the parietal pleura by means of cryo probe guided by videopleuroscopy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The study consisted of five patients with lesions of the parietal pleura and accumulation of fluid in the pleural space suspected of neoplastic disease. The previous diagnostic procedures did not confirm the etiology of the hydrothorax, therefore, the patients were qualified for the videopleuroscopy under local anesthesia and sedation. The ultrasound examination confirmed the presence of the pleural fluid and videotrocar was introduced into the pleural cavity. The videopleuroscope was inserted into the pleural cavity, the fluid was removed and the parietal lesions were visualised. The 1,9 mm cryo probe was introduced through the 2 mm working channel of the videopleuroscope and samples of the parietal pleura were taken. The sampling procedure was repeated with standard forceps. Talc slurry administration and drainage of the pleural cavity were performed eventually. All the patient were discharged a few days after the procedure.

      4c3880bb027f159e801041b1021e88e8 Result

      Mesothelioma was confirmed in one case, primary lung adenocarcinoma in one case, metastatic adenocarcinoma in one case, Ewing sarcoma in one case and chronic pleuritis in one case. Histology samples taken with the cryo probe were much bigger and of better quality than the samples taken by the forceps.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The cryo probe guided by the videopleuroscopy is an effective and safe procedure regarding diagnosing pleural lesions suspected of the neoplastic disease. The cryo probe provides very good samples of the parietal pleura for the pathologic and immunohistochemistry evaluation

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      P1.05-14 - Autofluorescence Mode of Thoracoscope Improves Visceral Pleural Invasion Diagnosis in Non-Small Cell Lung Cancer (ID 14368)

      16:45 - 18:00  |  Presenting Author(s): Toru Sawada  |  Author(s): Hiromitsu Takizawa, Mika Takashima, Daisuke Matsumoto, Naoya Kawakita, Mitsuhiro Tsuboi, Hiroaki Toba, Mitsuteru Yoshida, Yukikiyo Kawakami, Kazuya Kondo, Akira Tangoku

      • Abstract
      • Slides

      Background

      Visceral pleural invasion of non-small cell lung cancer is an important prognostic factor, and tumors with visceral pleural invasion are classified as T2a, even if they are 3 cm or less. However, visceral pleural invasion is usually diagnosed by postoperative pathologic examination and it is difficult to diagnose it by preoperative imaging or intraoperative macroscopic findings. This study was conducted to evaluate the accuracy of autofluorescence mode diagnosis for visceral pleural invasion of non-small cell lung cancer compared with white light mode diagnosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two thoracic surgeons blind to pathological diagnosis reviewed operation videos of 56 cases and evaluated visceral pleural invasion under white light mode and autofluorescence mode. These cases were selected according to the following criteria. 1) Primary non-small cell lung cancer patients who underwent video-assisted thoracic surgery from October 2011 to March 2018. 2) Tumor attached to visceral pleura on the lung window of CT images. 3) Thoracic cavity was explored using both white light and autofluorescence modes using a D-Light AutoFluorescence system (Karl Storz, Tuttlingen, Germany). 4) Lung tumors were resected and evaluated histopathologically using elastic stains. The mean age was 67 years and 31 patients (55%) were male. They included 43 adenocarcinomas, 11 squamous cell carcinoma and 2 others. The mean tumor size was 22 mm (7–30 mm). There were 9 pathological visceral pleural invasion positive cases. For white light mode, if either one of the following pleural change; 1) whitish, 2) granular, 3) hypervascular was observed at the tumor site, the tumor was diagnosed as visceral pleural invasion positive. For autofluorescence mode, we defined attenuation or a defect in autofluorescence of the pleura at the tumor site as a positive finding of visceral pleural invasion.

      4c3880bb027f159e801041b1021e88e8 Result

      The sensitivity, specificity, and accuracy of visceral pleural invasion diagnosis by white light vs autofluorescence mode were 77.8% vs 77.8%, 66.0%% vs 83.0%, and 67.9% vs 82.1%, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The specificity, and accuracy of visceral pleural invasion diagnosis was improved through the additional use of autofluorescence mode compared with white light mode alone.

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      P1.05-15 - Benign Lung Nodule Resections in the Era of Advanced Imaging and Clinical Guidelines: Imaging Features and How we can Reduce the Resection Rate (ID 13208)

      16:45 - 18:00  |  Presenting Author(s): Mohamed Sayyouh  |  Author(s): Paul Cronin, Ella Kazerooni

      • Abstract
      • Slides

      Background

      Evaluation of lung nodules is a long standing clinical problem. Despite advances in diagnostics, many nodules are still resected that are benign. Although certain imaging characteristic can distinguish benign from malignant lung nodules on CT and PET/CT, overlap exists. Our purpose is to understand the benign resection rate with use of PET and PET/CT, and to review the patient and imaging characteristics of benign resected nodules in the PET-PET/CT era.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed all 557 surgically resected lung nodules from 2001-2012. Patient demographics, smoking and cancer history, diagnostic tests prior to surgery, and pathology results were collected. All preoperative CT examinations were reviewed for nodule location, size, shape, border and attenuation, and PET/CTs for FDG-avidity.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 557 resected nodules in 541 patients, 39 nodules in 38 patients were benign (15 females, 23 male) for a benign resection rate of 7% (39/557). There was no significant difference between benign and malignant groups across sex, race, nodule size or attenuation. Patients with benign nodules were younger (mean age 59 vs. 65 years in the malignant group; p=0.005). 75% of patients with benign nodules were smokers versus 80% in the malignant group (p=0.04).

      In the benign nodule group, 14 patients (36%) had a cancer history. Benign pathology results were: 15 granuloma, 6 chronic inflammation, 5 hamartoma, 5 abscesses, 2 inflammatory pseudotumor, 2 organizing pneumonia and 1 case each of bronchogenic cyst, fibrous tumor, lipoid pneumonia and lymphoepithelioma. 62% of were in the right lung, and 46% were in an upper lobe. Nodule size was 10-95 mm (mean 29). CT nodule morphology was round/ovoid in 16, and triangular/angular in 3. Nodule border was lobulated in 4, smooth in 7 and spiculated in 8. Cavitation was present in 4 nodules, 14 were exclusively soft tissue attenuation and one contained fat. By attenuation, 18 were solid, and 1 was non solid (ground glass). Of the 18/38 (47%) patients who underwent preoperative PET/CT scan, nodule FDG uptake was: 5 intense, 10 mild, 3 none.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our benign resection rate for lung nodules is 7%. While in many cases the imaging characteristics of surgically proven benign lung nodules and their clinical management are appropriate, following clinical guidelines for nodule management may further reduce the benign resection rate. The use of PET/CT and follow up low dose chest CT for PET/CT negative or mild uptake lesions to confirm nodule stability over time is a pathway for management that requires reinforcement.

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      P1.05-17 - Clinicopathological Characteristics of Primary Lung Cancers Associated with Emphysematous Bullae (ID 13204)

      16:45 - 18:00  |  Presenting Author(s): Mikito Suzuki  |  Author(s): Kyohei Masai, Kaoru Kaseda, Tomoyuki Hishida, Takashi Ohtsuka, Yuichiro Hayashi, Hisao Asamura

      • Abstract
      • Slides

      Background

      Lung cancers associated with emphysematous bullae (EB) comprise approximately 5% of all primary lung cancers, but the clinicopathological characteristics remain unclear. This study aims to investigate the clinicopathological characteristics and postoperative prognosis of lung cancers associated with EB.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 2008 through 2012, consecutive 517 patients who underwent complete surgical resection for primary lung cancer at our institution, were retrospectively reviewed. Lung cancer associated with EB was defined as lung cancer adjoining emphysematous airspace >1cm, without lung parenchyma, on preoperative thin-slice computed tomography scans. Among the 517 patients, 35 (6.8%) had lung cancers associated with EB (EB group). Their clinicopathological features and prognosis were retrospectively compared with those in the patients having lung cancer not associated with EB (non-EB group).

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up duration was 42 months (range, 2-85 months). The median age of EB group was 70 (39-79) years, while that for non-EB group was younger 59 (33-91) years (p = 0.07). The EB group included more men (94% vs. 6%, p < 0.01), smokers (97% vs 63%, p < 0.01), and the patients with low FEV1.0% (< 70%) ( 91% vs 27%, p < 0.01). In the EB group, frequency of cancer in the right upper lobe was significantly higher than in the non-EB group (60% vs 25%, p < 0.01). Histologically, non-adenocarcinomas, including squamous cell carcinoma, neuroendocrine tumor and large cell carcinoma, were common in the EB group compared with in the non-EB group (57% vs 24%, p < 0.01). Among the EB group, 16 patients (45%) were p-stage I, 16 (45%) were p-stage II, three (9%) were p-stage III, and none (0%) were p-stage IV (WHO 8th classification). The 5-year overall survival (OS) rate for EB and non-EB groups was 75% and 88%, respectively, without significant difference (p = 0.20). The 5-year recurrence-free survival (RFS) rate was also not different between EB and non-EB groups (75% vs. 79%, p = 0.85). The multivariate analysis did not demonstrate that the association with EB to be a significant prognostic factor (p = 0.39).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung cancers associated with EB have clinicopathological features including the predominance of men, heavy-smoking history, and non-adenocarcinoma histology compared with lung cancer not associated with EB. However, in the current analysis, the survival was not different between patients with lung cancers with and without EB.

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      P1.05-18 - Predictive Performance of Semi-Quantitative Metabolic Metrics on FDG-PET/CT for the Identification of EGFR Mutations (ID 13190)

      16:45 - 18:00  |  Presenting Author(s): Taimei Tachibana

      • Abstract
      • Slides

      Background

      FDG-PET/CT is highly useful in evaluating biological malingancy of lung cancer cases. The maximum standardized uptake values (SUVmax) of the primary lesion is widely reported to be associated with prognosis in lung cancer while other metabolic metrics, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have also been explored as a measure of metabolic tumor burden in recent years. Several recent reports have shown that measurement of these metabolic metrics on PET/CT could be beneficial for the identification of driver gene mutational status such as EGFR and KRAS. The purpose of this study is to investigate the role of quantitative metabolic metrics (SUVmax, MTV, TLG) in identifying adenocarcinoma harboring EGFR mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled 247 patients with clinical stage I adenocarcinoma with pre- or postoperative EGFR genotyping. All the patients underwent surgical resection after preoperative FDG-PET/CT scanning during the period from January 2012 to January 2018. SUVmax, MTV, and TLG of each lung tumor were determined with Synapse Vincent System (Fujifilm Medical, Tokyo, Japan) as the volume viewer software. MTV is defined as the volume of the area of ​​SUV 2.5 or higher while TLG was calculated as meanSUV x MTV. Correlation between age, gender, smoking history, clinical stage, SUVmax, MTV, TLG, and EGFR gene mutation status was analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 114patients (46%) were identified as having EGFR mutations. Univariate analysis showed that sex (p = 0.001), smoking status (p = 0.019), SUVmax (p = 0.001), MTV (p = 0.007), and TLG (p = 0.014) were significantly associated with EGFR mutations. Multivariate analysis demonstrated that sex (p = 0.004) and SUVmax (P = 0.004) were independent predictors of EGFR mutations. The receiver operating characteristic curve yielded area under the curve values of 0.622, 0.604, and 0.609 for SUVmax, MTV, and TLG, respectively (SUVmax of 2.95, MTV of 0.10mm3, and TLG of 0.26, respectively). The frequency of EGFR mutations of patients with SUVmax < 2.95, MTV < 0.10mm3, TLG < 0.26, female, and never-smokers were 64.2%, 64.2%, 64.2%, 63.5%, and 61.2%, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In clinical stage I lung adenocarcinoma, SUVmax, MTV, and TLG measured by FDG-PET/CT were associated with EGFR mutation status.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.05-19 - CT and PET/CT Parameters of Lepidic Predominant Pattern Lung Adenocarcinoma and Invasiveness on Pathology (ID 14440)

      16:45 - 18:00  |  Presenting Author(s): Hiromitsu Takizawa  |  Author(s): Mika Takashima, Daisuke Matsumoto, Naoya Kawakita, Toru Sawada, Mitsuhiro Tsuboi, Hiroaki Toba, Mitsuteru Yoshida, Yukikiyo Kawakami, Kazuya Kondo, Akira Tangoku

      • Abstract
      • Slides

      Background

      The 8th edition of TNM classification of lung cancer introduced new categories of Tis and T1mi for adenocarcinoma. Patients classified into these categories are estimated to present 100% or near-100% disease-free survival after complete resection. It is expected we are able to identify them on preoperative imaging because they might fit for limited resection. A retrospective study was conducted evaluating preoperative radiologic parameters of lepidic predominant pattern lung adenocarcinoma to predict invasiveness on pathology.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pathologically classified 20 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA) and 8 lepidic predominant invasive adenocarcinoma (LPA) from 50 patients operated from January 2017 to March 2018 were evaluated. Preoperative CT parameters including maximum diameter, maximum area and mean CT value of the both whole lesions and solid components were evaluated. SUVmax of the lesions were measured at FDG-PET/CT images. Three experienced pathologist determined invasive size based on hematoxylin-eosin and Elastica van Gieson staining slides. Radiologic - pathologic associations were examined using Kruskal-Wallis test and the Spearman correlation coefficient.

      4c3880bb027f159e801041b1021e88e8 Result

      Increasing maximum diameter, maximum area and mean CT value of the whole lesions on CT were significantly associated with invasiveness (p=0.04, p=0.03 and p=0.002, respectively). Increasing maximum diameter and maximum area of the solid components were also significantly associated with invasiveness (p<0.001 and p<0.001, respectively). Higher SUVmax value of the lesions was significantly associated with invasiveness (p<0.015). However, we were not able to find any correlation between the radiologic parameters including maximum diameter of solid components and pathologic invasive size when we analyzed MIA and LPA cases. And, when we evaluated clinical T according to the 8th edition of TNM classification, the sensitivity to diagnose AIS, MIA and IPA were 57.1%, 14.8% and 87.5%, respectively, and the specificity to diagnose AIS, MIA and IPA were 97.5%, 82.1% and 48.9%, respectively,

      8eea62084ca7e541d918e823422bd82e Conclusion

      Both whole tumor size and solid component size increase in association with tumor invasiveness. And SUVmax value also increases with tumor invasion. However, it is difficult to predict pathologic invasive size based on radiologic parameters. It is expected that novel preoperative or intraoperative diagnostic tools for tumor invasiveness of lepidic predominant pattern lung adenocarcinoma will be developed.

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      P1.05-20 - Therapeutic Condition of Photodynamic Therapy Using Taraporfin Sodium for Central Airway Stenosis (ID 13807)

      16:45 - 18:00  |  Presenting Author(s): Takaaki Tsuchida  |  Author(s): Yuji Matsumoto, Midori Tanaka

      • Abstract
      • Slides

      Background

      Central airway stenosis is life threatening, and some kinds of debulking procedures are recommended especially for endobronchial lesions. Previous reports have shown the efficacy and safety of PDT using porphimer sodium as a photosensitizer in debulking. However, the detail of taraporfin sodium, the second generation photosensitizer in this setting has not been known well yet. Therefore, we reviewed the cases that underwent PDT using taraporfin sodium for central airway stenosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Consecutive patients who underwent PDT using taraporfin sodium for central airway stenosis in our institute from 2012 to 2017 were collected. The dose of the photosensitizer, the time to laser irradiation, the laser dose, the therapeutic effect and the adverse events were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventeen lesions were performed PDT in 9 patients (the average number of lesions was 1.9 per parson). The dose of taraporfin sodium was 40 mg/m2, and the time from administration of the photosensitizer to laser irradiation was 5 hours in all cases. The laser dose was 150 J/cm2 in 5 lesions, while 100 J/cm2 in 11 lesions, and 50 J/cm2 in 1 lesion. This treatment condition was selected in accordance with PDT for central type early stage lung cancer: the dose of the photosensitizer was 40 mg/m2, the time to laser irradiation was 4-6 hours, and the laser dose was 100 J/cm2. Meanwhile, 2 patients were treated after electrocautery, and 1 patient was after argon plasma coagulation. Almost all patients showed improvement of airway stenosis except for 1 lesion with the laser dose of 50 J/cm2. There was no significant difference in the effect between the laser dose of 150 J/cm2 and 100 J/cm2. There was no serious adverse event.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PDT using taraporfin sodium is a feasible procedure with sufficient efficacy and safety for central airway stenosis..

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      P1.05-21 - CT-Guided Biopsy of Lung Lesions with Outer Cannula Washing Cytology (ID 12818)

      16:45 - 18:00  |  Presenting Author(s): Fumiyasu Tsushima  |  Author(s): Shinya Kakehata, Hiroyuki Miura, Shuichi Ono, Masahiko Aoki

      • Abstract
      • Slides

      Background

      Although several studies have reported the use of CT lung biopsy for histological diagnosis or aspiration cytology, only a few have reported on the simultaneous use of biopsy and cytodiagnosis. Our hospital has used an outer cannula washing solution cytology in conjunction with a biopsy.

      We examined the usefulness of outer cannula washing cytodiagnosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      At our hospital, 37 patients (mean age, 68 [range, 33-84] years; 23 males and 14 females; 15 adenocarcinomas, 4 small cells, 3 SCC, 10 other cases, and 5 metastases) were diagnosed with pulmonary lesions between June 2016 and March 2018. While the inner needle was washed with formalin and submitted for tissue examination, the washing solution inside the outer cannula was submitted for cytodiagnosis.

      図2.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      In all 37 patients, we successfully performed the procedure without any serious complications. In 33 patients, we observed malignant findings in histopathology or cytodiagnosis. However, we obtained only cytological malignant findings in the three patients. Although one case was negative for histological diagnosis and cytological examination, it was malignant after that. Of note, remaining three other cases were benign. The sensitivity, specificity, and accuracy of the cutting-needle histological biopsy were 88.2%, 100%, and 89.2%, respectively; of washing cytology were 82.6%, 81.3%, and 81.8%, respectively; and of histology and cytology were 97.1%, 100%, and 97.3%, respectively. Although the accuracy was 89.2% only by the conventional tissue method, it was 97.3% when combined with cytodiagnosis (P=0.072).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Washing cytology of the outer cannula could be beneficial in the biopsy.

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      P1.05-22 - New Methods of Brachyradiotherapy Catheter Stabilization in the Airways (ID 14116)

      16:45 - 18:00  |  Presenting Author(s): Jiri Votruba

      • Abstract

      Background

      Endobronchial brachytherapy(EBBT) is mainly used for palliation of obstructive symptoms, most commonly

      for malignancies located in the central airways (ei. trachea and main bronchi). However, the EBBT

      has a curative potential in those tumors, which are small to moderate in size, are not metastasized to

      the lymph nodes and are other wisely untreatable. Typically, EBBT is indicated in patients diagnosed

      with locally advanced non-small cell lung carcinoma (NSCLC) in the central airways.

      Endobronchial brachytherapy, as other methods of interventional bronchoscopic procedures such as

      use of laser, cryo or electrotherapy, and variations of mechanical airways passage maintenance, should

      not be understood as a marginal option from the modalities list. All of these mentioned methods are

      complementary and by a combination, one can achieve satisfactory clinical results

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two new methods of brachyradiotherapy catether fixation are described . First one utilises unique star-shaped fixation device manually made from Microtech stent holding 5Fr probe in the center of airways. In the second case the brachytherapy catheter was fixed in the designated position in the trachea using a Novatech-Dumon stent (20x40 mm) and consecutively, single-dose brachytherapy of 8 Gy was applied.

      .

      4c3880bb027f159e801041b1021e88e8 Result

      In both our referred cases, the patients undergone procedure of HDR-EBBT without

      any complication with the use of a fixation devices which kept an afterloading probe in selected area

      of the airways and allowed a symmetrical radiation distribution

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our presented case studies local control of intraluminal tumor growth has been achieved with the HDR-EBBT. In

      the case of our first patient along with surgery and cryotherapy and in the other case along with the

      third-line chemotherapy based on docetaxel.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.05-23 - Evaluation of the 8th Edition of the TNM Classification for Lung Cancer at a Single Institution (ID 13730)

      16:45 - 18:00  |  Presenting Author(s): Jia Wang  |  Author(s): Yue Yang, Wu Nan

      • Abstract

      Background

      The 7th edition has been used more than10 y ears and has proven reliable, but various problems had been indicated.The latest (8th) edition of the lung cancer staging classification was published in 2017. The purpose of this retrospective study is to make a external validation to the 8th edition of the lung cancer staging system.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Subjects included 3,229 patients who underwent pulmonary resection for primary non-small cell lung cancer.Survival characteristics were compared using the 7th and 8th editions of the staging system.

      4c3880bb027f159e801041b1021e88e8 Result

      1 拷贝.jpg2 拷贝.jpgAccording to the 7th edition, there was no significant difference between pStages IIB and IIIA(P = 0.650), however, according to the 8th edition, there were significant differences between each adjacent stage group. Moreover, to the T descriptor(tumor size), which got most emphasis in the 8th edition, there were significant differences between each adjacent pT classification, either according to the 7th edition or the 8th edition.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The UICC 8th edition staging system is considered valid for non-small cell lung cancer patients and appears to be superior in defining different prognostic groups than the 7th edition.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.05-24 - Clinical Characteristics and Prognostic Analysis of Multiple Primary Malignant
      Neoplasms in Patients with Lung Cancer (ID 12840)

      16:45 - 18:00  |  Presenting Author(s): Huijuan Wang  |  Author(s): Jingjing Hou, Guowei Zhang, Mina Zhang, Xiaojuan Zhang, Zhiyong Ma

      • Abstract
      • Slides

      Background

      To investigate the clinical characteristics, survival status and prognostic factors of multiple primary malignant neoplasm (MPMN) patients with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The clinical and pathological data of 14,528 lung cancer patients who were diagnosed and treated in the affiliated cancer hospital of Zhengzhou University from January 2008 to August 2015 were retrospectively analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the total lung cancer patients, 2.5% (364/14,528) were MPMN cases and 3.6% (13/364) were diagnosed with 3 primary malignancies, 0.3% (1/364) with 4 primary malignancies and 96.2% (350/364) with 2 primary malignancies. Among the
      350 lung cancer patients diagnosed with 2 primary malignancies, 26.6% (93/350) had lung cancer diagnosed first (LCF) and 73.4% (257/350) had other cancers diagnosed initially (OCF), whereas synchronous MPMN (SMPMN) accounted for 21.1% (74/350) and metachronous MPMN (MMPMN) accounted for 78.9% (276/350) of cases.Detection of first primary neoplasms were at an early stage for LCF patients and the age of the first lung cancer diagnosis was 59.3 years vs 55.4 years in the OCF group (P = 0.008), whereas the onset age of second primary neoplasm diagnosis was similar in both groups (62.5 and 61.6 years, P = 0.544). The median survival times of the OCF and LCF groups were 86 months vs 58 months (P < 0.001). The median survival times of MMPMN and SMPMN patients were 94 months vs 27 months (P < 0.001).Multivariate analysis showed that SMPMN, LCF and the age of the primary cancer diagnosed first (≥ 60 years) were independent factors for inferior prognosis of patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Though LCF was diagnosed in earlier stages than OCF, the survival rate was inferior and the time until the development of the second primary malignancy was shorter than in the OCF group. SMPMN patients had a worse prognosis than MMPMN
      patients in both the LCF and OCF groups. Also ≥ 60 years of age at the time of the primary cancer diagnosis was an independent factor for inferior prognosis in all patients.

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    P1.09 - Pathology (Not CME Accredited Session) (ID 941)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 40
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.09-01 - PD-L1 Testing On NSCLC Cytology Samples in a UK Teaching Hospital (ID 12435)

      16:45 - 18:00  |  Presenting Author(s): Haider Al-Najjar  |  Author(s): Narine Nadira, Catherine Higgins, Sakinah Thiryayi, David Shelton, Simon Bailey, Durgesh Rana

      • Abstract
      • Slides

      Background

      Immunotherapy, specifically pembrolizumab, is now approved in the UK as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) and no activating EGFR mutation or ALK translocation if high PD-L1 expression (≥50%) can be demonstrated on tumour samples. Furthermore, second line treatment is approved with PD-L1 expression ≥1%. Initial studies were performed exclusively on histological samples. We present our experience of PD-L1 testing purely on cytology samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Prospectively maintained cytology databases were analysed to identify all lung cancer cytology samples from our institute tested for PD-L1 expression between January 2017 and March 2018. Cell blocks from endo-bronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) performed using rapid on-site evaluation (ROSE), FNA of other sites, pleural fluid and bronchial brush samples were prepared and immunohistochemistry performed on sections using the Dako 22c3 antibody to determine PD-L1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 99 samples were tested for PD-L1. There was sufficient material for PD-L1 testing in 95% (n=94). Male 62%, female 38%, age range 26-84. EBUS-TBNA accounted for 79% of samples, percutaneous Fine Needle Aspirate (FNA) 11%, pleural fluid samples 7%, bronchial brush 2% and endoscopic ultrasound FNA 1%. Table-1 provides a breakdown of the methods of sample acquisition with adequacy rates and PD-L1 expression.

      Table 1
      PD-L1 samples Adequate Inadequate Negative Positive Positivity
      EBUS 78 76 2 19 57

      1-50%

      31

      ≥50%

      26

      FNA 11 9 2 2 7

      1-50%

      2

      ≥50%

      5

      Pleural fluid 7 6 1 0 6

      1-50%

      5

      ≥50%

      1

      Bronchial brush 2 2 0 0 2

      1-50%

      0

      ≥50%

      2

      EUS FNA 1 1 0 1 0

      1-50%

      0

      ≥50%

      0

      Total 99 94 5 22 72

      1-50%

      38

      ≥50%

      34


      Overall PD-L1 expression was highly (≥50%) positive in 34/94 (36%), low (≥1-50%) positive in 38/94 (40%), and negative in 22/94 (23%). The proportion of patients expressing high (≥50%) PD-L1 positivity in the different pathological subtypes were: adenocarcinoma 23/62 (37%), squamous cell carcinoma 8/21 (38%), NSCLC-NOS 3/9 (33%).

      The proportion of patients with low (≥1-50%) PD-L1 positivity were: adenocarcinoma 27/62 (44%), squamous cell carcinoma 9/21 (43%), NSCLC-NOS 2/9 (22%).

      Neither of 2 neuroendocrine NSCLC tested expressed PD-L1

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our experience demonstrates that cytological samples obtained at our institute are suitable for PD-L1 testing with an adequacy rate of 95%.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • Abstract
      • Slides

      Background

      Large cell neuroendocrine carcinomas of the lung (LCNECs) are rare neoplasms with few therapeutics options especially for stage IV diseases. Pathological diagnostic of LCNECs may be difficult with low interobserver reproducibility and need immunohistochemical (IHC) staining. Immune checkpoint inhibitors targeting tumoral and immune cells interaction have revolutionized the treatment of NSCLC, but few data's are available on LCNECs immune environment and particulary the expression of PD-L1 on both tumors (TC) and immune infiltrating (IC) cells. The objective of the present study is to determine the pattern of PD-L1 staining in a cohort of LCNECs patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinical files and tumors biopsies of patients (pts) with a LCNEC diagnosed between 01.01.2014 and 31.12.2016 were retrospectively collected (GFPC 03-2017). All histological samples were centrally reviewed by a panel of six independent pathologists, according to the WHO 2015 classification. LCNEC was confirmed and PD-L1 expression was determined both in TC and IC, using the anti-PD-L1 antibody 22C3 (kit and automat Dako). PD-L1 expression was scored on TC as the percentage of PD-L1 positive cells (0 to 100%). PD-L1 expression on IC was determined as follows: IC0: positive IC representing<1% of the tumor surface; IC1: positive IC representing>=1% but<5% of the tumor surface; IC2: positive IC representing>=5% but<10% of the tumor surface; and IC3: positive IC representing>10% of the tumor surface.

      4c3880bb027f159e801041b1021e88e8 Result

      Eighty-six pts were initially included in the study.Twenty-eight (32%) of them were excluded for non-LCNEC diagnosis after review. Among the 58 remaining pts with confirmed LCNEC, five (8%) had a mixed histology with a NSCLC component.The mean age of the population was 65 years, mainly mens (86%) and former or current heavy smokers (93%). Fifty-five and 51 tumors samples were respectively available for TC and IC PD-L1 IHC expression. PD-L1 expression on TC was found in only 12% of the samples (7/55), while 76% (39/51) of the samples shows IC PD-L1 positive, with respectively 18 (35%) IC3, 8 (14%) IC 2, and 13 (25%) IC1.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Histological diagnosis of LCNEC remains difficult, and prospective studies concerning patients with LCNEC should include a centrally pathological review of tumors.The PD-L1 expression pattern looks different for LCNEC in comparison to other lung carcinomas, as few TC were found positive although IC were frequently positive, half of the tumors having high PD-L1 IC infiltration (IC3/2). This PD-L1 pattern may suggest a potential effectiveness of therapeutic anti PD-L1 antibodies and this hypothesis have to be adressed in clinical trials.

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      P1.09-03 - Challenges in PD-L1 Immunoexpression in Liquid Based Cytology Samples of Advanced Stage Non-Small Cell Lung Carcinomas (ID 11311)

      16:45 - 18:00  |  Presenting Author(s): Deepali Jain  |  Author(s): supraja K, Anant Mohan, V K Iyer

      • Abstract
      • Slides

      Background

      Study of programmed death-ligand 1 (PD-L1) expression is essential in patients of advanced lung cancer to determine their eligibility and predict responsiveness for immune-checkpoint inhibitors. Lung cancer is frequently diagnosed on cytology specimens. Although PD-L1 IHC assays are validated on formalin fixed paraffin embedded (FFPE) tissue, evidences are present in literature which showed high concordance of cytology samples with paired biopsies. However liquid based cytology (LBC) processed specimens have not been tested for PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Immunohistochemistry using the anti-PD-L1 clone SP263 was performed on BD SurePath LBC processed bronchial washing and brushing smears and paired FFPE endobronchial biopsy specimens. The presence of 100 viable tumor cells was considered adequate for PD-L1 testing. Staining was interpreted positive if membranous and/or cytoplasmic protein expression at any intensity greater than background staining was detected in at least 25% of tumor cells.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 26 patients with 13 adenocarcinomas and 13 squamous cell carcinomas which were diagnosed by bronchial brushings, washings and concurrently obtained endobronchial biopsy. Twelve out of total 26 biopsies showed cytoplasmic and membranous PD-L1 positivity in >25% tumor cells (46%). Corresponding LBC smear showed PD-L1 positivity in 9 cases establishing concordance of 88.4%. No negative case was positive on cytology. However, there were following challenges while interpreting PDL1 IHC on LBC processed smears: 1. Thick clusters of cells: LBC can cause rounding up of epithelial cells and create thick clusters of tumor cells. Therefore, it was necessary to see under higher magnification (40x) for proper interpretation of membrane staining. 2. Identification of tumor cells: Although identification of tumor cells was done before PD-L1 staining, after staining they were interpreted only on higher magnification to better differentiate them from alveolar macrophages. 3. PD-L1 staining in macrophages: Five cases showed very strong cytoplasmic positivity in macrophages. Since tumor cells showed cytoplasmic and membranous positivity it was easy to differentiate tumor cell positivity from macrophage positivity. Necrotic background in one case stained strongly with PD-L1 immunocytochemistry. 4. Nuclear positivity of PD-L1 positivity: One case, where corresponding biopsy was positive for PD-L1 IHC, showed aberrant nuclear positivity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PD-L1 IHC can be performed on LBC processed smears. Though there are challenges in interpretation of immunoexpression inherent to the LBC smears, they can be used in situations when histology material is not available. Future studies are needed to determine their ability to predict response to immunotherapy.

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      P1.09-04 - Optimization of PD-L1 Testing Specimen Flow in the Greater Hamilton, Ontario Region (ID 12767)

      16:45 - 18:00  |  Presenting Author(s): Rosalyn Juergens  |  Author(s): Martin Butcher, Asghar Naqvi, Jean-Claude Cutz, Michael Bonert

      • Abstract

      Background

      Immunotherapy targeted at the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) is a new treatment option for non-small-cell lung cancer (NSCLC). Immunohistochemistry (IHC) for the PD-L1 protein has been shown to predict response. The 22C3 IHC assay is the only clinically validated PD-L1 test. We present the Hamilton, Ontario, Canada experience of local PD-L1 analysis using the 22C3 assay including both histology and cytology specimens.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All data for requests for PD-L1 testing from within Hamilton were collected for one year. Unstained slides were cut for IHC analysis. Both histology and formalin fixed cytology specimens were accepted. Slides were sent for PD-L1 staining centrally at Dynacare in Bowmanville, Ontario, Canada. IHC interpretation was done in Hamilton. The assay was positive if ≥50% of tumour cells (TCs) had any intensity staining. The assay was negative if no TCs had staining. The assay was interpreted as low positive if 1-49% TCs had any intensity staining. Samples with less than 100 cells were considered inadequate. Turn around-time was defined as the accession date to PD-L1 sign out date.

      4c3880bb027f159e801041b1021e88e8 Result

      401 samples were evaluated; 108 cytology(C) and 293 histology(H). 36% of samples tested positive (43%:C;33%:H); 20% of samples tested low positive (14%:C;23%:H); 39% of samples tested negative (29%:C;42%:H); 5% were insufficient for evaluation (15%:C;1%:H). Chi-squared analysis identified a statistically significant (χ2 < 0.02) difference in the distribution of test results comparing histology and cytology. The mean turn-around-time (TAT) was 28.9 days (range 12-144). TAT varied by hospital of origin. TAT for PD-L1 results from the hospital with dedicated thoracic pathologists was on average 10 days shorter than from other Hamilton hospitals. TAT in our hospital with dedicated thoracic pathologists improved with time from a mean of 49 days to a mean of 22 days while TAT from other hospitals did not improve over the course of the year.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our cohort mirrors findings in the literature and demonstrates that the 22C3 assay for PD-L1 can be done on both histology and cytopathology specimens; however, the insufficient rates are higher for cytopathology. Cytopathology specimens have a higher PD-L1 positivity rate, a finding that may reflect differences in tumour biology and/or stage in this subgroup. Turnaround times were different based on the hospital of origin, and suggest centralized specimen collection or use of dedicated thoracic pathologists may be advantageous. Correlation with clinical outcomes on our cytology cases will be presented in a separate abstract.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-05 - Why Does PD-L1 (22C3) Expression Rate Show Difference Among Regional Hospitals? (ID 12123)

      16:45 - 18:00  |  Presenting Author(s): Yuko Minami  |  Author(s): Masayuki Noguchi, Ibaraki Pathologist Association

      • Abstract
      • Slides

      Background

      The immune checkpoints inhibitors, such as anti-programmed cell death 1 (PD-1) receptor antibodies and anti-PD-L1 (its major ligand against PD-1) were applied for several advanced cancer. On 2017, Pembrolizumab was approved for non-small cell lung cancer (NSCLC) as 2nd immune checkpoint inhibitor in Japan. At same time, immuneohistochemical examination by anti-PD-L1 antibody (22c3) was approved as companion diagnostic staining for Pembrorizumab treatment. However, PD-L1 expression rate shows quite difference among hospitals in routine clinical examination. The purpose of this study is probed the reason of the difference in each hospital.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The questionnaire about PD-L1 staining was sent via e-mail to 14 Hospitals in Ibaraki prefecture, Japan. The questionnaire included PD-L1 expression in each histology (adenocarcinoma (AD), squamous cell carcinoma (SQ), and other NSCLC, and fixation condition.

      4c3880bb027f159e801041b1021e88e8 Result

      Eleven hospitals (A to K) answered with the questionnaire. Total staining cases were 651: ADs were 384, SQs were 185 and the other NSCLCs were 79. The rates of PD-L1 No expression showed 18% to 71% among each hospitals. (figure 1 and 2)

      スライド1.jpg

      スライド2.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The result of TPS is quite different from clinical study. The reason is thought to be caused of the histological configuration was appreciably difference among regional hospitals.

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      P1.09-06 - The Incidence of PD-L1 in NSCLC and its Correlation with Driver Mutations in Turkish Patients; A Single Center Experience. (ID 12506)

      16:45 - 18:00  |  Presenting Author(s): Buge Aysim Oz  |  Author(s): Onur Dülger, Sebnem Batur, Kerem Özcan, Gamze Özcan, Veysel Gökçek

      • Abstract
      • Slides

      Background

      PD-L1 testing have become the new standard of care for patient diagnosis in advance Non-Small Cell Lung Carcinoma (NSCLC). NSCLC also is characterized by driver mutations in epidermal growth factor receptor (EGFR), alterations anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). This study aimed to evaluate and to compare with immunotherapy related biomarker PD-L1 and driver mutations biomarkers (EGFR, ALK, and ROS1) in Turkish patients with NSCLC retrospectively. PD-L1 positivity also was examined whether related to some clinico-pathological parameters in NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort composed of 650 consecutive patients diagnosis with NSCLC were tested for PD-L1 between November of 2016 and February of 2018. PD-L1 immunostaining was performed using and 22c3 (DAKO platform) or SP263 (Ventana platform). Pathology report were reviewed to collect patient demographic data, smoking status, tumor sup-types, and specimen types. For EGFR mutational analysis were examined using a real time assay (The cobas v2 ® EGFR Mutation Test). ALK and ROS1 translocations were evaluated by IHC + FISH method. For statistical analysis Pearson chi -square test was used.

      4c3880bb027f159e801041b1021e88e8 Result

      TABLE I

      Parameter

      PD-L1 status

      Statistic

      total

      <1%

      1-49%

      ≥50%

      P-value (Pearson
      Chi-Square)

      Age

      ≤60

      282 (44.4%)

      80 (28.4%)

      110 (39.0%)

      92 (32.6%)

      0.070

      >60

      353 (55.6%)

      113 (32.0%)

      154 (43.6%)

      86 (24.4%)

      Gender

      female

      140 (22.0%)

      46 (32.9%)

      65 (46.4%)

      29 (20.7%)

      0.090

      male

      495 (78.0%)

      147 (29.7%)

      199 (40.2%)

      149 (30.0%)

      Smoking

      no

      77 (14.4%)

      27 (35.1%)

      37 (48.1%)

      13 (16.9%)

      0.072

      yes

      456 (85.6%)

      143 (31.4%)

      179 (39.3%)

      134 (29.4%)

      Pathology

      adenoca

      404 (63.8%)

      134 (33.2%)

      171 (42.3%)

      99 (24.5%)

      0.018

      non-adenoca

      229 (36.2%)

      59 (25.8%)

      91 (39.7%)

      79 (34.5%)

      EGFR status

      wild type

      429 (90.7%)

      120 (28.0%)

      179 (41.0%)

      130 (30.3%)

      0.002

      exon 19

      26 (5.5%)

      17 (65.4%)

      7 (26.9%)

      2 (7.7%)

      exon 21

      13 (2.7%)

      6 (46.2%)

      6 (46.2%)

      1 (7.7%)

      others

      5 (1.1%)

      2 (40.0%)

      1 (20.0%)

      2 (40.0%)

      ALK status

      negative

      414 (94.7%)

      116 (28.0%)

      177 (42.8%)

      121 (29.2%)

      0.890

      positive

      23 (5.3%)

      6 (26.1%)

      11 (47.8%)

      6 (26.1%)

      ROS1 status

      negative

      412 (97.6%)

      116 (28.2%)

      179 (43.4%)

      117 (28.4%)

      0.251

      positive

      10 (2.4%)

      1 (10.0%)

      4 (40.0%)

      5 (50.0%)

      Clinico-pathological characteristics of NSCLC patients (n=650) and their relationships with PD-L1 expression were presented on Table I.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first study to compare PD-L1 expression with clinico-pathological parameters in Turkish NSCLC patients (n=650).

      The majority of Turkish patients were smokers (85.6%). Although there was no statistical significance between PD-L1 positivity and smoking status, smoker patients showed more PD-L1 high tumor proportion score (H-TPS = ≥50%) than non-smoker patients; 29.4% to 16.9% respectively.

      The majority of patients were Adenocarcinoma patients (63.8%).

      PD-L1 positivity was higher in Non-adenocarcinoma patients than Adenocarcinomas (p=0.018).

      This study demonstrated that PD-L1 positivity in lung adenocarcinoma, was strongly associated with EGFR wild-type status (p=0.002) which was parallel to literature.

      There was no correlation between ALK and ROS1 translocation with PD-L1 status.

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      P1.09-07 - PD-L1 Protein Expression is a Predictor of Benefit from Adjuvant Chemotherapy in Resected Non-Small Cell Lung Carcinoma (ID 11326)

      16:45 - 18:00  |  Presenting Author(s): Naoki Yanagawa  |  Author(s): Satoshi Shiono, Makoto Endo, Katsuyuki Suzuki, Kazuki Hayasaka, Akimi Saito, Shin-ya Ogata

      • Abstract
      • Slides

      Background

      Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) are important targets of immunotherapy and its expression has been closely correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). But it is still unclear whether PD-L1 is a prognostic or a predictive marker of adjuvant chemotherapy. The aim of this study is to examine the prognostic value of PD-L1 protein expression and its predictive role for adjuvant chemotherapy in surgically resected NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 407 NSCLC were examined. The male:female ratio was 288:119; the age range was between 38 and 85 years of age and the mean age was 68.5 years. Pathological stage’s ratio (I:II:III) was 147:154:106. Adenocarcinoma:Squamous cell carcinoma:Others’ ratio was 251:135:21 in histology. Adjuvant chemotherapy was performed in 173 patients. The follow up duration was from 0.4 months to 168.7 months and the mean duration was 61.9 months. Tissue microarray was constructed and PD-L1 protein expression was analyzed using immunohistochemistry (clone SP263, Ventana Medical Systems. Inc., Tucson, AZ). The PD-L1 staining percentage in tumor cells were classified as follows: Negative, 0%; Weak positive, 1-49%; Strong positive, 50-100%. The score of PD-L1 staining was correlated with clinicopathological backgrounds, molecular features, patient outcome and potential benefit of adjuvant chemotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      The score of PD-L1 staining was as follows: Negative, 265 (65%); Weak positive, 82 (20%); Strong positive, 60 (15%). PD-L1 expression status was associated with sex, smoking history, pathological stage, histology, p53 protein expression, MIB-1 labeling index. 5-year overall survival (OS) was as follows: Negative, 63.5%; Weak positive, 62.1%; Strong positive, 54.8% and 5-year recurrence-free survival (RFS) was as follows: Negative, 51.6%; Weak positive, 55%; Strong positive, 42.5%, respectively. These results were not statistically significant. Untreated patients with a strong positive PD-L1 expression had significantly worse OS than patients with a negative PD-L1 expression {hazard ratio (HR)=1.98; 95% CI, 1.21-3.24; p=0.006}. However, patients with a strong positive PD-L1 expression had a significantly better survival benefit from adjuvant chemotherapy (HR=0.43; p=0.03) compared with patients with a negative PD-L1 expression (HR=1.04; p=0.82).

      8eea62084ca7e541d918e823422bd82e Conclusion

      PD-L1 protein expression is not a prognostic marker, however it is a significant predictive marker of benefit from adjuvant chemotherapy in resected NSCLC.

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      P1.09-08 - Integrating NGS Information for Staging Multiple Lung Adenocarcinoma: A McGill University Health Centre Retrospective Study. (ID 12635)

      16:45 - 18:00  |  Presenting Author(s): Ayesha Baig  |  Author(s): Jonathan David Spicer, Pierre Olivier Fiset, Hangjun Wang, Scott Owen, Richard Fraser, Lorenzo Ferri, Christian Sirois, Leon van Kempen, George Chong, Alan Spatz, Sophie Camilleri-Broët

      • Abstract
      • Slides

      Background

      The incidence of patients with multiple primary lung adenocarcinoma (MPLC) is increasing and the optimal management of these patients remains unclear. Distinguishing between MPLC and intrapulmonary metastases is at the heart of the diagnostic dilemma. The Comprehensive Histologic Assessment (CHA) relies on microscopic examination including histological subtypes, cytological and stromal features. CHA has shown a good reproducibility but with a non-negligible rate of disagreement, even between expert pathologists. Moreover, predictive biomarker testing has become standard of care for lung cancer patients and the use of Next-Generation Sequencing (NGS) is now widely available. The goal of this study was to evaluate how the NGS information may be integrated in the diagnostic strategy for distinguishing between MPLC and patients with stage III/IV disease.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a retrospective study of all surgical patients with > 1 synchronous lung carcinoma over two years. We identified 59 cases and reviewed initial clinical, pathological and molecular reports. Patients having multifocal lung adenocarcinoma with prominent lepidic component or an adenocarcinoma associated with another histological type were considered as synchronous primaries and not tested for molecular aberrations. The NGS panel analysis using an Illumina miSeq platform included the following genes: AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3A, RET, and TP53.

      4c3880bb027f159e801041b1021e88e8 Result

      Histologically, the majority were considered as MPLC with only four suspected metastases. Twenty-five patients had adenocarcinoma with prominent lepidic component and one case had two different histological differentiations (adenocarcinoma and squamous cell carcinoma). Most of the suspected synchronous primary tumours had different mutations in the separate tumours. Relevant mutations were found in KRAS and P53 genes, with fewer mutations in EGFR, PIK3CA and BRAF genes, in accordance with known frequencies. In 12% of the cases, the NGS was not informative with no molecular mutation in either tumours. One case was reclassified from MPLC to intra-pulmonary metastases and restaged after NGS. For one patient, a TP53 mutation allowed us to reclassify two nodules as metastases from a previous adenocarcinoma originally diagnosed in 2012. In one patient having three separate nodules, different KRAS and TP53 mutations allowed the diagnosis of two nodules as intrapulmonary metastases and one contralateral nodule as synchronous primary adenocarcinoma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although CHA is an efficient method for diagnosing MPLC from intra-pulmonary metastases there are still difficult cases with a risk of misdiagnosis. Integrating NGS analysis in the diagnostic strategy may lead to improved quality and accuracy in the staging of MPLC.

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      • Abstract

      Background

      After the approval of crizotinib in ROS1 rearranged NSCLCs, the importance of accurately identifying those patients has never been greater. Although the recently updated guideline for molecular testing supports the use of ROS1 IHC as a screening test, to the best of our knowledge, only one ROS1 clone is commercially available and most published comparison studies involve a relatively small numer of positive cases. This situation prompted us to investigate a novel ROS1 IHC antibody in a large series of ROS1 positive NSCLCs samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Thirty-nine ROS1 FISH-positive (i.e., gold standard) samples from patients with NSCLCs procured at 22 hospitals were used for this study. In addition, 20 consecutive ROS1 FISH-negative samples from NSCLCs diagnosed at the referral institution were included as negative controls. The material available for all tumors had been formalin-fixed and paraffin-embedded. The specifics of formalin fixation were unknown. All specimens were independently screened for ROS1 expression by two IHC antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 provided by Ventana Medical Systems, Inc.) according to previously published methodology or the manufacturer´s instructions. FISH-validated ROS1-positive external controls were included in all the slides. The slides were reviewed by two pathologists blinded to FISH results. The results of both ROS1 IHC assays were evaluated using a modified H-score: strong cytoplasmic staining (3+), clearly visible using a ×2 or ×4 objective; moderate staining (2+), requiring a ×10 or ×20 objective to be clearly seen; and weak staining (1+), cannot be seen until a ×40 objective is used. Both anti-ROS1 IHC staining results were finally interpreted using a binary scoring system: positive (3+ or 2+) or negative (1+ or 0).

      4c3880bb027f159e801041b1021e88e8 Result

      In ROS1 FISH-negative cases, positive immunoreactivity (3+ or 2+) was observed in 25% and 5% of samples by SP384 and D4D6, respectively. In ROS1 FISH-positive cases, positive expression above the threshold was always present with both antibodies except for one sample that was only stained with SP384. In 4 positive cases (10.3%) by SP384 and 22 positive tumors (56.4%) by D4D6, we noted significant intratumoral heterogeneity, ranging from weak to strong protein expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have studied a very large series of ROS1 FISH-positive NSCLCs with a novel IHC clone, which showed excellent sensitivity. The predominantly homogeneous and intense staining may support the use of a dichotomous scoring approach, before confirmation with FISH or a molecular method.

      Funding: I+D+I 2013-2016/Feder. ISCIII: PI14/01176

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-10 - Targeted Sequencing of Pulmonary Enteric Adenocarcinoma Reveals Distinctive Mutation Profile from Conventional Type of Lung Adenocarcinoma (ID 12468)

      16:45 - 18:00  |  Presenting Author(s): Likun Hou  |  Author(s): Chunyan Wu

      • Abstract
      • Slides

      Background

      Pulmonary primary enteric adenocarcinoma (PEAD) is a rare subtype of lung cancer, which is defined in the new edition of 2015 WHO classification. However, genetic profiling and information about targeted therapy of PEAD remain unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Resected 56 cases of PEAD were retrospectively reviewed. The pathological diagnosis of PEAD was confirmed by immunohistochemistry based on morphology and over 1 year’s follow-up. We use targeted ultra-deep sequencing to test 56 therapeutically relevant genes alterations of PEAD.

      4c3880bb027f159e801041b1021e88e8 Result

      The majority of PEAD patients were male (41/56, 73.2%). Molecular analysis revealed that KRAS was the most frequently mutated gene (18/56, 32.1%) with no targetable mutation co-existence, and then EGFR (9/56, 16.1%), ERBB2 exon 20 insertion mutations (4/56, 7.1%) and ERBB2 amplification (8/56, 14.3%). 3 cases harboring rare fusion genes were identified, TACC3-FGFR3 (2/56, 3.6%) in 2 cases and CD74-NRG1 in one case, respectively. APC gene mutation was negative in all cases. One postoperative patient with EGFR exon 21 L858R mutation was treated with 4 cycles’ NP chemotherapy regimen. PET-CT found the progression lesion of right rib. Treatment was switched to gefitinib for 8 monthly cycles. Response was poor with brain metastasis. Patient received gamma knife treatment. And then, the results of molecular testing showed no EGFR T790M mutation by using the pleural effusion specimen. Pemetrexed regimen was employed to patient. Follow-up of the patient remains ongoing.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pulmonary primary enteric adenocarcinoma exhibited distinctive features of genetic profile. Despite KRAS appearing as the most important mutated gene in PEAD tumors, PEAD patients with sensitive mutations were eligible for targeted therapy.

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      P1.09-11 - Immunohistochemical Assessment of BRCA1 Associated Protein-1 (BAP1) in Pulmonary Mucoepidermoid Carcinomas (ID 11322)

      16:45 - 18:00  |  Presenting Author(s): Deepali Jain  |  Author(s): Aanchal Kakkar, Prerna Guleria, Sunil Kumar

      • Abstract
      • Slides

      Background

      Primary pulmonary mucoepidermoid carcinomas (PMEC) are rare tumors that account for <1% of all lung carcinomas. They are presumed to originate from the minor salivary glands lining the tracheobronchial tree. PMEC are the most common malignant salivary gland tumors of tracheobronchial tree. Despite recent advances in diagnosis and treatment, there has not been much improvement in the outcome of patients with MECs, thus necessitating the identification of novel targeted therapeutic agents. Comprehensive genomic profiling has recently revealed genomic aberrations in BRCA1 associated protein-1 (BAP1) gene in a subset of their non-pulmonary salivary gland counterparts. We conducted this study to identify loss of BAP1 by immunohistochemistry (IHC) in a cohort of PMECs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Cases of PMECs were retrieved from the departmental archives. Hematoxylin and eosin stained sections were reviewed. Immunohistochemistry for BAP1 was performed on formalin fixed paraffin-embedded tumor sections.

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-five PMEC cases were retrieved, out of which sufficient tumor tissue for IHC was available only in 15 PMECs. Thirteen (86.7%) tumors were tracheobronchial in location, while two (13.3%) were intraparenchymal. All were low grade MECs. On immunohistochemistry, BAP1 nuclear staining was retained in all cases (100%), irrespective of tumor location or grade.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Identification of easily applicable techniques to detect BAP1 loss in PMECs is needed for therapeutic decisions. Using IHC, loss of BAP1 staining was not seen in any of our cases, suggesting either the extreme rarity of BAP1 loss in PMEC or insensitivity of BAP1 IHC to detect aberrations at genomic level. Analysis of aberrations in BAP1 gene by genomic approaches in PMECs may be done before excluding the possibility of BAP1 gene as a predictive biomarker for targeted therapies.

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      P1.09-12 - Simultaneous Platform of Genotyping EGFR, ALK, and ROS1 in Patients with NSCLC Highlights Correlation of ROS1 and PD-L1 Expression (ID 12719)

      16:45 - 18:00  |  Presenting Author(s): Tae-Jung Kim  |  Author(s): Jongmin Lee, Jung Im Na

      • Abstract
      • Slides

      Background

      ROS1oncogene rearrangement is targetable oncogene of non-small-cell cancer (NSCLC) and recently approved for crizotinib. Prior to drug approval, we integrated ROS1fluorescent in situ hybridization (FISH) screening test in our routine simultaneous genotyping platform. Furthermore, the frequency of overlap of above oncogenic aberration with programmed death ligand 1 (PD-L1) in routine clinical practice is not well known in Asian cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Reflex simultaneous genomic screening panel of EGFRby PNA clamping, ALKand ROS1by FISH was performed on all NSCLCs at the time of pathologic diagnosis in our institution. PD-L1 22C3 assay kit was then integrated in our routine biomarker test panel. We retrospectively evaluated genetic aberration, clinicopathologic characteristics and PD-L1 status.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 407 consecutive NSCLC patients, simultaneous genotyping identified 14 (3.4%) ROS1and 19 (4.7%) ALK rearrangements,106 (26%) EGFR(26%) mutations in tumors. All three genetic aberrations shared similar clinical features including younger age, female, adenocarcinoma, and advanced stage. PD-L1 assay was performed on 130 consecutive NSCLC samples. High PD-L1 expression ( 50%) was seen in 22.3% of tumors. PD-L1 expression (≥ 1%) was significantly associated with EGFR Wild typestatus, while ROS1rearrangement was associated with High PD-L1 TPS (≥ 50%). Of 14 cases with ROS1rearrangement, 5 (35.7%) showed High PD-L1 expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our routine simultaneous biomarker screening of NSCLCs, 22C3 PD-L1 high expression was frequently overlapped with ROS1rearrangement in comparison to its negative correlation with EGFRmutation. PD-L1 expression status may not be characterized according to status of oncogenic driver mutation.

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      P1.09-13 - Detection of Actionable Mutations in Plasma cfDNA Samples From NSCLC Patients Using a Novel Amplicon-Based Firefly NGS Assay (ID 12401)

      16:45 - 18:00  |  Presenting Author(s): Jiatao Lou  |  Author(s): Lin Wang, Li Weng, Xiao Chen, Min Li, Qiaomei Guo, Wenjun Yu, Qinghe Meng, Hongyan Wang, Tobias Wittkop, Grace Q. Zhao, Malek Fahem, Shengrong Lin

      • Abstract

      Background

      Detection of EGFR, KRAS and BRAF mutations can help guide cancer treatment for non-small cell lung cancer (NSCLC) patients. To identify an easy to use, accurate, multiplex molecular diagnostic assay, we evaluated the performance of a novel next-generation sequencing (NGS)-based cell-free DNA (cfDNA) assay, Firefly assay, which employs a concatemer-based noise suppression mechanism with an amplicon workflow.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Performance of amplicon based Firefly assay, with a panel covering EGFR, BRAF, and KRAS mutations designed for targeted therapy selection of NSCLC was first evaluated using a cfDNA reference standard and blank control samples. This panel was then used to analyze plasma cfDNA samples from 134 NSCLC cancer patients and 50 non-cancerous controls, and results were compared with tumor tissue ARMS and cfDNA ddPCR results.

      4c3880bb027f159e801041b1021e88e8 Result

      Firefly assay demonstrated superior sensitivity and specificity with median detection of 100% at allele frequency of 0.1% for 20ng of cfDNA and zero false positive in all blank control samples. In cfDNA from plasma collected before treatment, EGFR mutation detection by Firefly assay was 94% concordant with tumor tissue ARMS. Firefly assay demonstrated strong per-variant detection-rate concordance (98%) and allele frequency concordance (R2 = 0.95) when compared with cfDNA ddPCR result.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The amplicon-based Firefly assay offers multiplex capacity, de novo variant detection, high sensitivity and specificity. Thus, Firefly assay is a kitable NGS solution for cfDNA analysis, which can help guide targeted therapy selection, drug resistance detection, and disease monitoring in NSCLC and other cancer patients.

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      P1.09-14 - Analysis of Real-Word Mutations of Lung Cancer Driver Genes in 3081 Patients from China (ID 13649)

      16:45 - 18:00  |  Presenting Author(s): Ye Guo  |  Author(s): Kewei Ma, Mengyao Sun, Yinghui Xu, Xu Wang

      • Abstract
      • Slides

      Background

      Patients with different races and regions have different mutation characteristics in driver genes. This study included 3081 lung cancer patients that were detected for three major driver genes from five regions of China.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFR, EML4-ALK and ROS1 gene mutations were detected by fluorescence quantitative PCR (all use the same kit from AmoyDx). Chi-square test and logistic regressive analysis were used to analyze the clinicopathological features.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 1 to December 31, 2017, a total of 1,449 driver genes were detected mutations (47.03%). The EGFR gene mutation rate was 40.1% (1259/3081), the EML4-ALK was 5.5% (169/3081), and the ROS1 was 1.3% (39/3081). EGFR and EML4-ALK coexistence in 17 cases (0.5%), 1 case of EGFR and ROS1 coexistence (0.03%). The EGFR gene mutation sites were mainly 19Del (557/3081) and 21 exon L858R (575/3081). The proportions of EGFR mutation sites are shown in the figure. EGFR gene mutation was negatively correlated with EML4-ALK and ROS1. Patients with EGFR, EML4-ALK, and ROS1 mutations have different population characteristics, which were listed in the table.egfr mutation.jpg

      logistic.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The real-word driver gene mutations in large population of China are far higher than in the US and Europe, slightly less than in other reports of specially screened Asian populations.

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      P1.09-15 - Preliminary Experience with Liquid Biopsies in a Resource Constrained Setting and its Impact on Treatment Decision Making (ID 13411)

      16:45 - 18:00  |  Presenting Author(s): Valliappan Muthu  |  Author(s): Kuruswamy Thurai Prasad, Amanjit Bal, Nalini Gupta, Digambar Behera, Rakesh Kapoor, Navneet Singh

      • Abstract
      • Slides

      Background

      Liquid biopsies are potentially useful for molecular testing in the presence of inadequate tissue and for detection of resistance mechanisms in EGFR mutated NSCLC patients. Initial experience with liquid biopsies for advanced/metastatic NSCLC patients in a resource constrained setting is described herein.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective audit of liquid biopsies performed over a 21-month period for NSCLC patients at a tertiary referral centre in North India. Testing methods included digital-droplet-PCR (ddPCR), Next-Generation-Sequencing (NGS) and Real-Time-PCR (RT-PCR). ddPCR was used to detect specific EGFR mutations (L858R exon21, E746_A750 exon19 deletions and T790M exon20) in ctDNA (detection limit based upon amplifiable DNA ranging from 0.5%-<0.01% of mutant allele). For NGS, cfDNA extracted from plasma was subjected to target enrichment by high multiplex PCR amplification and analyzed for mutations using gene panel (BRAF, EGFR, ERBB2/HER2, KRAS, MET) on the Ion Proton semiconductor sequencer (Life Technology, USA). RT-PCR assay using EGFR-RT52 kit (EntroGen USA) detects known somatic mutations in exons 18-21 of EGFR by amplifying mutant-specific sequences and relies on fluorescent probes for detection (detection limit of 1%).

      4c3880bb027f159e801041b1021e88e8 Result

      42 patients [61.9% (n=26) males] underwent liquid biopsies. ddPCR, NGS and RT-PCR were performed in 31(73.8%), 7(16.7%) and 4(9.5%) patients respectively. Timing was prior to/during first-line treatment in 23(54.8%) and at progression on first-line treatment in 19(45.2%) patients. In the former, indication was inadequate tissue for molecular analysis (n=15), detection of other targetable mutation (after EGFR wild type status on tissue; n=3) and checking ctDNA status of T790M exon 20 detected in tissue (n=5). Among 19 patients with progression on first-line treatment, 17 were those with a sensitizing EGFR mutation at baseline who had progressed on EGFR-TKI of which 47.1% (n=8) were found to have T790M exon 20 mutation. The primary EGFR sensitizing mutation detected in tissue at baseline was also detected in ctDNA in 9 of 20 patients with a sensitivity of 45.0%. Agreement between results of tissue testing and liquid biopsy testing for EGFR mutations was 48.0% (12/25). Potential change in management with use of liquid biopsies was observed in 12 patients (28.6% overall and 52.6% if done at progression).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preliminary experience in our resource constrained setting indicates that greatest utility of liquid biopsies is for EGFR mutated patients with progression on EGFR-TKI wherein T790M detection rates are comparable to those reported in literature. However, the overall sensitivity and agreement is lower than that reported in literature and perhaps may be related to small number of patients.

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      P1.09-16 - Novel Somatic Gene Mutation of SLC17A9, Detected in Early-Stage Lung Adenocarcinoma (ID 12518)

      16:45 - 18:00  |  Presenting Author(s): Shingo Sakashita  |  Author(s): Maki Masahiro, Ryota Matsuoka, Masafumi Muratani, Masayuki Noguchi

      • Abstract
      • Slides

      Background

      Lung adenocarcinoma is an example of a tumor that shows a wide range of mutations, such as EGFR, KRAS, ALK, ROS, and RET. However, with the exception of EGFR and KRAS, most mutations in lung adenocarcinoma have been detected in advanced tumors.

      We have encountered one interesting case of multiple lung adenocarcinomas. The patient was a 68-year-old Japanese male in whom two tumors were detected in the left upper lobe and lobectomy was performed. One of which was diagnosed as lepidic adenocarcinoma and the other as minimally invasive adenocarcinoma (MIA). We considered that these two adenocarcinomas were synchronous and independent. Two years later, eight ground glass nodules were newly found in the left lower lobe. After chemotherapy, these tumors were also resected surgically, and all eight were found to show a lepidic pattern histologically. Moreover, two of the tumors were diagnosed as MIA. Therefore, it was very difficult to determine which of the tumors were multicentric and which were possibly metastatic from the previous adenocarcinoma.

      In order to clarify the genetic background of these tumors, we examined the resected materials using next-generation sequencing.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We secured snap-frozen samples from one primary adenocarcinoma and two secondary adenocarcinomas. The DNAs were extracted and subjected to exome sequencing (Next-seq-500, Illumina). The mutations were validated by amplicon sequencing. Amplicon sequencing was also performed using DNAs extracted from FFPE blocks of the other tumors.

      4c3880bb027f159e801041b1021e88e8 Result

      From the exome sequences, 26, 365 and 308 mutations were detected from one primary tumor and two secondary tumors, respectively. Among these mutations, those of two genes, EGFR (L858R) and SLC17A9 (G78R), were detected as common mutations. This result was validated by amplicon sequencing of the same DNA. Amplicon analysis of the remaining 7 tumors revealed that all tumors had the same EGFR mutation, but that only 6 had the SLC17A9 mutation and one primary adenocarcinoma (MIA) lacked the mutation. These results indicated that the primary tumors were multicentric whereas the secondary tumors were metastatic from the primary lepidic adenocarcinoma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study of multiple early-stage adenocarcinomas and their metastases has revealed a common somatic mutation of SLC17A9 as well as EGFR mutation (L858R). SLC17A9 is a lysosomal ATP transporter that regulates cell viability. Although somatic mutation of SLC17A9 has not been reported previously in lung adenocarcinoma, SLC17A9 has been considered to have an oncogenic function. The present findings suggest that SLC17A9 gene alteration and its dysfunction may contribute to progression of lung adenocarcinoma.

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      P1.09-17 - CTNNB1 (Beta-Catenin) Mutations in Non-Small Cell Lung Carcinoma: A Clinicopathological Study of 18 Cases (ID 12163)

      16:45 - 18:00  |  Presenting Author(s): Vincent Thomas De Montpreville  |  Author(s): Rida El Ayoubi, Maria Mamodaly, Ludovic Lacroix, Olaf Mercier, Elie Fadel, Benjamin Besse, Maria-Rosa Ghigna

      • Abstract
      • Slides

      Background

      Beta-catenin, encoded by the CTNNB1 gene, plays an important role in a signaling pathway of progenitor cell proliferation and differentiation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Otherwise, beta-catenin expression by immuno-histochemistry has been described as a prognostic factor in non-small cell lung carcinomas.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our study was conducted on 18 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Fifteen cases (2.6%) were from a series of 568 consecutive and contributive analyses performed between January 2017 and March 2018, on 417 adenocarcinomas, 60 squamous cell carcinomas and 91 large cell carcinomas. The 3 other cases dated from before this series. The hospital files of the 18 patients and pathological data from surgical samples (n=11), small biopsies (n=3) and trans-bronchial fine needle aspirations (n=4) were reviewed. Immuno-histochemistry was performed with an anti-beta-catenin antibody.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 6 female and 12 male patients aged 54 to 83 (mean = 66). Six of the 18 patients were non-smokers (< 5 pack-years). There were 17 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas were TTF1-positive (16/17) and had a papillary component accounting for more than 30% of their volume (n=11). Eight cases (44%) with CTNNB1 mutations showed associated EGFR mutations including exon 19 deletion (n=5) and L858R (n=2). Oncogenic KRAS mutations were only found in 3 cases (17%). The frequency of CTNNB1 mutations among EGFR mutated adenocarcinomas was 9% (7/79). The most frequent CTNNB1 mutations were S37F (n=7) and S45P (n=4). Immuno-histochemistry showed normal membrane expression with no nuclear or cytoplasmic abnormal expression in all cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study shows that CTNNB1 mutations are rare in non-small cell lung carcinomas and mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are similar to those observed in other tumor types but they probably do not play the same oncogenic role. Furthermore, in lung carcinomas, CTNNB1 mutations were often associated with EGFR mutations and may interfere in the mechanism of resistance to tyrosine kinase inhibitors. This should be thoroughly investigated in larges series evaluating the degree of response to EGFR tyrosine kinase inhibitors.

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      P1.09-18 - 15 Cases of Clinical and Molecular Features Analysis in Pulmonary Adenoid Cystic Carcinoma (ID 11108)

      16:45 - 18:00  |  Presenting Author(s): Chunwei Xu  |  Author(s): Wenxian Wang, Rongfang Huang, Cheng He, Youcai Zhu, Wu Zhuang, Yunjian Huang, Meiyu Fang, Yanping Chen, Gang Chen, Tang Feng Lv, Yong Song

      • Abstract
      • Slides

      Background

      Pulmonary adenoid cystic carcinoma (PACC) of the lung is a malignant tumor arising in the tracheobronchial glands distributed in the airway submucosa. The aim of this study is to investigate the molecular characteristics of PACC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From July 2013 to December 2016, 15 PACC patients received treatment. All the patients were diagnosed by pathology. We retrospectively reviewed the clinical data and genetic state.

      4c3880bb027f159e801041b1021e88e8 Result

      EGFR mutation rate was 6.67% (1/15), and it was 19del, the relationship between EGFR gene status and gender (P=1.000), age (P=1.000), smoking status (P=1.000) and stage (P=1.000) were no significant, and ALK fusion and ROS1 fusion gene was not detected.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Gene change exists PACC, and the gene detection cannot be ignored in PACC.

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      P1.09-19 - Positive Correlation Between Whole Genomic Copy Number Variant Scoring and the Grading System in Lung Non-Mucinous Invasive Adenocarcinoma  (ID 12047)

      16:45 - 18:00  |  Presenting Author(s): Zheng Wang  |  Author(s): Shenglei Li, Lin Zhang, Lei He, Di Cui, Chenglong Liu, Yuyan Gong, Bi Liu, Xiaoyu Li, Wang Wu, David Cram, Dongge Liu

      • Abstract
      • Slides

      Background

      Grading systems of Lung adenocarcinoma have been proposed by Sica and Kadota in stage I tumors,but the predominant architectural subtypes grading system is applicable for resection samples mostly. The correlation between the histological subtypes and grading with whole genomic copy number variation(WGCNV) is unknown, and was investigated in lung non-mucinous invasive adenocarcinoma (LNMIA) at this study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The predominant histological subtype from 58 resection specimens of LNMIA and 20 para-cancerous lung tissues were collected by laser microdissection from HE staining FrameSlides PEN-Membrane slides.7 of 58 specimens,two predominant subtypes in one cancerous nodule were collected simultaneously. Whole genome amplification followed by high-throughput sequencing was used to deteted WGCNV with the para-cancerous lung tissues as normal reference set and WGCNV was scored by a particular formula.
      .

      4c3880bb027f159e801041b1021e88e8 Result

      table 1.jpgfigure 1  upload.jpg

      WGCNV median scores of 5 histological subtypes of LNMIA with three tiered architectural grades are shown in Table1. The WGCNV scores have a positive correlation with either histological subtypes and architectural grading system (Figure1 A and B). The differences of WGCNV scores are detected betweem two predominant subtypes in one cancerous nodule.

      8eea62084ca7e541d918e823422bd82e Conclusion

      GWCNV scores display a positive correlation with three tiered architectural grading system and may has a potential value to predict prognosis in LNMIA.

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      P1.09-20 - Correlation Between Whole Genomic Copy Number Variant Scoring and Pathological Classification, Staging in Lung Non-Mucinous Adenocarcinoma (ID 12126)

      16:45 - 18:00  |  Presenting Author(s): Zheng Wang  |  Author(s): Dongge Liu, Shenglei Li, Lin Zhang, Shurong He, Jun Du, Jing Di, Min Zhang, Yuyan Gong, Bi Liu, Xiaoyu Li, Wang Wu, David Cram

      • Abstract
      • Slides

      Background

      The new classification of lung adenocarcinoma composing of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA) has been applicable worldwide. Both the histological classification and TNM staging of lung adenocarcinoma have important values in indicating prognosis, but their correlations with whole genomic copy number variation (WGCNV) are still unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lung non-mucinous adenocarcinoma(LNMA) including AIS, MIA and IA resection specimens, malignant pleural effusion (MPE), metastatic nodules (MN) biopsy and 20 para-cancerous non-tumor lung tissue samples were selected. The cells of predominant histological subtype from each LNMA and non-tumor smaples were collected by laser microdissection from HE staining FrameSlides PEN-Membrane slides. Whole genome amplification followed by high-throughput sequencing was used to detect the somatic CNV with the para-cancerous lung tissues as normal reference set. WGCNV was scored by a particular formula.

      4c3880bb027f159e801041b1021e88e8 Result

      12126 figure upload.jpg12126 table upload.jpg

      WGCNV median scores and distributions of pathological subcategories and TNM staging were shown in Table 1 and their trends were displayed in Figure 1.WGCNV scores display the positive correlation or significant differences among diversified histological subcategories of LNMA, but not in T & TMN staging

      8eea62084ca7e541d918e823422bd82e Conclusion

      WGCNV scoring displays the positive correlation or significant differences among diversified subcategories and may has a potential value prediecting prognosis in LNMA.

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      P1.09-21 - Circulating Tumor DNA Improves Genotypification and Detection of Targetable Alterations in Selected Lung Cancer Patients (ID 12218)

      16:45 - 18:00  |  Presenting Author(s): Zyanya Lucia Zatarain-Barrón  |  Author(s): Feliciano Barron, Andrés F. Cardona, Graciela Cruz-Rico, Oscar Arrieta, Karen Yocelin Flores-Veles, Carin R. Espenschied, Victoria M. Raymond, Richard B Lanman, Carlos Vargas

      • Abstract
      • Slides

      Background

      Several studies have shown that NSCLC genomic background among Hispanics differs from other populations. The finding of low frequency genomic alterations in cfDNA to increase diagnostic accuracy in NSCLC could refine the treatment. We hypothesized that cfDNA can be an alternative or complement for detection of low frequency genomic targets. We aimed to understand the landscape of cfDNA-identified genomic drivers in a cohort of patients (pts) with NSCLC of Hispanic ancestry.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We collected data from 51 Hispanic pts (Mexico and Colombia) with advanced NSCLC (Stage III/IV) who previously underwent tissue screening for ALK, EGFR, and ROS1. CfDNA was extracted from plasma and analyzed by a commercial NGS test (Guardant360â) which detects genomic alterations (alts) in up to 73 genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Median age was 56 years (31-83). Most pts were female (64.7%) and never smokers (76.5%). 94% of cases (48/51) had cfDNA detectable alts with a mean number of 3.37 cfDNA alts per test (range, 1 -10). Of the 48 pts with cfDNA genomic alts, 23 (47.9%) had a known genomic driver (EGFR (27.4%), TP53 (13.7%), ALK (7.8%), KRAS (5.8%), and BRAF (3.9%)). Interestingly, cfDNA was able to detect some genomic alts previously undetected by tissue biopsy (either due to false negatives or to technical limitations such as insufficient or low-quality DNA). In the case of EGFR, 12 pts had EGFR alts through cfDNA which were previously undetected by tissue biopsy. Similarly, cfDNA detected 3 alterations in ALK which were previously undetected by tissue sample. Of 48 pts, 35.4% were switched to a targeted therapy as a result of alts detected through cfDNA, with adequate responses: disease control rate was 82.4% (partial response 47.2% and stable disease 35.2%) and progression free survival was 7.4 months (95%CI 2.6-28.1).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a selected population of young Hispanics (especially never smokers and women) with NSCLC the use of comprehensive cfDNA analysis allowed a treatment change in 35% of the cases. Our data confirms the usefulness of Guardant360â as non-invasive panel to identify genomic alts in cfDNA.

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      P1.09-22 - Detection of ALK Gene Rearrangement in FFPE Tissues of Non-Small Cell Lung Cancer Using in Situ RNA Hybridization (ID 12108)

      16:45 - 18:00  |  Presenting Author(s): Xuan Zeng  |  Author(s): Shafei Wu, Na Li, Xiaohua Shi, Mindy Wang, Hongzhe Sun, Xiaojun Ma, Zhiyong Liang, Emily Park, Robert Momroe

      • Abstract

      Background

      Approximately 4-7% of non-small cell lung cancer (NSCLC) harbor anaplastic lymphoma kinase (ALK) gene rearrangements which lead to overexpression of ALK fusion protein and constitutive activation of the kinase. The tumor with ALK gene rearrangements is sensitive to its inhibitor, so identification of this molecular feature from the patients accurately is important. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are conventional methods for testing ALK gene rearrangement and protein overexpression respectively; however it is challenge for distinguishing some rare variations by FISH, or determining the equivocal stain by IHC. A morphology related method under bright field about rearranged mRNA expression (RNAscope) of ALK gene fusion was developed, which is helpful to realize the biological behavior of ALK gene, together with FISH (break apart FISH probe kit, Abbott) and IHC (D5F3 clone, Ventana).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We explored 7 cases of formalin-fixed paraffin-embedded (FFPE) samples from NSCLC patients by RNAscope® 2.5 Red assay

      4c3880bb027f159e801041b1021e88e8 Result

      Three of seven samples were found with ALK positive by RNAscope, which matched with FISH and IHC results. In these 3 ALK positive samples, exon 19-29 of ALK gene transcribed RNA signals were revealed by probe-Hs-ALK E1-E18 (score 1 to 2 in >50% cells), whereas exon 1-18 transcribed RNA signals were not shown by probe-Hs-ALK E19-E29, which confirmed by FISH results (with break apart signals). In 2 of 4 ALK RNAscope negative cases, ALK RNA signals were detected by both probe-Hs-ALK E1-E18 (score 2) and probe-Hs-ALK E19-E29 (score 2) in small regions (showed a small number of signals), which may indicate that ALK gene amplification and also confirmed by FISH results (with more than 2 fusion signals). And these 2 typical ALK RNAscope negative samples were considered close to be disomy by FISH.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results demonstrate that RNAscope® 2.5 Red assay is a reliable and precise method to detect ALK mRNA expression caused by ALK gene fusion and also a one to discover the ALK gene amplification as well in FFPE samples of NSCLC, even though latter’s clinical significant is not clear. RNAscope® 2.5 Red assay is a both sensitive and specific method to provide information on the spatial distribution of ALK gene status and morphologic characteristic of tumors simultaneously under the bright field microscope.

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      P1.09-23 - Effect of Plasma Input on the Clinical Sensitivity of a Real-Time PCR Assay for the Detection Of EGFR Mutation in Plasma ctDNA From NSCLC Patients (ID 12256)

      16:45 - 18:00  |  Presenting Author(s): Guanshan Zhu  |  Author(s): Yuki Gao, Yuping Li, Fengge Jiang, Qingtao Song

      • Abstract
      • Slides

      Background

      Plasma based EGFR mutation testing is a less invasive and feasible testing option for patients with advanced non-small cell lung cancer (NSCLC) when traditional tissue biopsy testing is challenging. A fast and sensitive real-time PCR method has been developed for the detection of EGFR mutations in plasma circulating tumor DNA (ctDNA). To define the effect of plasma input on the clinical sensitivity of the assay, clinical evaluation was conducted in the present study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 203 patients with advanced NSCLC were recruited who provided plasma and matched tumor tissue samples, 109 of whom providing samples had adequate plasma for both 2 mL and 4 mL plasma testing, and the rest providing 2 mL plasma samples. ctDNA was isolated and tested for the presence of EGFR mutation by the AmoyDx Super-ARMS EGFR Mutation Detection Kit (Super-ARMS EGFR). Tumor tissue DNA was isolated and tested for EGFR mutation by AmoyDx ARMS EGFR Mutation Detection Kit (ARMS EGFR). Clinical sensitivity and specificity of ctDNA testing were analyzed by using tumor tissue testing as a reference.

      4c3880bb027f159e801041b1021e88e8 Result

      In pairs of tumor biopsy and plasma samples, the sensitivity, specificity and overall concordance of EGFR mutation status determined in 4 mL of plasma by Super-ARMS EGFR test and matched tissue samples were 82.0% [50/61], 100% [48/48], and 89.9% [98/109] (N=109), respectively. These rates were much higher than those of mutation status determined in 2 mL of plasma and matched tissue samples (65.55% [78/119], 97.62% [82/84] and 78.82% [160/203], N=203).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Super-ARMS EGFR assay is a highly reliable and sensitive method for the detection of EGFR mutation in lung cancer plasma ctDNA samples. Plasma samples of 4 mL volume is more appropriate for ctDNA EGFR mutation assessment than determination in 2 mL volume of plasma.

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      P1.09-24 - The Effects of NLR and PLR of Effect on Prognosis in Patients with the Lung Cancer (ID 11912)

      16:45 - 18:00  |  Presenting Author(s): Fazıl Aydın  |  Author(s): Nurcan Ince, Elanur Karaman, Feyyaz Ozdemir, Elif Merev

      • Abstract
      • Slides

      Background

      Inflammation has an important role in the pathogenesis of cancer. Platelet/Lymphocyte (PLR) and Neutrophil/Lymphocyte ratios (NLR) are known as parameters that indicate the status of inflammation and can be used in determining the prognosis of cancer. The object of this study is to investigate the effect of the preoperative NLR and PLR on disease-free (DFS) and overall survival (OS) in patients with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this study, 68 patients, who underwent surgery and received a diagnosis of lung cancer between 2004 and 2014 were evaluated retrospectively. Date of diagnosis, demographic characteristics, tumor stage and location, vascular invasion status, perineural invasion status, lymph node involvement, histological type, grade, adjuvant treatment status, preoperative neutrophils, lymphocytes and platellet number were analyzed. Preoperative PLR and NLR computed and median value of these rates were determined. The Kaplan-Meier method was used for DFS and OS analysis of patients who were above or below the median. Confidence interval and statistically significant p-value was considered respectively %95 , <0.05.

      4c3880bb027f159e801041b1021e88e8 Result

      68 patients, 7 were female and 61 male, mean age was 57. 23 of 68 patients Stage1, 33 patients Stage 2, 12 patients and Stage 3. Histopathological analyse performed, and the end of analyse; 48,5% adenocarcinoma, 42,6% squamous cell carcinoma 8,9% other types were watched. Average PLR and average NLR was seen as respectively 120 and 2,2. DFS (47.3 months versus 50.8 months) was shorter in lung cancer patients with high NLR, but OS was longer (82.3 months versus 78.2). DFS (42.8 months versus 55.4 months) was shorter in lung cancer patients with high PLR and OS was longer (84.5 months versus 76.7 months). The difference between the two groups was not statistically significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The effect of high NLR and PLR on DFS and OS in patients with lung cancer was not statistically significant. Prognostic value of NLR and PLR before treatment is not clearly demonstrated, and extensive prospective studies should be performed with multiple centers and more patient.

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      P1.09-25 - Invasive Size (Not Total Size) Predicts Overall Survival in Invasive Mucinous Adenocarcinomas (ID 12127)

      16:45 - 18:00  |  Presenting Author(s): Wei-Chin Chang  |  Author(s): Yu Zhi Zhang, Eric Lim, Andrew G Nicholson

      • Abstract
      • Slides

      Background

      The 8th TNM pathological staging system advocates usage of the invasive size, rather than the total size, in the pT staging of pulmonary non-mucinous adenocarcinomas. However, few studies have addressed this issue regarding invasive mucinous adenocarcinomas (IMAs). Our study aimed to determine whether invasive size correlates with individual histological parameters and also whether it provides better prognostic stratification than overall tumour size.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed a series of 101 cases of IMAs resected between 2000 to 2012, comprised of stage I~IV tumours. In each IMA, the percentage of each growth pattern (lepidic, acinar, papillary, solid, micropapillary, and cribriform) was assessed in 5% increments. Due to the frequent multifocal nature of IMAs, the invasive size was calculated by multiplying the total tumour size with the total percentage of invasive (non-lepidic) components in all cases. The adjusted T (aT) stage, as determined by the cumulative size of invasive components, was correlated with disease-free (DFS) and overall survival (OS). Correlation with 7th and 8th T stage (using total tumour size) were also performed as comparison.

      4c3880bb027f159e801041b1021e88e8 Result

      The 7th aT stage was positively correlated with higher host response (tumour-associated inflammation), necrosis, pleural invasion, and nodal metastasis, while the 8th aT stage was significantly correlated with necrosis, vascular invasion, pleural invasion, and nodal metastasis. Using aT stage for risk stratification, we found a significant difference in OS in both 7th and 8th aT stage between the subgroups (p = 0.002 and 0.006, respectively), whereas DFS failed to reach statistical significance. There was a significant difference in DFS when using the 8th T stage (p = 0.002), whereas no significant difference was noted in OS. A trend was noted in DFS (p = 0.054) while OS failed to reach statistical significance when applying the 7th T staging.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study showed that invasive size may be a superior prognostic indicator compared to total size, which provides a rationale for prognostic stratification of IMAs based on the extent of invasive growth patterns (or invasive size) rather than total tumour size.

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      P1.09-26 - A Case Report of Discordant Markers of Lung Cancer Tumor Cells: An Unusual Immunophenotype of Uncertain Significance (ID 12379)

      16:45 - 18:00  |  Presenting Author(s): Lisa Giscombe  |  Author(s): Matthew Keating, Maria Dominguez, Pouyan Changizzadeh, Elias Jabbour, Bassam Aswad, Rabih Elbizri, Bharti Rathore

      • Abstract
      • Slides

      Background

      Introduction

      Non Small Cell Lung Cancer (NSCLC) is the most frequent type of lung tumor, with two major histological subtypes: adenocarcinomas and squamous cell carcinomas. Tissue transcription factor-1 (TTF-1) and Napsin A are expressed in up to 75%- 80% of primary lung adenocarcinomas respectively and the sensitivity of both p40 and p63 for squamous cell carcinoma is 92%. Here, we report an unusual case of NSCLC with coexisting histology within the same tumor cells.

      Case

      A 65-year-old male with 50 pack year smoking history underwent screening CT chest and was found to have a right upper lobe mass measuring 10 cm x 8.6 cm x 6.9 cm with narrowing of the right upper lobe bronchus in the posterior segment. Bronchoscopy and EBUS guided biopsy of the right paratracheal node revealed NSCLC, poorly differentiated, with TTF-1, Napsin A, P40 and P63 staining positive (70-80%) for both adenocarcinoma and squamous cell carcinoma within the same tumor cells. Subsequent Brain MRI and PET did not reveal any evidence of metastatic disease and the patient was classified as T4 N1 stage IIIB disease.

      Discussion

      The line between lung adenocarcinoma and squamous cell carcinoma has already been shaken by an uncommon adenosquamous variant, but our case represents a new histologic subtype that expands on the understanding of lung cancer. Adenosquamous carcinoma (ADSQC) of the lung is a rare classification of NSCLC with a reported incidence of 0.4-4%. Histology defined by the World Health Organization defines ADSQC as a mixed type of tumor, with each component representing greater than 10% of the entire tumor. Based on studies by Naunheim et al, the median survival of patients with stage III ADSQC was 5.0 months compared to 9.0 months with adenocarcinoma and 7.8 months with squamous cell carcinoma.

      However, our case is different, as immunohistochemistry was positive for TTF-1, Napsin A, p40 and p63 biomarkers within the same individual tumor cells, thus diagnosing an entirely different pathology. After review of the literature, this is the third case with such co-expression. This case is important as it promotes awareness of this rare pathology. Both clinicians and pathologists need to be aware of its existence, in order to prevent misdiagnosis and treatment delay in what may be hypothesized as an aggressive tumor. As more cases emerge, further studies can determine incidence, prognosis, presence of driver mutations, and treatment implications.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Section not applicable

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-27 - Clear Cell Adenocarcinoma Subtype is an Independent Predictor of Better Survival in Patients with Lung Adenocarcinoma (ID 11663)

      16:45 - 18:00  |  Presenting Author(s): Takefumi Komiya  |  Author(s): Achuta Kumar Guddati

      • Abstract
      • Slides

      Background

      Clear cell adenocarcinoma (CCA) has been considered as a rare subtype of lung adenocarcinoma. However, the 2011 World Health Organization (WHO) classification of lung adenocarcinoma proposed to discontinue CCA due to lack of available data with clinical significance. The role of CCA in patient prognosis needs to be investigated by using large data sources.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lung adenocarcinoma patients were queried from The Surveillance, Epidemiology, and End Results Program (SEER) database and were divided into CCA and ‘not otherwise specified’ category (NOS). Cancer-specific survival was studied according to gender (male, female), age (0-69,70+), SEER specific stage A system (localized, regional and distant), year of diagnosis (1973-2000, 2001-2013), surgery (yes, no), and radiation therapy (yes, no) using Kaplan–Meier curves. Statistical difference was estimated with log-rank test using JMP software. Multivariate analysis was used to study independent predictors of cancer-specific survival.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 198,042 patients with the diagnosis of lung adenocarcinoma were found in the SEER database of which 921 patients were diagnosed with CCA. CCA histology was significantly associated with an early year of diagnosis, younger age, early stage, surgery, and lack of radiation. Kaplan–Meier curves showed that patients with CCA histology, age 0-69, year of diagnosis 2001-2013, female gender, localized disease, undergoing surgery, and lack of radiation had significantly better cancer-specific survival (p<0.0001, Log-Rank). Subset analysis demonstrated difference in cancer-specific survival between CCA and NOS histology was significant in localized and regional but not distant stage (p=0.0453, 0.0009, 0.0664, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients with CCA histology have superior survival according to our SEER analysis, suggesting its unique role in prognosis despite its removed from 2011 WHO classification.

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      P1.09-28 - Clinical Utility of Rapid Immunohistochemistry for Differentiation of Solitary Pulmonary Adenocarcinomas (ID 12333)

      16:45 - 18:00  |  Presenting Author(s): Hayato Konno  |  Author(s): Hajime Saito, Kazuhiro Imai, Nobuyasu Kurihara, Yoshihiro Minamiya, Hiroshi Nanjo, Yuko Hiroshima

      • Abstract

      Background

      Intraoperative differentiation between pulmonary metastasis and primary lung cancer is necessary for determining the appropriate range of excision. Although conventional immunohistochemistry is often used for such differentiation, its intraoperative use is limited by time constraints. We therefore developed a device that enables complete and rapid immunohistochemistry (R-IHC) within 20 minutes, and used it with anti-thyroid transcription factor-1 (TTF-1) for differential diagnosis of pulmonary adenocarcinoma. However, the diagnostic accuracy of the method likely can be improved by using a combination of two or more antibodies. We therefore evaluated the clinical utility of R-IHC with combinations of antibodies for discriminating the etiology of solitary pulmonary adenocarcinomas.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Twenty-two patients with pulmonary adenocarcinomas treated between February 2015 and May 2017 were enrolled in this prospective study. Tumor samples were sectioned, labeled with multiple antibodies using R-IHC, and pathologically evaluated. The standard used for comparison was conventional hematoxylin eosin (HE) staining and IHC.

      4c3880bb027f159e801041b1021e88e8 Result

      All intraoperative diagnoses made using R-IHC were consistent with the final diagnosis; that is, the accuracy was 100%. Moreover, the respective staining with each antibody corresponded between intraoperative R-IHC and IHC with the permanent specimen. For rapid intraoperative diagnosis differentiating pulmonary adenocarcinoma from lung metastasis from colon cancer, R-IHC with a combination of TTF-1, cytokeratin (CK) 7, and CK20 antibodies was highly effective.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our novel R-IHC method with multiple antibodies was highly effective for diagnosis and differentiation of solitary pulmonary adenocarcinomas. This technology may prove to be an important supplement to standard intraoperative pathologic diagnosis in routine practice.

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      P1.09-29 - In Situ Growth Pattern in Lung Adenocarcinoma Is Divisible into Distinct Categories with Divergent Biological and Survival Implications (ID 13872)

      16:45 - 18:00  |  Presenting Author(s): John Le Quesne  |  Author(s): David Moore, Juvenal Baena, Marco Sereno, Claire Smith, Leah Officer, Madhumita Das

      • Abstract

      Background

      The morphological stepwise progression of lung adenocarcinomas is well established, but little is known about the molecular events that underlie this. In particular, in situ patterns of growth are frequently seen in adenocarcinomas, and often it is not clear if this truly always represents early-stage preinvasive disease. Therefore we set out to better characterise in situ tumour growth, and to identify molecular and biological correlates of tumour invasion.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We constructed a retrospective cohort of 964 locally held adenocarcinomas, with patient data and tissue microarrays (TMAs). Immunohistochemistry for Ki67 and epithelial-mesenchymal transition markers was applied to TMAs and quantified.

      In situ and adjacent invasive areas of 23 early tumours were subjected to further in situ assays and laser capture microdissection. Genomic DNA was extracted and driver genes were panel sequenced.

      4c3880bb027f159e801041b1021e88e8 Result

      We morphologically identified two distinct types of in situ tumour growth in early mixed pattern tumours: a low-grade precursor ('C1'- after the classic Noguchi classification) associated with higher-grade invasive disease, and a high-grade lepidic outgrowth ('C2') associated with invasive growth of similar cytological grade.

      C1 and C2-type in situ tumour growth are sharply separated by their proliferation rate (P=0.005) and their propensity for nodal metastasis (P=0.03), suggesting that this distinction is likely to be important in future grading/growth pattern classification. Furthermore, molecular analysis supports the classification; invasive areas of C1 tumours show driver mutations which are absent from neighbouring in situ disease (4/18 cases), indicating molecular progression, while in 5 sequenced C2 cases no evidence of molecular progression was seen.

      The difference between low-grade precursor and high-grade in situ patterns was further investigated in our full set of 964 tumours. We find that the prognostic power of proliferation rate (Ki67) is driven almost entirely by its effects in in situ areas of tumour growth. Proliferation rate in invasive tumour areas at most weakly predictive of patient outcome.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We make several key findings:

      i) In situ disease in lung adenocaricnoma is divided into two biologically and prognostically distinct groups, with implications for our understanding of stepwise progression in lung cancer

      ii) These two groups can easily be separated on the basis of cellular proliferation rate

      ii) We identify mutations in key driver genes that are explicitly asociated with the transition from in situ to invasive growth

      iii) Proliferation rate is a potentially valuable prognostic marker, but this may be restricted to its ability to separate these two key biologically distinct growth patterns

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-30 - Heterotopic Expression of Ceruloplasmin in Lung Adenocarcinoma and its Possible Clinical Use as a Tumor Biomarker (ID 12100)

      16:45 - 18:00  |  Presenting Author(s): Ryota Matsuoka  |  Author(s): Aya Shiba, Shingo Sakashita, Yuko Minami, Masayuki Noguchi

      • Abstract
      • Slides

      Background

      Ceruloplasmin (CP) is a well-known copper binding protein synthesized mainly in the liver, and its expression is well known to be elevated in the serum of cancer patients and in malignant tumor cells. Lung cancer is the leading cause of cancer-related death worldwide, and adenocarcinoma is the main histological type of lung cancer. Previously, we reported that the expression of CP mRNA was significantly higher in early but invasive adenocarcinoma than in adenocarcinoma in situ (AIS) on the basis of cDNA microarray analysis (Shiba, Int. J. Cancer 2011). However, the role of CP in lung adenocarcinoma is still unclear. Here, we examined and compared the expression of CP in various histological subtypes of lung adenocarcinoma and its correlation with patient outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CP expression in resected specimens of lung adenocarcinoma and lung adenocarcinoma cell lines was determined using quantitative real-time RT-PCR and western blot analysis. Immunohistochemistry for CP was carried out using 196 specimens of lung adenocarcinoma and we divided the cases into a high expression group (H-score >90: 92 cases) and a low expression group (H-score <90: 104 cases).

      4c3880bb027f159e801041b1021e88e8 Result

      CP expression was significantly higher in invasive adenocarcinoma than in AIS. The high expression group had a significantly poorer outcome than the low expression group (p<0.01) and high expression of CP was also correlated with pathological stage, pT, and pN (p<0.01). Multivariate analysis showed that CP expression was an independent prognostic factor in lung adenocarcinoma patients (HR 1.642, 95%CI 1.050-2.568, p=0.030). CP secreted from cancer cells was also detected by western blot analysis the medium used for culture of lung adenocarcinoma cell lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CP is produced heterotopically by lung adenocarcinoma cells and its expression is associated with tumor progression. In view of the presence of the secreted form of CP in tumor cells, CP may be a useful biomarker for lung adenocarcinoma.

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      P1.09-31 - Preliminary Experience with Liquid Biopsies in a Resource Constrained Setting and Its Impact on Treatment Decision Making (ID 11718)

      16:45 - 18:00  |  Presenting Author(s): Valliappan Muthu  |  Author(s): Kuruswamy Thurai Prasad, Amanjit Bal, Nalini Gupta, Digambar Behera, Rakesh Kapoor, Navneet Singh

      • Abstract

      Background

      Liquid biopsies are potentially useful for molecular testing in the presence of inadequate tissue and for detection of resistance mechanisms in EGFR mutated NSCLC patients. Initial experience with liquid biopsies for advanced/metastatic NSCLC patients in a resource constrained setting is described herein.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective audit of liquid biopsies performed over a 21-month period for NSCLC patients at a tertiary referral centre in North India. Testing methods included digital-droplet-PCR (ddPCR), Next-Generation-Sequencing (NGS) and Real-Time-PCR (RT-PCR). ddPCR was used to detect specific EGFR mutations (L858R exon21, E746_A750 exon19 deletions and T790M exon20) in ctDNA (detection limit based upon amplifiable DNA ranging from 0.5%-<0.01% of mutant allele). For NGS, cfDNA extracted from plasma was subjected to target enrichment by high multiplex PCR amplification and analyzed for mutations using gene panel (BRAF, EGFR, ERBB2/HER2, KRAS, MET) on the Ion Proton semiconductor sequencer (Life Technology, USA). RT-PCR assay using EGFR-RT52 kit (EntroGen USA) detects known somatic mutations in exons 18-21 of EGFR by amplifying mutant-specific sequences and relies on fluorescent probes for detection (detection limit of 1%).

      4c3880bb027f159e801041b1021e88e8 Result

      42 patients [61.9% (n=26) males] underwent liquid biopsies. ddPCR, NGS and RT-PCR were performed in 31(73.8%), 7(16.7%) and 4(9.5%) patients respectively. Timing was prior to/during first-line treatment in 23(54.8%) and at progression on first-line treatment in 19(45.2%) patients. In the former, indication was inadequate tissue for molecular analysis (n=15), detection of other targetable mutation (after EGFR wild type status on tissue; n=3) and checking ctDNA status of T790M exon 20 detected in tissue (n=5). Among 19 patients with progression on first-line treatment, 17 were those with a sensitizing EGFR mutation at baseline who had progressed on EGFR-TKI of which 47.1% (n=8) were found to have T790M exon 20 mutation. The primary EGFR sensitizing mutation detected in tissue at baseline was also detected in ctDNA in 9 of 20 patients with a sensitivity of 45.0%. Agreement between results of tissue testing and liquid biopsy testing for EGFR mutations was 48.0% (12/25). Potential change in management with use of liquid biopsies was observed in 12 patients (28.6% overall and 52.6% if done at progression).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preliminary experience in our resource constrained setting indicates that greatest utility of liquid biopsies is for EGFR mutated patients with progression on EGFR-TKI wherein T790M detection rates are comparable to those reported in literature. However, the overall sensitivity and agreement is lower than that reported in literature and perhaps may be related to small number of patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-32 - Classification and Mutation Prediction from Non-Small Cell Lung Cancer Histopathology Images Using Deep Learning (ID 12631)

      16:45 - 18:00  |  Presenting Author(s): Paolo Ocampo  |  Author(s): Andre Moreira, Nicolas Coudray, Theodore Sakellaropoulos, Navneet Narula, Matija Snuderl, David Fenyö, Narges Razavian, Aristotelis Tsirigos

      • Abstract

      Background

      Visual inspection of histopathology slides of lung tissues is one of the primary methods used by pathologists to assess pathological stage and classifications of lung cancer. Adenocarcinoma and squamous cell carcinoma are the two most prevalent types of non-small cell lung cancer (NSCLC), but their distinction can be challenging and time-consuming even for the expert eye. Furthermore, the increasing prevalence of new treatment modalities relies on classification of NSCLC mutational analyses of the tumor to guide targeted therapy and provide prognostic information.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this study, we trained a deep convolutional neural network (CNN) model (inception v3) on histology images obtained from The Cancer Genome Atlas (TCGA) to accurately and automatically classify whole-slide images into adenocarcinoma, squamous cell carcinoma or normal lung tissue. Furthermore, we trained the neural network to predict the ten most commonly mutated genes in lung adenocarcinoma. Our model was then validated on independent datasets of images obtained from both frozen and formalin-fixed paraffin-embedded tissue, including resection and biopsy specimens.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that the performance of our method is comparable, in terms of sensitivity and specificity, to that of pathologists, with a 0.97 average Area Under the Curve (AUC) on a held-out population of whole-slide images for the sub-type classification on frozen sections. Additionally, we found that six of the ten most commonly mutated genes – STK11, EGFR, FAT1, SETBP1, KRAS and TP53 – can be predicted by the algorithm solely using information from histologic images with an accuracy ranging from 0.733 to 0.856, as measured by the AUC on the held-out population.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These findings suggest that deep learning models can offer both pathologists and patients a fast, accurate, and inexpensive classification of NSCLC or gene mutations, and thus have a significant impact on cancer treatment. Our computational approach can be applied to any cancer type and the code is available as free open-source software at https://github.com/ncoudray/DeepPATH.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-33 - Validity of Non-Small Cell Lung Cancer Not Otherwise Specified to Use Immunohistochemistry on Treatment Outcome (ID 11190)

      16:45 - 18:00  |  Presenting Author(s): Takahiro Ota  |  Author(s): Keisuke Kirita, Hibiki Udagawa, Shigeki Umemura, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Genichirou Ishii, Koichi Goto

      • Abstract

      Background

      In non-small cell lung cancer, histologic samples have become significantly important to administrate tumor type specific cytotoxic and molecular-targeted therapies. When a biopsy sample shows lacking definite morphology, diagnosis is made into three subtypes, favour adenocarcinoma, favour squamous cell carcinoma and NOS-null, according to the immunohistochemistry (IHC) results. However, in terms of the patient outcome, validity of IHC-based these classification have been unknown yet.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A series of 152 advanced NSCLC patients whose diagnosis was made by morphology and homogeneously treated was enrolled. We performed IHC staining (TTF-1, SP-A, p40, and CK5/6) of these samples and refined diagnoses into 3 subtypes. We analyzed the pathological subgroup depends on IHC staining with clinical characteristics including molecular analysis, response of chemotherapy and prognosis.

      4c3880bb027f159e801041b1021e88e8 Result

      IHC profiling displayed that 50% of cases was favour Ad, 31% was favour SqCC, and 19% was NOS-null. On the patient background, there was no difference in age, smoking history, and PS, but there were differences in gender, and the favour Ad group had more females than other groups. EGFR mutation was significantly more expressed in favour Ad group than in the other groups, and molecular targeted drugs in initial treatment were used in favour Ad group in a large proportion. Compared with favour Ad and SqCC group, NOS-null group showed significantly poorer outcome in terms of median overall survival (OS). Between favour Ad and favour SqCC group, median OS was better in favour Ad group (19.5 months vs 15.0 months, p = 0.018). Excluding patients using molecular targeted drugs, there was no difference in median OS between favour Ad and favour SqCC group (15.2 months vs 15.0 months p = 0.29). Pemetrexed containing platinum regimen showed similar response rate as other platinum regimen in the favour Ad cohort (43% vs 46%), whereas poorer response in the favour SqCC (0% vs 50%) and NOS-null (0% vs 24%) cohort. Although patients to be received pemetrexed containing platinum regimen compared to those to be received other platinum regimen demonstrated a trend toward good PFS in favour Ad group, there were no statistically differences.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study made clear chemo-responsiveness, the expression frequency of driver mutation and prognosis in NSCLC favour Ad, SqCC and NOS-null. These findings support that histological subtyping in biopsy specimen by IHC would be mandatory to archive appropriate therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-34 - Prognostic Impact of Invasive Size, Actual Tumor Size, and Mucinous Tumor Size in Invasive Mucinous Adenocarcinoma of the Lung. (ID 12752)

      16:45 - 18:00  |  Presenting Author(s): Tomohito Saito  |  Author(s): Koji Tsuta, Mitsuaki Ishida, Hiroshi Matsui, Yohei Taniguchi, Tomohiro Murakawa

      • Abstract
      • Slides

      Background

      Currently, tumor size of invasive mucinous adenocarcinoma such as invasive mucinous adenocarcinoma (IMA) is defined by the spread of mucinous component regardless of the existence of tumor cells. The aim of this study is to investigate the prognostic impact of the size of invasive lesion, actual tumor spread, mucinous component in IMA.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Consecutive 19 patients with pN0M0 IMAs which were completely resected between Jan. 2009 and Dec 2015 were retrospectively analyzed. Invasive size (IS), actual tumor size (aTS), and mucinous tumor size (mTS, current T factor) were measured on the identical pathological section, and radiological tumor size (rTS) was also recorded by thorax computed tomography. The prognostic value for postoperative recurrence was evaluated by area under the receiver-operating characteristic (ROC) curves and compared by DeLong’s test.

      4c3880bb027f159e801041b1021e88e8 Result

      Based on mTS, study population included 2 patients T1a, 3 with T1b, 7 with T1c, 4 with T2a, and 3 with T2b. Median age, follow-up, IS, aTS, mTS, and rTS were 75 years, 39 monts, 11mm, 25mm, 26mm and 30mm, respectively. During follow-up, 1 mortality and 3 recurrences were observed. The area under the ROC curves for IS, aTS, mTS,, and rTS were 0.833 (p=0.074)0.979 (p=0.01)1.0 (p=0.007)0.958(p=0.014). The mTS showed no significant difference compared to IS, aTS or rTS.

      figure roc curves for recurrence .jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In IMA, aTS and mTS might have prognostic value for recurrence. Prospective study with larger population would be necessary to validate the results.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • Abstract
      • Slides

      Background

      Tumor grade is an important factor of cancer outcome. Systematic inflammation has been associated with tumorigenesis and tumor aggressiveness and prognosis in several human malignancies. Cancer cells create an inflammatory peritumoral microenviroment by releasing a number of cytokines.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In total, 100 patients (88 males) with histologically proven NSCLC and no signs of active infection were evaluated. Tumor grade was examined and systematic inflammatory response was assessed by circulating levels of C-reactive protein (CRP), albumin, ferritin, transferring and the modified Glasgow Prognostic Score (mGPS). Patients were followed up and survival data were subsequently collected. Associations with clinicopathological, histological parameters and patients’ survival were studied.

      4c3880bb027f159e801041b1021e88e8 Result

      Histological grade was associated with tumor size, the presence of pathological lymph nodes, organ metastases and advanced disease stage (p=0.010, p<0.001, p<0.001 and p<0.001, respectively). There was a trend of higher histological grade in adenocarcinomas compared to squamous carcinomas (p=0.263). High tumor histological grade was also significantly associated with elevated serum CRP levels (p<0.001), hypoalbuminemia (p=0.009), elevated ferritin levels (p=0.049), abnormal mGPS (p=0.006) and a trend for reduced transferrin levels (p=0.101). In multivariate analysis, histological grade, stage, ECOG performance status and mGPS were identified as independent prognostic factors for overall survival (Cox regression analysis, p=0.002, p=0.001, p=0.010 and p=0.019, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data support the association of tumour grade with the presence of systemic inflammation; two well described negative prognostic factors for NSCLC. To our knowledge this is the first time that these factors are associated with each other giving more information about the prognosis in patients with NSCLC.

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      • Abstract
      • Slides

      Background

      Cannabinoid receptor CB2 expression has been identified to be high in various malignant neoplasms and it is involved in the pathophysiological mechanisms related to carcinogenesis. Lung cancer is an important health problem and new biomarkers are needed for better patients’ stratification. This study was conducted to elucidate the clinical significance of cannabinoid receptor CB2 expression in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Cannabinoid receptor CB2 expression was evaluated immunohistochemically on Tissue MicroArrays (TMAs) of 79 tissue samples from NSCLC patients and it was correlated to clinicopathological parameters and overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      79 NSCLC patients (48 adenocarcnomas and 31 squamous carcinomas) were studied. Enhanced cannabinoid receptor CB2 expression was observed in 20/79 (25.3 % ) NSCLC patients. In particular, enhanced cannabinoid receptor CB2 expression was found in 9 out of 48 (18.8%) adenocarcinomas and in 11 out of 31 (35.5%) of squamous cell carcinomas. Cannabinoid receptor CB2 expression was significantly associated with sex, smoking history and histological type (p=0.019, p=0.022 and p=0.032, respectively). In adenocarcinomas, cannabinoid receptor CB2 expression was correlated with overall survival (log-rank test, p=0.031), while there was a trend for correlation with tumor size (p=0.091) and lymph node metastasis (p=0.074). However, in squamous carcinomas cannabinoid receptor CB2 expression was not found to be significantly correlated with any of clinicopathological parameters or survival.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Cannabinoid receptor CB2 receptor may be involved in NSCLC malignant tranformation and growth particularly in adenocarcinomas. Therefore, cannabinoid receptor CB2 receptor could be considered as a potential biomarker or a therapeutic target in NSCLC. More studies needed to elucidate the role of this molecule in NSCLC.

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      P1.09-37 - Tumor Spread Through Air Spaces (STAS) in Stage I Lung Squamous Cell (ID 12094)

      16:45 - 18:00  |  Presenting Author(s): Hironori Uruga  |  Author(s): Takeshi Fujii, Shuhei Moriguchi, Yui Takahashi, Kazumasa Ogawa, Ryoko Murase, Shigeo Hanada, Hisashi Takaya, Atsushi Miyamoto, Nasa Morokawa, Sakashi Fujimori, Tadasu Kono, Kazuma Kishi

      • Abstract
      • Slides

      Background

      Tumor spread through air spaces (STAS) has been reported as a form of tumor invasion having an unfavorable prognosis mainly in small lung adenocarcinomas, but the significance of STAS in lung squamous cell carcinomas is not well known. The aim of this study was to analysis STAS in stage I lung squamous cell carcinomas.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      39 completely surgically resected (lobectomy) stage I lung squamous cell carcinomas from 2005 to 2009 were included in this study. We examined all tumor edges to find floating tumor cells or clusters, STAS. A statistical analysis was performed to determine the impact of clinicopathologic parameters on STAS and to clarify the relationship between STAS and patient survival.

      4c3880bb027f159e801041b1021e88e8 Result

      STAS was present in 18 of 39 cases (46.2%). There were no statistically significant associations between STAS and any clinicopathologic parameters including stage and lymph-vascular invasions. There was a significant association between presence of STAS and shorter recurrence-free survival (RFS) in univariate analysis (104.7 months with STAS, 145.5 months without STAS). In a multivariate Cox proportional hazards model, STAS (p=0.06) couldn’t reach a significant predictor of RFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We found STAS about in half of resected stage I lung squamous cell carcinomas. Presence of STAS was predictive factor of worse RFS in univariate analysis, but not significant in multivariate analysis.

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      P1.09-38 - Pulmonary Epithelioid Hemangioendothelioma (EHE) with Von Recklinghausen Disease (ID 11764)

      16:45 - 18:00  |  Presenting Author(s): Satoshi Yamamoto  |  Author(s): Motohisa Kuwahara

      • Abstract

      Background

      Malignant thoracic epithelioid tumors are an uncommon. The heterogenous group of tumors that include the low to intermediate grade epithelioid hemangioendothelioma(EHE) and epithelioid angiosarcoma under examination of the morphologic and immunohistochemical features. We here reported a rare case of multiple pulmonary epithelioid hemangioendothelioma with von Recklinghausen disease.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Case

      A 34–year–old male was admitted to our hospital with an abnormal shadow in the bilateral lung field. He has von Recklinghausen disease, and non-smoker. The laboratory data and physical examination are normal. A chest computed tomography scan showed multiple nodal lesions of 2 mm to 12 mm in diameter in the bilateral lung fields.

      4c3880bb027f159e801041b1021e88e8 Result

      Thoracoscopic partial resection of the right middle lobe was performed. The tumor was well-circumscribed lesion. In the pathological findings, sections showed a proliferation of epithelioid tumor cells having oval-shaped and vesicular nuclei, prominent nucleoli and pale eosinophilic cytoplasm arranged in small nested or cord patterns. Intracytoplasmic vacuoles some of which contain erythrocytes were recognized. Mitotic figures were rarely seen. In the immunohistochemical examination, the tumor cells were positive for CD31 and CD34, but negative for D2-40, CAM5.2, Ber-EP4, alpha-SMA, desmin, S-100 protein, NSE, TTF-1, calretinin, claudin-4, CD36 and c-kit. RT-PCR analysis showed CAMTA1-WWTR1 fusions was negative. Those features were consistent with pulmonary epithelioid hemangioendothelioma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pulmonary epithelioid hemangioendothelioma(EHE) is rare tumor and there is no report in the literature of EHE with von Recklinghausen disease. The behavior of this neoplasm is uncertain, so the methods of diagnosis and treatment will demand to do careful observation and further examination.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-39 - Spread Through Air Spaces Predicts a Worse Survival in Patients with Stage I Adenocarcinomas > 2.0cm After Radical Lobectomy (ID 11202)

      16:45 - 18:00  |  Presenting Author(s): Lin Yang  |  Author(s): Yikun Yang, Yousheng Mao, Ning Lv

      • Abstract
      • Slides

      Background

      Spread through air spaces (STAS) has been reported a predictor for recurrence or metastasis for lung cancer patients after limited resection, however, the significance of STAS for patients with lobectomy remains inconsistent. The aim of this study was to evaluate the significance of Spread Through Air Spaces (STAS) in early lung adenocarcinomas after radical lobectomy and lymphadenectomy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 242 patients with lung adenocarcinomas less than 4cm (8th pStage I) were selected from the lung cancer patients surgically treated from January, 2009 to September, 2011. Pathological review focused on STAS, and recurrence or distant metastasis-free survival(DFS) and overall survival(OS) were compared between patients as stratified by STAS and tumor size.

      4c3880bb027f159e801041b1021e88e8 Result

      STAS was observed in 33.47%(81/242) patients, which was significantly correlated with histological predominant subtype (χ2=25.903, p=0.000) and differentiation grade(χ2=23.986, p=0.000).Patients with STAS (+) showed a comparable PFS(p=0.268) and OS rates(p=0.100) in all stage I cases, but a significant lower PFS(p=0.029) and OS(p=0.013) in tumors within 2.1~4.0cm. Multivariate analysis revealed STAS to be an independent worse prognostic factor in lung adenocarcinomas within 2.1~4.0cm, both for PFS(p=0.004) and OS(p=0.002) , while no significant difference was found in patients with tumors≤2.0cm(PFS, p=0.537; OS, p=0.448), after adjusting by other clinicopathological parameters as age, gender, smoking etc.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Presence of STAS was a significant worse predictor for pStage I patients with lung adenocarcinoma>2.0cm who underwent radical lobectomy, while it is not significant in patients with tumor ≤2.0cm. These findings may be helpful in assessing postoperative therapy stratified by tumor size and STAS status.

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      P1.09-40 - Metastatic Endometrial Sarcoma Presenting as a Spontaneous Pneumothorax and Masquerading as a Pulmonary Blastoma. (ID 14400)

      16:45 - 18:00  |  Presenting Author(s): Giselle Alexandra Suero-Abreu  |  Author(s): Rahim Wooley, JunChih Wang, Narjust Duma, Miguel Gonzalez Velez, Arturo Perez, Analise Y Douglas, Martin Gutierrez, Keith Guevarra

      • Abstract

      Background

      For the proper evaluation of pulmonary cavitary lesions, it is essential to obtain an adequate assessment of the patient’s clinical history. Imaging studies can be equivocal and adequate pathological diagnosis can also be challenging. This is particularly important in the case of metastatic lung tumors with extra-thoracic origin, such as certain gynecologic malignancies, which—owing to their late metastatic potential—can be noted years after removal of the primary tumor, causing a misdiagnosis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We illustrate this scenario with an interesting case of an endometrial stromal sarcoma which presented as a cavitary lesion causing a spontaneous pneumothorax and initially diagnosed as a pulmonary blastoma.

      4c3880bb027f159e801041b1021e88e8 Result

      44 year old woman presented with a one day history of left sided chest pain and shortness of breath. The pain was sudden, sharp and associated with dyspnea. The patient denied any fevers, chills, cough, hemoptysis, weight loss, recent travel, sick contacts or tuberculosis. A chest X-ray demonstrated a large left-sided pneumothorax and a chest CT showed a left upper lobe cavitary lesion (Figure 1). Subsequently, a left upper lobe and lingual wedge resection were performe and biopsies of the cavitary lesion were sent. The initial pathological impression was that this was a pulmonary blastoma with heterologous leiomyosarcomatous differentiation. However, further history revealed that the patient had chronic anemia and menometrorrhagia secondary to uterine fibromas and had a total abdominal hysterectomy one year prior to presentation. This finding prompted a review of the pathological specimen and positive immunoreactivity to estrogen/progesterone receptors (ER+/PR+), and CD10+ provided the alternate diagnosis of a metastatic low-grade stromal sarcoma of endometrial origin. Patient followed with medical oncology and gynecology and is currently undergoing hormonal therapy.

      cavitary lesion.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      This case highlights the importance of a proper correlation of clinical history alongside imaging studies and immunohistochemical findings in the diagnosis of certain lung lesions, in particular thoracic gynecological malignancies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.11 - Screening and Early Detection (Not CME Accredited Session) (ID 943)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 19
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.11-01 - The NELSON Triage Algorithm Applied to a Chinese Biopsied Population: A Pilot Study (ID 12115)

      16:45 - 18:00  |  Presenting Author(s): Hubert Beaumont  |  Author(s): Jie Hu, Dawei Yang, Ningfang Wang, Pengyuan Li, Shaohua Lu, Weibin Shi, Di Ge, Nathalie Faye, ChunXue Bai

      • Abstract
      • Slides

      Background

      The Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) lung cancer screening study sequentially tests nodules’ volume, growth and doubling time with an increasing screening interval length. For now, classification performances of NELSON are known only for a European population with specific eligibility criteria.

      We tested the NELSON trial triage algorithm on a cohort of biopsied Chinese patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our study utilized a data subset from the NCT02693496 clinical trial. The data consisted of onsite prospective evaluations of 85 Chinese patients who underwent CTs within an average time interval of 259 days (Min=63; Max=1092). NCT02693496 readers applied the Chinese consensus low-dose CT management guidelines with referral to biopsy, when required.

      The eligibility criteria were: All genders; age: 18 to 90 years old; chest lesion <3cm. Smoking status was not considered.

      In our subset of 85 patients, 15 nodules from 15 patients were biopsied: 10 were confirmed malignant; of these, 3 were solid nodules (SN) and 7 were sub-solid nodules (SSN). Five biopsied nodules were confirmed benign. Of the whole cohort, 11.8% (10/85), were declared positive patients. The 75/85 others (88.2%) were declared negative by radiologists and/or pathologists.

      Using the Lesion Management Solution (LMS) platform (Median Technologies), we retrospectively re-processed the subset of images to analyze NELSON sensitivity at detecting malignant lung nodules. We used R CRAN software for statistics and Chi-Squared test for non-parametric comparison of two sample proportions.

      4c3880bb027f159e801041b1021e88e8 Result

      We found 12.9% of patients (11/85) displayed no findings. There were 155 detected findings in the remaining 74 patients, which were documented as: 5.2% (8/155) benign as NODCAT I; 9.0% (14/155) pleural; 27.7% (43/155) SSN and 58.1% (90/155) SN. According to NELSON triage, five Patients were declared positive.

      In the biopsy-confirmed nodules group (10 patients), four were detected by NELSON, one at baseline.

      All patients displaying SNs were detected (3/3) whereas only one (1/6) patient displaying SSNs was detected. NELSON was better at detecting SNs (p=0.036).

      One patient with confirmed negative biopsy patient (1/5) was declared positive by NELSON with one SN and one SSN.

      Additionally, one SN in patient without biopsy was declared positive at baseline by NELSON triage algorithm.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Prevalence of different nodule types in this Chinese population was different from the observations of the original European NELSON trial. The NELSON triage algorithm correctly classified patients with malignant SNs but misclassified most patients displaying SSNs. Further studies are needed to better evaluate SSNs by NELSON.

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      P1.11-02 - Pathologic Comparison of Prevalent vs. Incident CT Lung Screen Detected Cancer in NCCN High-Risk Subjects: Are They Different? (ID 13518)

      16:45 - 18:00  |  Presenting Author(s): Eric J Burks  |  Author(s): Jacob M Sands, Travis B Sullivan, Shawn M Regis, Brady J McKee, Andrea B McKee, Kimberly R Christ

      • Abstract

      Background

      CT lung screening (CTLS) detects two overlapping but potentially distinct groups of tumors. Prevalent tumors, found at baseline screening, are thought to be enriched with slow-growing, potentially indolent cancers while incident tumors, found on annual repeat scans, are thought to be more uniformly fast-growing and aggressive. Pathologically, squamous cell carcinomas, small cell carcinomas (SCC) and large cell neuroendocrine carcinomas (LCNEC) are uniformly fast-growing and aggressive while adenocarcinomas are more heterogenous in their growth-rates, behavior and histology. By comparing pathologic subtypes, I-ELCAP investigators reported a higher frequency of adenocarcinomas compared to squamous cell carcinomas in prevalent compared to incident tumors (ratio 8:1 vs. 3.4:1) and conversely a 4-fold lower frequency of SCC/LCNEC (7% vs. 30%, respectively). Based partly on these data, some worry about the risk of overdiagnosis in CTLS subjects undergoing baseline screening in which the proportion of slow-growing potentially indolent adenocarcinomas may be enriched. Current guidelines recommend screening specific high-risk subjects for which pathologic comparisons of prevalent and incident cancers have not been thus far described.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The pathology of 134 CTLS cancers detected at Lahey Hospital & Medical Center was reviewed, including 93 detected at baseline and 41 at annual repeat screening. All individuals met the NCCN Guidelines Lung Cancer Screening v1.2012 high-risk criteria, were asymptomatic, had no known metastatic disease and were free of lung cancer for at least 5-years. Detailed pathologic analysis was performed for 65 stage I resected adenocarcinomas whereas lineage alone was determined for the cytologically diagnosed tumors.

      4c3880bb027f159e801041b1021e88e8 Result

      The proportion of adenocarcinomas to squamous cell carcinomas was similar in prevalent compared to incident tumors (ratio 2.6:1 vs. 3.1:1). Small cell carcinomas were only half as frequent among prevalent vs. incident cancers (5% vs. 12%). Among stage I adenocarcinomas, a similar proportion of prevalent vs. incident cancers exhibited a ≥5% solid pattern (32% vs. 30%), ≥5% micropapillary pattern (23% vs. 22%), ≥10% cribriform pattern (30% vs. 26%), intermediate/high mitotic grade (57% vs. 57%), angiolymphatic invasion (43% vs. 48%), and STAS (36% vs. 39%). Visceral pleural invasion was actually higher in the prevalent cancers (27% vs. 17%) however no statistically significant differences were observed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pathologic comparison of prevalent vs. incident CTLS cancers among NCCN defined high-risk subjects reveals less variability than previously described by I-ELCAP. In particular, histologically indolent adenocarcinomas are not enriched in prevalent compared to incident tumors and thus the risk of overdiagnosis in baseline detected cancers may be less than once thought.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.11-03 - MicroRNA with Ability to Reciprocal Regulation of Dicer and Drosha – Plasma Expression Status and Diagnostic Value in Non-Small Cell Lung Cancer (ID 12133)

      16:45 - 18:00  |  Presenting Author(s): Pawel Krawczyk  |  Author(s): Anna Grenda, Michał Szczyrek, Barbara Kuźnar-Kamińska, Marek Sawicki, Maciej Głogowski, Anna Rolska-Kopińska, Grażyna Balicka, Marcin Nicoś, Monika Jakimiec, Halina Batura-Gabryel, Dariusz Kowalski, Radosław Mlak, Maciej Krzakowski, Janusz Milanowski

      • Abstract
      • Slides

      Background

      Examination of microRNAs expression in plasma could be useful in screening and in early detection of non-small cell lung cancer (NSCLC). One of the most important enzymes in miRNA biogenesis are Dicer and Drosha. Disrupted expression of miRNA with ability to reciprocal regulation of Dicer and Drosha could participate in cancer development.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Plasma expression of miR-27-3p, miR-31, miR-182 and miR-195 were analysed in 138 Polish NSCLC patients (median age 65 years, 83 male and 55 female) and in 45 healthy people (median age 62 years, 28 male and 17 female). 57 (41.3%) NSCLC patient were in I-IIIA stage and 81 (58.7%) patients were in IIIB-IV stage. Relative expression of microRNAs between studied groups was compared using U Mann-Whitney test. For assessment of diagnostic accuracy (test sensitivity and specificity), the receiver operating curves (ROC) with area under curve (AUC) analysis were generated.

      4c3880bb027f159e801041b1021e88e8 Result

      We demonstrated that plasma levels of miR-27-3p, miR-31 and miR-182 were significantly higher (p<0.000001, p=0.00008, p=0.006 respectively) and miR-195 significantly lower (p=0.000002) in NSCLC patients in comparison with healthy donors. Moreover, patients with early stages (I-IIIA) of NSCLC showed significantly higher expression of miR-27a-3p (p<0.000001), miR-31 (p=0.0003) and miR-182 (p=0.000003) than healthy persons. Expression of miR-195 was significantly lower in patients with early stages (I-IIIA) of NSCLC than in healthy donors (p<0.000001). AUC for miR-27a was 0.95 (94% sensitivity and 81% specificity, p<0.00001), for miR-31 was 0.71 (73% sensitivity and 61% specificity, p=0.001), for miR-182 was 0.77 (70% sensitivity and 79% specificity, p<0.00001) and for miR-195 was 0.82 (74% sensitivity and 80% specificity, p=0.00001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Expression of miR-27a, miR-31, miR-182 and miR-195 could distinguish patients with NSCLC from healthy people. The examination of these microRNAs in plasma could be used in non-invasive lung cancer diagnosis. Deregulation of Dicer and Drosha expression by microRNAs could have oncogenic character.

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      P1.11-04 - Size Measurement Variability of Solid Component of Lung Adenocarcinoma (ID 12451)

      16:45 - 18:00  |  Presenting Author(s): Kazutoshi Hamanaka

      • Abstract
      • Slides

      Background

      In the current TNM classification for lung cancer, the solid size is used for tumor diameter measurement as dense component. However, in daily practice, it is sometimes difficult to measure the solid size, so the variability between the observer may increase, and therefore it is presumed that the measurement variability between radiological and pathological size become large particularly in subsolid nodules. In this study, we investigate the interobserver variability and differences between the radiological and pathological tumor size in lung adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Interobserver variability: We assessed 47 cases of subsolid type lung adenocarcinoma operated in our department from January to December 2016. Six physicians including surgeons and radiologist measured the solid and total size using preoperative CT and assessed the interobserver measurement variability. Furthermore, we assessed the interobserver variability using 5 subclassified patterns of the tumor.

      Radiological-pathological variability: Radiological-pathological variability in measurement of solid size in adenocarcinoma using database of 554 surgical cases from January 2010 to Jun 2017 was investigated. We also assessed the stage migration using radiological and pathological T stage classified by only tumor size.

      4c3880bb027f159e801041b1021e88e8 Result

      The mean interobserver variability of six observers of 47 cases was 9.7 mm in solid size, and 7.7 mm in total size. The tumor images were subclassified into the following 5 patterns: ①minimally invasive ②peribronchovascular ③spicula/atelectasis ④adjacent to cystic lesions ⑤pneumonia-like consolidation. To correct for differences in mean tumor diameter in each pattern, comparison was made using coefficient of variation (CV) calculated by SD/mean. The pattern of minimally invasive (①) became the largest value for CV in the measurement of solid size.

      The mean radiological-pathological variability of 554 cases was 5.9 mm in solid size, and 5.4 mm in total size. In cases of Tis, T1mi in T stage, and adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) in histological type, the CVs were larger than others. The comparison of radiological and pathological T stage, the accurate staging rate was 41.8%, and upstage were seen in 28.8% in all cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Interobserver measurement variability of solid size of the lung adenocarcinoma was larger than those of total size. The difference between radiological and pathological invasion size tend to be larger in small-sized tumor as Tis and T1mi, and low-grade malignant potential lesions as AIS and MIA.Therefore, a careful consideration must be given to decide the management plan of these cases.

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      P1.11-05 - Metabolomic Profiling for Second Primary Lung Cancer Among Lung Cancer Survivors (ID 13995)

      16:45 - 18:00  |  Presenting Author(s): Summer S Han  |  Author(s): Li Su, Nancy Diao, David C Christiani, Heather A Wakelee

      • Abstract

      Background

      Survivors of lung cancer(LC) have a high risk of developing second primary lung cancer(SPLC), the incidence of which is 4-6 times higher than that of initial primary lung cancer(IPLC). While national lung screening guidelines have been established for IPLC, no consensus guidelines exist for LC survivors. Furthermore, the factors that contribute to SPLC risk have not yet been established. The purpose of this study is to examine the potential of metabolomics to identify non-invasive blood-based biomarkers for SPLC screening.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We applied an untargeted metabolomics approach based on a liquid chromatography-tandem mass spectroscopy(UPLC-MS/MS) method to discover metabolic biomarkers using blood serum samples from the Boston Lung Cancer Study. Our study cohort consisted of 177 subjects diagnosed with IPLC between 1992 and 2012 and who survived >=5 years after the initial diagnosis. The cohort included 82 SPLC cases and 95 matched controls (i.e. IPLC patients without SPLC as of Dec, 2017) based on the age of initial diagnosis, sex, race, and smoking status. We applied random forest and Welch’s t-test to identify metabolomic features associated with SPLC risk and to build a risk prediction model.

      4c3880bb027f159e801041b1021e88e8 Result

      Our analysis detected 1008 named and 316 unnamed metabolites. The metabolites that were statistically significantly associated with SPLC risk (False Discovery Rate q-value<0.05) included 5-methylthioadenosine (MTA), phenylacetylglutamine, and umbelliferone sulfate, which showed 1.4-3.8 fold increases among SPLC cases versus controls (Figure 1). These metabolites were involved in amino acid, peptide, and xenobiotics pathways. The stratification by quintiles of estimated risk using the prediction model based on the metabolites showed that the observed incidence of SPLC was significantly higher in the fifth quintile(69.4%) versus the first-quintile(36.1%;P<0.05).

      figure1_splc.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified potential metabolic biomarkers for SPLC among LC survivors. A risk-stratification approach based on metabolic biomarkers can be potentially useful for identifying high-risk LC survivors to be screened by CT.

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      P1.11-06 - Lung Cancer Probability in New Perifissural Nodules Detected in a Lung Cancer Screening Study (ID 13427)

      16:45 - 18:00  |  Presenting Author(s): Marjolein A Heuvelmans  |  Author(s): Lisa H Van Smoorenburg, Joan E Walter, Uraujh Yousaf-Khan, Carlijn M. Van Der Aalst, Monique Dorrius, Mieneke Rook, Rozemarijn Vliegenthart, Harry J De Koning, Matthijs Oudkerk

      • Abstract

      Background

      In incidence lung cancer screening rounds, new lung nodules are a regular finding, with a higher lung cancer probability than baseline nodules. A substantial number of screen-detected nodules is classified as perifissural nodule (PFN). Previous studies showed that baseline PFNs and PFNs in clinical settings represent non-malignant lesions such as intrapulmonary lymph nodes. Whether this is also the case for incident PFNs is unknown. This study evaluates all newly detected nodules in the Dutch-Belgian randomized-controlled NELSON study with respect to perifissural classification and lung cancer probability.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All NELSON participants with a new solid nodule detected in screening round 2, 3 or 4 (1, 3, and 5.5 years after baseline, respectively), were enrolled in this substudy. Nodules were classified into three groups: intraparenchymal, vessel attached or fissure attached. Screening CT scans of participants with lung cancer based on a nodule classified as fissure attached, were re-evaluated by two radiologists (4 and 6 years of experience) to check whether this nodule was a typical, atypical or non-PFN. The fissure-attached cancers were matched based on size with benign cases (1:4), and the radiologists were blinded for the final nodule outcome. In case of discrepancy, a third radiologist (13 years of experience) arbitered.

      4c3880bb027f159e801041b1021e88e8 Result

      1,484 new nodules were detected in the second, third and final NELSON screening round in 949 participants (77.4% male, median age 59 [interquartile range: 55-63]). 1,393 nodules (93.8%) were benign based on 2 year follow-up or pathology; 96 of these (6.9%) were fissure attached. Lung cancer diagnosis was made in 74 new nodules in 74 participants (7.8% of participants with a new nodule). Nine lung cancers (12.1%) were fissure attached and re-evaluated by the radiologists. None of the fissure attached malignant new nodules was classified as a typical or atypical PFN.

      8eea62084ca7e541d918e823422bd82e Conclusion

      None of the lung cancers that originated from a new nodule in the NELSON study was classified as a typical or atypical PFN. Our results suggest that also in the case of a new PFN, it is highly unlikely that these PFNs will be diagnosed as lung cancer.

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      P1.11-07 - Utility of the Maximum CT Value in Predicting Invasiveness of Pure GGNs (ID 12197)

      16:45 - 18:00  |  Presenting Author(s): Junji Ichinose  |  Author(s): Masayuki Nakao, Yosuke Matsuura, Mingyon Mun, Ken Nakagawa, Makoto Nishio, Sakae Okumura

      • Abstract
      • Slides

      Background

      In the current TNM classification of lung cancer, the pulmonary lesions presenting pure ground-glass nodules (GGNs) without solid component are classified as cTis tumor. However, some of them are pathologically diagnosed as invasive adenocarcinomas. This study aimed to predict the histological invasiveness using the computed tomography (CT) value in pure GGN lesions.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      138 patients underwent resection of pure GGNs between 2011 and 2016. The maximum diameter and CT value were measured using a computer graphics support system. We selected the axial section which showed the densest component of each GGN. The CT value was measured separately in several areas excluding portions of apparent vessels and bronchi manually. We analyzed the correlation between the CT value of pure GGNs and the histological diagnosis, such as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (Ad).

      4c3880bb027f159e801041b1021e88e8 Result

      The number of the patients with AAH, AIS, MIA and Ad was 6, 81, 45 and 6, respectively. 37% of the pure GGN lesions contained histologically invasive component and 4% of them were diagnosed as Ad. One tumor of Ad had lymphatic invasion, while there was no case with vascular invasion. 37 lobectomies, 38 segmentectomies and 63 wedge resections were performed and there was no recurrence. In comparison between the preinvasive lesions (AAH and AIS) and the invasive lesions (MIA and Ad), the latter was significantly correlated with the higher age of the patients (60 ± 9 years vs 67 ± 7 years), the larger total size (12 ± 5 mm vs 16 ± 5 mm), the higher maximum CT value (-388 ± 125 HU vs -208 ± 129 HU) and the presence of pleural indentation (odds ratio, 2.8).

      When the cut-off point of the maximum CT value in predicting histological invasiveness was set at -300 HU using the ROC curve analysis, the sensitivity, specificity, positive predictive value and negative predictive value were 80%, 77%, 67% and 87%, respectively. The 100% of Ad and the 78% of MIA were correctly estimated.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Invasive adenocarcinoma and MIA accounted for 4% and 33% of the pure GGN lesions, respectively. The maximum CT value was correlated with the pathological diagnosis. It may be useful as a predictor of histological invasiveness. The threshold at -300 HU can be the basis of the computer-aided automatic diagnosis.

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      P1.11-08 - AI Based Malignancy Prediction of Indeterminate Pulmonary Nodules: Robustness to CT Contrast Media (ID 13904)

      16:45 - 18:00  |  Presenting Author(s): Timor Kadir  |  Author(s): Quentin Chometon, Lyndsey Pickup, Carlos Arteta, Heiko Peschl, Sarim Ather, Maria Tsakok, Catarina Santos, Petr Novotny, Jerome Declerck, Fergus V Gleeson

      • Abstract

      Background

      Artificial Intelligence (AI) based malignancy prediction of indeterminate pulmonary nodules has been previously demonstrated to perform well on screen-detected nodules imaged with low-dose, non-contrast CT. This study aimed to assess the impact of contrast media on the classification performance of such a system.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Convolutional Neural Network (CNN) was trained on the US National Lung Screening Trial (NLST), which contained only low-dose non-contrast screening images, selecting all nodules 6mm and greater in size (14761 benign nodules from 5972 patients; 932 cancer from 575 patients). A CNN classifier was trained using Deep Learning on this data to produce a malignancy score per nodule.

      For validation, an independent retrospective dataset of incidentally detected solid nodules was used. None of the patients had a cancer diagnosis within the past 5 years, and all had fewer than 5 nodules. The dataset contained 571 nodules from 505 patients, including 42 cancer from 39 patients.

      A CT was considered to be contrasted if the mode HU value within an ROI placed at the aortic arch was greater than 60HU. This resulted in two groups: the non-contrast group had 313 nodules from 276 patients (16 cancer from 14 patients); the contrast group had 258 nodules from 229 patients (26 cancer from 25 patients). The overall efficacy was assessed using Area-Under-the-ROC-Curve analysis (AUC) for each group.

      4c3880bb027f159e801041b1021e88e8 Result

      The AUC on the non-contrast CT group was 0.96 (95% CI 0.93 to 0.98) and 0.95 (95% CI 0.90 to 0.99) on the contrast CT group. Further analysis revealed that excluding high contrast cases, where the HU in the aortic arch was greater than 300HU (40 nodules from 38 patients; 4 cancer), resulted in an AUC of 0.97 (95% CI 0.92 to 1.00).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The CNN classifier seems to be robust to the presence of contrast media with only a moderate reduction in performance. Excluding cases with high contrast restored the performance, although, with only 38 nodules excluded by this, the result may be not statistically significant. These results indicate that a CNN developed to predict pulmonary nodule malignancy, that has been trained on low-dose, non-contrast enhanced CT images, may be used with CT images with moderate levels of contrast without retraining.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.11-09 - The Delay of Lung Cancer Diagnosis Due to Misdiagnosing as Pulmonary Tuberculosis (ID 12797)

      16:45 - 18:00  |  Presenting Author(s): Ana Rima  |  Author(s): Jatu Avi, Satria Maulana E.h, Ita Hariyati, Yusup Subagio Sutanto

      • Abstract
      • Slides

      Background

      Indonesia is a country with the second largest number of Tuberculosis (TB) cases in the world. Clinical symptom similarities of lung cancer to those of pulmonary TB can lead lung cancer patients to be diagnosed as pulmonary TB and receive Anti Tuberculosis Treatment (ATT) especially in TB endemic countries. The evaluation of ATT responses is often less stringent, resulting in delayed diagnosis of lung cancer. This study aimed to investigate the percentage of delayed lung cancer diagnosis due to misdiagnosing as pulmonary TB thus receiving ATT over one month.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A descriptive study was conducted in Dr. Moewardi Hospital, Solo Indonesia by using patients’ medical record data from January 2014 to February 2016.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 305 lung cancer patients, 194 (63.6%) were males and 111 (36.4%) were females and the average age was 48 years old. History taking and Acid Fast Bacillus (AFB) smear revealed 93 (30.5%) patients were diagnosed as pulmonary TB and received ATT. Three (1%) were found to have lung cancer in conjunction with pulmonary TB with positive AFB while 90 (29.5%) lung cancer patients had been misdiagnosed as pulmonary TB and had been given ATT with the average duration of 3.26 months and the longest administration was 7 months. Based on the duration of ATT there were 22 (24.4%) and 68 (75.6%) patients receiving ATT for ≤ 1 month and > 1 month respectively. Of the 90 lung cancer patients who had misdiagnosis as pulmonary TB, there were 56.7% males, 94.4% aged over 40 years old and 62.2% smokers. The types of lung cancer were non-small cell lung carcinoma (NSCLC) consisted of 68 (75.6%) adenocarcinoma, 13 (14.4%) squamous cell carcinoma, 5 (5.6%) large cell carcinoma, and 2 (2.2%) neuroendocrine carcinoma. Two (2.2%) of the patients were small cell lung cancer (SCLC). Based on NSCLC staging there were 0% stage I, 0% stage II, 0% stage IIIa, 11.1% IIIb and 88.9% stage IV. The most common metastasis was pleural effusion (58.9%) followed by other organ (27.8%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study revealed that 29.5% lung cancer patients who were previously misdiagnosed as pulmonary TB, 75.6% of them received ATT over a month with the average duration of 3.26 months. This misdiagnosis resulted in the delay of lung cancer diagnosis.

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      P1.11-10 - Optimizing Radiomics Features by Minimizing Boundary Effects and Normalizing with Opposite Lung Tissue Characteristics (ID 14062)

      16:45 - 18:00  |  Presenting Author(s): Saeed Seyyedi  |  Author(s): John Mayo, Sukhinder Atkar-Khattra, Ren Yuan, Stephen Lam, Calum Macaulay

      • Abstract
      • Slides

      Background

      For wide adoption of LDCT screening it is thought that CAD will likely by necessary. We hypothesize that CAD features that minimizes perimeter effects and normalizes nodule CT features using the lung parenchyma from the opposite lung will improve the ability to determine nodule malignancy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have developed a CAD system that includes lung tissue segmentation, nodule detection and feature extraction from the segmented nodule, the segmented nodule minus the perimeter transition pixels (Core), and the opposite lung parenchymal tissue. (See Figure 1).

      We use the Mann-Whitney U test to compare teh discriminating ability of individual features and combinations of features) extracted from the nodule, nodule core and nodule normalized by mirror region features.

      figure-1 (1).jpg

      4c3880bb027f159e801041b1021e88e8 Result

      In total, 34 early small suspect baseline nodules detected as part of the PanCan screening trial were used, these include 17 nodules proven to be cancer and 17 nodules that resolved on follow-up scans. The comparison of classification ability of features from nodules without edge vs. nodules with edge pixels reveals that the core features show better classification ability for 76 out of the 136 calculated features.

      Performing a leave-one-out LDA classifier cross-validation approach in using core features, gives an accuracy of 76% with only 1 feature through 3 features, and 82% with 4 features. However, repeating the same experiment for core plus edge features, shows accuracy of 67% with only 1 feature, 73% with 3 features, 79% with 4 features. Normalizing the core texture features by the texture features of the mirrored region in the opposite lung shows an improved classification ability for 52 out of the 89 texture features.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, the results suggest using the nodule core improves feature classification as does normalizing of the nodule by the mirrored region in opposite lung.

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      P1.11-11 - Comparing Lung Cancer Diagnosed by Low Dose CT (LDCT), Incidental Lung Nodule Program (ILNP), and Non-Program-Based Detection (ID 14379)

      16:45 - 18:00  |  Presenting Author(s): Matthew P Smeltzer  |  Author(s): Nicholas R. Faris, Jennifer Kethireddy, Meghan Meadows, Mary Catherine Nalan, Meredith A Ray, Amanda Epperson, Diane Richards, Kim Adams, Angela Fulford, Ajay Wagh, James Machin, Keith Tonkin, Robert Optican, Jeff Wright, Edward Todd Robbins, Raymond U. Osarogiagbon

      • Abstract
      • Slides

      Background

      The aggregate 5-year survival of lung cancer patients is <20%, partly because most patients present with advanced disease. LDCT screening and algorithmic management of patients with incidentally-detected nodules are two methods for early detection, but rigorous evaluation is needed for effective implementation. We compared patients with lung cancer diagnosed via LDCT vs. ILNP vs. neither in a lung cancer-endemic US region.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We compared demographic, clinical, and treatment characteristics of patients diagnosed via LDCT and ILNP with those treated in a multidisciplinary program (MDP) who were not diagnosed through either early detection program. LDCT screening was implemented in 2015 using Medicare eligibility criteria. In the ILNP, navigators and a multidisciplinary team prospectively tracked patients with suspicious findings flagged by radiologists, using Natural Language Processing software. All patients were diagnosed within the same healthcare system from 2015-2018. Statistical comparisons used chi-square, Fishers Exact, and ANOVA.

      4c3880bb027f159e801041b1021e88e8 Result

      Lung cancer diagnoses included 111 from 5,954 ILNP scans, 11 from 400 LDCT scans (1.9% v 2.8%, p=0.21), and 273 from MDC. An additional 40 (10%) LDCT scans were Lung RADS 3 or 4. Average ages were 70/68/68 years for ILNP/LDCT/MDC and patients were 43%/64%/48% male. African Americans were underrepresented in both early detection groups (23%/9%/36%; p=0.0111); Medicare patients were over-represented (83%/91%/42%, p<0.001). Active smoking was highest in LDCT (73%, 79 pack-year average), but similar between ILNP and MDC (39%, 50 pack-year average vs 36%, 63 pack-year average).

      Early detection cases were more frequently adenocarcinoma (61%/ 55%/48%; p=0.0595) with smaller lesions (2.2cm/1.0cm/4.2cm; p<0.001). Stage I/II cancers were more likely with early detection (71%/89%/42%; p<0.001), leading to substantially higher rates of surgical resection (75%/73%/31%; p<0.001). Median time from lesion detection to treatment initiation was similar between groups (61/74/58 days, p=0.48).

      62% of patients with lung cancers diagnosed by ILNP and 57% by MDC were not eligible for LDCT screening. The most common disqualifying criteria were a 30 pack-year smoking history (unmet: 41% ILNP/ 41% MDC) and active smoking within 15 years (unmet: 41% ILNP/ 27% MDC).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung cancers diagnosed by ILNP and LDCT had better prognosis than the MDC population, with smaller tumors, earlier stage, and more treatment with surgical resection. African Americans were underrepresented in these groups. Less than half of ILNP and MDC cases had enough smoking exposure to qualify for LDCT screening. ILNP is a critical component of early detection programs, reaching an element of the population that did not qualify for LDCT screening.

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      P1.11-12 - Interrogation of an Exhaled MicroRNA Panel for Lung Cancer Risk Assessment (ID 14317)

      16:45 - 18:00  |  Presenting Author(s): Simon D Spivack

      • Abstract

      Background

      Background: There is a need for non-invasive airway-based biomarkers in lung carcinogenesis for both risk assessment of the ex-smoker, and earlier diagnosis. Exhaled breath condensate (EBC) contains airway lining fluid molecules, including nucleic acids, presumably in part from epithelial cellular origins. MicroRNAs play important regulatory roles in many processes, including carcinogenesis. Here we further develop and begin validation of the detection of microRNAs in EBC from lung cancer patients and controls.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EBC was collected non-invasively, using a handheld commercial RTube® device in a clinical series of ambulatory subjects. We generated a 40 miR panel based on literature-derived microRNAs, bronchial brushed microRNA discovery by collaboration, and a lung parenchymal tissue discovery effort we have performed using microRNA-seq on lung tumors and surrounding non-tumor tissue. The PCR primers were designed using our previously published RNA-specific RT-PCR technique. All samples were run twice with positive and negative controls. Calls was made of individual miR present or absent in a given EBC sample, by one of two replicates being positive. The data were analyzed by random forests.

      4c3880bb027f159e801041b1021e88e8 Result

      We applied the panel to EBC from 177 individuals, 89 NSCLC predominantly early stage (I and II) cases and 88 controls of similar smoking history. We used an empirically-derived base clinical model that included age, smoking status, pack-years, quit-years, and underlying lung disease. MicroRNA signatures alone discriminated cases from controls with ROC-AUCs of 0.64-0.76. Both analyses revealed a small set of incrementally informative miRs (e.g., miRs-21**, 33b**, 96*,105*, `130b.3p*, 200a*, 200b**, 205, 212***, 221***, 345***, 767**, 944*, 1269a***, 1293*, 1910**, 3648*, 3662*, where number of ‘*’ implies number of appearances in each of three models). Here some modest incremental case-control discriminant capacity was conferred by the respective microRNA signature over and above the base clinical model. The magnitude of the increment was typically 2-3% [RF AUC 0.84 clinical model=>0.86 clinical+microRNA (all lung cancer histologies, Welch p=1.33e-05); 0.82=>0.84 (adenocarcinomas, Welch p=3.13e-03); 0.84=>0.86 (NSCLC, Welch p=4.10e-05). Quantitative RT-PCR using this platform set-up was not sufficiently robust to further analyze.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This new exhaled biomarker platform can yield case-control discriminant microRNA sets. albeit modest in incremental impact as formulated so far. Once quantified, further distilled and validated, our goal is to test this non-invasive biomarker approach to prospective cohorts for non-invasive lung cancer risk assessment, in order to non-invasively better select higher risk individuals to undergo effective CT screening.

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      P1.11-13 - Noninvasive Detection of Early Stage NSCLC EGFR Mutations Using Electric Field Induced Release and Measurement (EFIRM) (ID 11776)

      16:45 - 18:00  |  Presenting Author(s): Charles Strom  |  Author(s): Fang Wei, Wei Liao, Jordan Cheng, Michael Kai Tu, David Chia, Feng Li, Yong Kim, Wu-Chou Su, Chien-Chung Lin, David Elashoff, David Wong

      • Abstract
      • Slides

      Background

      The ability of liquid biopsy to detect circulating tumor mutations has proved especially valuable in the treatment of patients with NSCLC since well characterized variants inform small molecule chemotherapeutic options.

      EFIRM is a signal amplification technology that allows direct detection of mutations in native plasma and saliva without amplification or sequencing. Previously published work demonstrated a near perfect correlation between biopsy and EFIRM results for the Exon19 del and p.L858R mutations in EGFR in late stage NSCLC patients. In this study we investigated the performance of EFIRM in patients early stage (I and II) NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Plasma samples were collected from 33 healthy controls with biopsy proven benign lung masses and 21 stage I and II NSLC patients with biopsy proven EGFR mutations The samples were immediately centrifuged and frozen. The samples were then blinded and sent for EFIRM analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 12 biopsies positive for p.L858R (11 stage 1 and 1 stage II) and 9 positive for Exon 19 del (7 stage 1A, and 2 stage II). Using statistically derived cut-offs to optimize sensitivity and specificity, there were 2 false positives (both for p.L858R) in the controls yielding an overall specificity of 91% for the 2 SNP Mutation assay. The sensitivity was 92% for the p.L858R with only one negative in 12 samples in a patient with stage 1 and 77% for Exon 19 del with 2 negatives in 9 samples in a single patient each for stage 1 and 2.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The preponderance of patients in this study had stage I NSCLC. The sensitivity of 94% and 77% respectively for the 2 most common mutations is remarkable for patients with Stage 1 lung cancer and a correspondingly low tumor burden and more importantly at a potentially curable stage. We are in the process of improving the technical performance of this assay and adding additional variants to the panel in order to increase clinical utility. These data are promising for the potential use of the EFIRM platform for the purposes of drug selection, disease recurrence, follow-up of indeterminate lung nodules from spiral CT screening programs, and / or population screening.

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      P1.11-14 - Radiological Pleura-Tumor Proximity in Pure-Solid Clinical Stage I Lung Cancer: Its Influence on Lymph Node Metastasis and Recurrence (ID 12206)

      16:45 - 18:00  |  Presenting Author(s): Toshiki Tanaka  |  Author(s): Kazuhiro Ueda, Junichi Murakami, Tamami Nakamura, Sota Yoshimine, Kimikazu Hamano

      • Abstract
      • Slides

      Background

      Lymph node metastasis of lung cancer is an important factor for deciding on surgical indications. Radiological pure-solid lung cancer is a highly aggressive feature, even in small lesions, and it is generally difficult to evaluate lymph node metastasis based on preoperative clinical examinations. We focused on the radiological association between the tumor and pleura and assessed the influence of pleura-tumor proximity on the risk of lymph node metastasis and postoperative recurrence.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed a consecutive series of 133 patients with clinical stage I lung cancer possessing pure-solid nodule on chest computed tomography who had undergone lobectomy with systematic lymph node dissection between January 2009 and December 2016. Figure shows the definition of positive pleura-tumor proximity. A multiple logistic regression analysis was used to identify the predictors for lymph node metastasis, and a multiple Cox proportional hazards model was used to identify the predictors for postoperative recurrence, with covariates of age, gender, performance status, resected side, pulmonary function, tumor size, pleural tag, pleura-tumor proximity, and maximum standardized uptake on positron emission tomography.

      figure.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      There were 89 men (mean age 70.7 ± 9.6 years). The mean tumor size was 22.9 ± 8.7 mm. Lymph node metastasis was found in 21 patients (15.7%), and postoperative recurrence was found in 24 patients (18%). According to the multivariate analysis, the age (p = 0.013) and positive pleura-tumor proximity (p = 0.036) were the independent predictive factors of lymph node metastasis, and the positive pleura-tumor proximity (p = 0.035) was an independent predictive factor of postoperative recurrence.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pleura-tumor proximity in radiological pure-solid lung cancer was associated with lymph node metastasis and postoperative recurrence. Such pleura-tumor proximity should therefore be taken into consideration in the therapeutic decision-making for stage I lung cancer possessing pure-solid nodules.

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      P1.11-15 - Application of Lung-RADS vs. PAN-CAN Nodule Risk Calculation in the Alberta Lung Cancer Screening Study (ID 13052)

      16:45 - 18:00  |  Presenting Author(s): Alain Tremblay  |  Author(s): Niloofar Taghizadeh, John-Henry Macgregor, Gavin Armstrong, Mike Bristow, Tracy Elliot, Lancia Guo, Andrew Lee, Carmen Lydell, Raoul Pereira, Paul Maceachern, Andrew Graham, James A Dickinson, Stephen Lam, Huiming Yang, Eric Bedard, Martin Tammemägi, Paul Burrowes

      • Abstract
      • Slides

      Background

      False positive or negative examinations and high early recall rates are important factors in the performance of lung cancer screening programs. How low-dose chest tomography (LDCT) scans are interpreted and classified may impact these metrics.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LDCT examinations for participants in the Alberta Lung Cancer Screening Study (ALCSS) were interpreted by chest radiologist with information entered in a synoptic report. Baseline scans were classified according to highest risk of malignancy nodule as per the PAN-CAN nodule risk calculator (NRC) and according to the Lung-RADS scheme. A positive scan was any baseline LDCT requiring any intervention beyond an annual screening examination (NRC nodule with ≥5% malignancy risk; Lung-RADS category ≥3). In the calculation of sensitivity, false negative scans could include reader error or classification errors (NRC <5% or Lung-RADS <3 but cancer present regardless of perceived appropriateness of resulting management).

      4c3880bb027f159e801041b1021e88e8 Result

      Seven hundred and seventy-six participants in the ALCSS underwent LDCT screening and had no prior chest CT imaging on file. Median follow-up was 572 days (+/-205) with lung cancer confirmed in 16 (2.1%) participants. The early recall rate was 9.0% for NRC and 11.2% for Lung-RADS (p=0.044), with fair concordance between each approach (kappa 0.554). Sensitivity for malignancy was 87.5% vs. 87.5% (difference 0%, 95%CI -0.44%-0.44%) and specificity 92.6% vs. 90.4% (difference 2.2%, 95%CI 0.2%-4.3%) for NRC and Lung-RADS respectively. False negative screens were due to reader error (same case in both systems); and classification error (one different case for each system).

      Cancer +

      Cancer -

      Total

      NRC +

      14

      56

      70

      NRC -

      2

      704

      706

      Lung-RADS +

      14

      73

      87

      Lung-RADS -

      2

      687

      689

      Total

      16

      760

      776

      8eea62084ca7e541d918e823422bd82e Conclusion

      Performance of both the NRC and Lung-RADS in the ALCSS was very good, with NRC resulting in a lower early recall rate. Application of the NRC demonstrated increased specificity over Lung-RADS without a change in sensitivity for lung cancer detection. Lung cancer program performance may be improved with the use of the PAN-CAN NRC classification.

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      P1.11-17 - Discriminating Less Invasive Lesions of Early-Stage Lung Adenocarcinoma by Three-Dimensional Computed Tomography Analysis (ID 11151)

      16:45 - 18:00  |  Presenting Author(s): Nobuyuki Yoshiyasu  |  Author(s): Fumitsugu Kojima, Kuniyoshi Hayashi, Toru Bando

      • Abstract
      • Slides

      Background

      In the revised TNM classification for non-small cell lung cancer, the clinical T factor is specified by the maximum diameter and by the diameter of the solid component for subsolid nodules. However, as radiological measurement of the solid part is sometimes difficult, errors can occur among observers. If less invasive lesions can be truly predicted using computed tomography (CT) images, it will be very useful for determining treatment strategies. Hence, we investigated the ability to detect less invasive lesions in pathologically early-stage adenocarcinomas by evaluating the whole tumor based on three dimensional (3D) images from high-resolution CT (HRCT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Among patients who underwent lung resections for primary lung cancer between February 2014 and December 2016 in our institution, we retrospectively reviewed 127 patients with pathological stage 0 or IA adenocarcinoma. All the lesions were divided into two groups: the less invasive group comprised adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), and the invasive group comprised invasive adenocarcinoma. Radiological occupied lesion volumes (cm3) were semi-automatically calculated using 3D-CT volumetry, which included the data of CT values and voxels. The following six factors were also evaluated using voxel-based histogram analysis (VHA): % solid (the ratio of the volume with CT values above -300 Hounsfield units to the whole CT value), mean CT values, variance, kurtosis, skewness, and entropy. Using multivariate logistic regression analysis, the relationship between these seven variables and pathological less invasive lesions were analyzed to prepare an optimal model for detecting the less invasive group.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 131 lesions, there were 39 lesions in the less invasive group (AIS/MIA = 16/23) and 94 in the invasive group. In univariate analysis, all the seven variables were significantly different between the two groups. Multivariate analysis using three variables revealed an odds ratio of 0.52 (95% confidence interval [CI]: 0.34-0.79, p = 0.002) for radiological lesion volume (cm3), 0.94 (95% CI: 0.89-0.99, p = 0.016) for % solid, and 1.58 (95% CI: 1.11-2.23, p = 0.01) for kurtosis. The optimal cut-off values were less than 8.2% for % solid, less than 5.8 cm3 for lesion volume, and greater than 3.6 for kurtosis. The area under the receiver operating characteristic curve was 0.92 (95% CI: 0.88-0.97) with the model, which achieved a 90% sensitivity and 84% specificity.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Semi-automated objective discrimination of less-invasive lung adenocarcinomas can be achieved with high accuracy using VHA based on 3D-HRCT.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.11-18 - A Classification-Based Machine Learning Method Reveals Exosomal miRNA Biomarkers for Patients with Pulmonary Ground Glass Nodule (ID 12462)

      16:45 - 18:00  |  Presenting Author(s): Jia-Tao Zhang  |  Author(s): Jia-Jia Xu, Jian Su, Rui Fu, Jun-Tao Lin, Ben-Yuan Jiang, Song Dong, Ri-Qiang Liao, Xue-Ning Yang, Hao Qin, Fu-Gen Li, Lei Xiong, Yi-Long Wu, Wen-Zhao Zhong

      • Abstract

      Background

      Non-invasive detection of lung cancer is of critical importance but has proven challenging due to the rate of false-negative diagnosis with current tests. Plasma exosomes have been implicated as a non-invasive diagnostic source. However, little high throughput screening has been done in the early-stage lung cancer and problems such as bias of enrollment, less rigorous identification exists. This study aimed to reveal the plasma exosome-derived miRNA biomarkers for early-stage lung cancer patients, especially those with ground glass nodule (GGN).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pre-operative and paired post-operative plasma samples from patients with solitary pulmonary nodule and healthy volunteers were prospectively collected. Finally 38 malignant nodules, 7 benign nodules and 5 healthy volunteers were enrolled. The malignant nodules included 9 pure GGNs, 11 mixed GGNs and 18 solid nodules. Exosomes were collected from 1mL plasma and were isolated with 3D Medicine EV isolation kit. Exosomal miRNA profiling was performed using miRNA-seq. And an exosomal miRNA diagnostic model for patients with malignant nodules was constructed by using support vector machine (SVM).

      4c3880bb027f159e801041b1021e88e8 Result

      In general, malignant nodules, benign nodules and healthy volunteers were indistinguishable based on overall clustering. Regarding to malignant nodules, pure GGNs and solid nodules could be separated under principal component analysis (PCA), and the mixed GGNs presented a transitional state between the pure GGNs and the solid nodules. Ultimately, a two-dimensional SVM diagnostic model for discriminating malignant and benign nodules was established. The optimal miRNA combination could reach an area under curve (AUC) of 0.96, with sensitivity and specificity of 94.7% and 91.7%, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This preliminary analysis highlights the potential of exosomal miRNA based liquid biopsy for non-invasive detection of early-stage lung cancer. The SVM model seems could effectively distinguish pulmonary nodules, but needs further verified.

      fig.png

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.11-19 - Expression of TNFRII in Serum is Correlated with the Significant Risk of Subcentimeter Lung Adenocarcinoma (ID 12954)

      16:45 - 18:00  |  Presenting Author(s): Yanwei Zhang  |  Author(s): Xueyan Zhang, Yuqing Lou, Tianqing Chu, Baohui Han

      • Abstract
      • Slides

      Background

      With the rapid advances of low-dose computed tomography (LDCT) screening for lung cancer, the opportunity to detect subcentimeter non-small cell lung cancer (NSCLC) is gradually increasing. The results of many previous studies have shown that even subcentimeter NSCLCs are not always in the early stage. Thus, it is quite important for us to judge the possibility of malignancy for these patients, even the tumor size is less than 10mm. However, subcentimeter lung cancer is hard to diagnose only via biopsy and imaging features because of its tinny size. Chronic inflammation is well established as a hallmark in lung carcinogenesis. In our previous study, B lymphocyte chemoattractant (BLC), is found to be slightly associated with the risk of subcentimeter lung adenocarcinoma. The aim of the present study is to evaluate the correlation between TNF receptor type II (TNFRII) and the risk for subcentimeter lung adenocarcinoma, and the efficacy of diagnosing subcentimeter lung cancer after combining TNFRII and BLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Inflammatory biomarkers were measured in 71 subcentimeter lung adenocarcinoma patients and 71 age-, sex- and smoking-matched healthy controls by using the Luminex bead-based assay.

      4c3880bb027f159e801041b1021e88e8 Result

      The mean (standard deviation or SD) age of patients was 56.01 (8.91) years, and 73.20% of them were female patients (n=52). Never smokers accounted for 85.96% of patients (n=57). The expression level of TNFRII is significantly down-regulated in subcentimeter lung adenocarcinoma patients compared with the healthy controls (P<0.001). And the results were validated by oncomine data mining analysis.

      Elevated levels of TNFRII were associated with an 89% reduced risk for subcentimeter lung adenocarcinoma. (OR=0.11, 95% CI: 0.04-0.30, P=2.4*10-5). BLC was associated with a 2.70-fold (95% CI: 1.31-5.58, P=7.0*10-3) increased risk of subcentimeter lung adenocarcinoma for the comparison of patients in the higher-level group with the lower-level group. To yield more information, the BLC/TNFRII ratio was created to examine their prediction for the risk of subcentimeter lung adenocarcinoma, and as expected there was a 35- fold increased risk for patients in the higher-level group relative to patients in the lower-level group. Further ROC curve analysis revealed that TNFRII was a significant diagnostic biomarker for subcentimeter lung adenocarcinoma, with the area under the curve of 0.73 (95% CI: 0.65-0.82, P=2.0*10-6). The sensitivity, specificity and accuracy were 0.75, 0.72 and 0.73, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings demonstrated that TNFRII was associated with the significant risk of subcentimeter lung adenocarcinoma, and could be a promising biomarker for accessorily diagnosing subcentimeter lung adenocarcinoma.

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      P1.11-19a - Gender Comparison in Lung Cancer Screening (ID 13069)

      16:45 - 18:00  |  Presenting Author(s): Simran K Randhawa  |  Author(s): Shelby Rebecca Sferra, Grace X Ma, Verdi Disesa, Larry R Kaiser, Cherie Parungo Erkmen

      • Abstract
      • Slides

      Background

      Persistent underrepresentation of females in lung cancer screening (LCS) trials has raised concerns regarding the accurate perception of differences between the sexes and its generalizability. We examined a balanced cohort of men and women undergoing LCS with the hypothesis that gender does not affect the ability of LCS to successfully detect early-stage lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In an urban, academic medical center, we prospectively collected data on patients referred for LCS from June 2015 to May 2017. We compared age, ethnicity, level of education and smoking history and outcomes of LDCT between men and women. We also measured treatment and complications.

      4c3880bb027f159e801041b1021e88e8 Result

      Two hundred and thirty-six patients underwent LCS. 115 (48.7%) were females and 121 (51.3%) were males. Age did not significantly differ between females (63±5.19) and males (63.93±5.56; p=0.187). There was no gender difference amongst the distribution of ethnicity, education or smoking with 77 (67%) females and 70 (57.9%) males being active smokers (p=0.149). There was a significant difference in the pack years smoked between males (54.8±35.6) and females (43.88±15.54; p=0.024). There was no gender difference in the distribution of LDCT results. 41 (35.7%) females and 56 (46.3%) males diagnosed with Lung-RADs 1, 57 (49.6%) females and 48 (39.7%) males with Lung-RADs 2, 5(4.3%) females and 6 (4.9%) males with Lung-RADs 3 and 8 (6.9%) females and 7 (5.8%) males with Lung-RADs 4 (p=0.542). Three females and 2 males were diagnosed with lung cancer. 4 patients (2 females and 2 males) were treated with surgery and 1 female underwent radiation therapy, all without complications or death.

      iaslc table 2.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study of LCS demonstrates the equal participation of men and women. Gender did not impact early detection and successful treatment of lung cancer. This is an opportunity to advocate for enhanced female participation in LCS research to provide meaningful guidance to women and their physicians.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 944)

    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 23
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.12-01 - A Single-Arm Multi-Center Phase II Study of Apatinib in Patients with ES-SCLC After Second/Third-Line Chemotherapy (ID 12960)

      16:45 - 18:00  |  Presenting Author(s): Yun Fan  |  Author(s): Zhiyu Huang, Wenfeng Li, Yuping Li, Jun Chen, Yanjun Xu, Hongyang Lu, Xinmin Yu, Yu Jin Xu, Jing Qin, Ying Jin, Xiaoling Xu, Lei Gong, Fajun Xie, Na Han, Peng Zhang, Kaiyan Chen

      • Abstract
      • Slides

      Background

      The survival of patients (pts) with extensive-stage small-cell lung cancer (ES-SCLC) was poor. And the standard treatment strategies have not yet been established for those who failed from second/third-line chemotherapy. Apatinib, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been shown anti-cancer activity and manageable toxicities in several solid cancers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A single-arm multi-center phase II study was designed to determine the efficacy and safety of apatinib in pts with ES-SCLC after second/third-line chemotherapy (clinical trial information: NCT02945852). The inclusion criteria mainly included aged 18-75 years; pathologically confirmed SCLC; received chemotherapy with two or three regimens previously, including first-line platinum-based regimen. Pts were treated with afatinib 500 mg/day p.o. until tumor progression or lack of tolerability. One treatment cycle was 28 days long. The full analysis set included patients who received at least one cycle of treatment. Treatment interruptions or dose reductions were allowed when grade 3 hematologic or grade 2 nonhematologic toxicities occurred. The primary endpoint is progression-free survival(PFS); secondary endpoint includes the safety of afatinib, overall survival (OS), objective response rate (ORR) and disease control rate (DCR).

      4c3880bb027f159e801041b1021e88e8 Result

      As of Mar 2018, 40 pts from 3 institutions were recruited into the trial. Median age was 60 years, and 37 pts were male (92.5%). 17/40 (42.5%) pts experienced dose reduction or treatment interruptions. Followed up to Apr 26, 2018, the median during time of afatinib treatment was 80 days and 36 pts were eligible for assessing tumor responses. In the 36 pts, 8 (22.2%) pts achieved partial responses [PR], 20 (55.5%) pts achieved stable disease [SD] and 8 (22.2%) pts were assessed as progressive disease [PD]. The ORR was 22.2% (8 pts PR) and the DCR was 77.8% (8 pts PR, 20 pts SD). During the follow-up, a total of 25 pts died. The median PFS and OS was 86 days and 105 days, respectively. The most common adverse events were anemia (69.4%, 25/36), hand-foot syndrome (61.1%, 22/36), urine protein (55.6%, 20/36), hypertension (52.8%, 19/36) and fatigue (44.4%, 16/36). The related grade 3-4 toxicities included hypertension (47.2%, 17/36), hand-foot syndrome (5.6%, 2/36), Oral ulcer (5.6%, 2/36) and elevated aminotransferase (5.6%, 2/36).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this prospective phase II trial, apatinib showed encouraging durable response rates and survival in patients with ES-SCLC after second/third-line chemotherapy, with an acceptable safety profile.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-02 - Phase II Study of Amrubicin Monotherapy in Elderly or Poor-Risk Patients with Extensive Disease of Small Cell Lung Cancer (ID 11133)

      16:45 - 18:00  |  Presenting Author(s): Satoshi Igawa  |  Author(s): Tomoya Fukui, Masayuki Shirasawa, Takahiro Ozawa, Hideyuki Sone, Seiichiro Kusuhara, Noriko Nishinarita, Yasuhiro Hiyoshi, Masaru Kubota, Hisashi Mitsufuji, Jiichiro Sasaki, Masato Katagiri, Katsuhiko Naoki

      • Abstract

      Background

      Previous study indicated that an optional anti-cancer drug for the treatment in pretreated patients with small-cell lung cancer (SCLC) is amrubicin. However, no prospective studies have evaluated amrubicin in chemo-naive elderly or poor-risk patients with SCLC. Therefore, this study aimed to evaluate the efficacy of amrubicin as first-line chemotherapy for elderly or poor-risk patients with extensive-disease SCLC (ES-SCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with chemotherapy-naive ES-SCLC received multiple cycles of 40 mg/m2 amrubicin for 3 consecutive days every 21 days. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Between March 2011 and August 2015, 36 patients were enrolled in this study. Each patient received a median of four treatment cycles (range, 1–6 cycles). ORR was 52.8% [95% confidence interval (CI), 37–69%]. The median PFS and OS periods were 5.0 months (95% CI, 3.4–6.6 months) and 9.4 months (95% CI, 5.2–13.6 months), respectively. Neutropenia was the most common grade 3 or 4 adverse event (69.4%), with febrile neutropenia developing in 13.9% of patients. No treatment-related death occurred. At the time of starting second-line chemotherapy, 19 of 22 patients (86%) had significantly improved or maintained their performance status (PS) relative to their PS at the time of starting amrubicin monotherapy as first-line chemotherapy (P = 0.027).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The results of the present study suggest that amrubicin could be considered as a viable treatment option for chemotherapy-naive elderly or poor-risk patients with ES-SCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-03 - A Prospective Study of Apatinib in Advanced Small Cell Lung Cancer Patients Failed from Two or More Lines of Chemotherapy (ID 13140)

      16:45 - 18:00  |  Presenting Author(s): Yutao Liu  |  Author(s): Xingsheng Hu, Shengyu Zhou, Junling Li, Peng Liu, Yan Wang, Xueyu Hao, Yuankai Shi, Jun Jiang

      • Abstract
      • Slides

      Background

      Small lung cancer (SCLC), a highly malignant neoplastic, chemoresponsive disease. For SCLC patients who with worsening status after second-line treatment, there is currently no affirmative and widely accepted chemotherapy regimen. Apatinib is a novel oral multi-target small-molecule TKI mainly targeting the intracellular ATP-binding domain of VEGFR-2, which has a significant effect of anti-angiogenesis to suppress the growth of tumors. This study evaluated the efficacy and safety of Apatinib in SCLC patients who failed from second- or further-line chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data was collected from the files of patients treated with Apatinib 500mg qd who diagnosed with advanced SCLC and failed from second or more lines of chemotherapy. Efficacy assessed after one cycles (4 weeks), then every two cycles (8 weeks) once again. The primary endpoint was PFS and the tumor response was determined according to the RECIST 1.1. PFS were graphed by Kaplan-Meier curves of progression-free survival. AEs were also evaluated and toxicity grade was determined based on CTCAE 4.0.

      4c3880bb027f159e801041b1021e88e8 Result

      22 patients were enrolled from November 10, 2016 to April 18, 2018, the number of patients that can be evaluated is 19. One patients obtained partial response, and 15 obtained stable disease, representing a DCR of 84.11%. Median PFS was 140 days (95% confidence interval [CI] 94.84–185.16). Although only one patient showed PR, all the patients’ target lesions were reduced. A total of 46 AEs were reported during the trial, grade 3-4 AEs were hypertension (9.09%), leukopenia (4.55%) and proteinuria (4.55%) which most could be relieved by dose reduction. figure 1..jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, Apatinib has a certain therapeutic effect in patients with advanced SCLC (third- or further-line). To further investigate the role of Apatinib in advanced SCLC patients, large sample and additional clinical trials are needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-04 - A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients (ID 12119)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu  |  Author(s): Liyan Jiang, Xinghao Ai, Junling Li, Xiaorong Dong, Dan Zhang, Qi Liu

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-05 - Efficacy of Perioperative Chemotherapy for High-Grade Neuroendocrine Tumors (ID 13135)

      16:45 - 18:00  |  Presenting Author(s): Hiroyuki Ogawa  |  Author(s): Yugo Tanaka, Yoshitaka Kitamura, Hiroki Tanaka, Yuuki Nishioka, Shinya Tane, Wataru Nishio, Yoshimasa Maniwa, Masahiro Yoshimura

      • Abstract
      • Slides

      Background

      Large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are categorized as high-grade neuroendocrine tumors (HGNECs). There have been few studies to show the efficacy of perioperative chemotherapy for HGNEC as a single entity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the medical records of patients who underwent tumor resection and were diagnosed with HGNECat Hyogo Cancer Center (Akashi, Japan) and Kobe University Hospital (Kobe, Japan)between January 2001 and December 2016. Overall survival (OS) was estimated by the Kaplan–Meier method. Multivariate analyses using a Cox proportional hazards model were performed to search for prognostic factors for HGNEC. Propensity score matching was performed to compare the OS between the treatment groups.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 197 patients who underwent surgery and who were diagnosed with HGNEC. Forty-three patients were excluded for the following reasons: pathological stage 4 or incomplete resection (n=25), synchronous multiple cancers (n=14), and insufficient medical records (n=5) We finally analyzed 153 HGNEC patients (LCNEC n=95, SCLC n=58). Seventy patients (LCNEC n=34, SCLC n=36) received perioperative chemotherapy. All of them received a platinum-based anticancer drug, and 80% received combined treatment with irinotecan or etoposide (n=56). The 5-year OS rates of the surgery plus chemotherapy and surgery alone groups were 75.5% and 34.7% (P<0.01), respectively. The HR for death in the surgery plus chemotherapy group was 0.34 (95% CI 0.20-0.56; P<0.01) in comparison to the surgery alone group. The multivariate analysis revealed that perioperative chemotherapy (HR 0.30, P<0.01), sublobar resection (HR 2.04, P=0.04), and lymph node metastasis (HR 3.54, P<0.01) were independently associated with survival. After adjustment for the patients’ background characteristics by propensity matching, the 5-year OS rates of the surgery plus chemotherapy group were significantly higher than those of the surgery alone group (78.7% and 32.9%; P < 0.01). The HR for death in the surgery plus chemotherapy group was 0.33 (95% CI 0.15-0.68; p<0.01) in comparison to the surgery alone group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Surgical resection combined with perioperative chemotherapy was considered to be effective for HGNEC. Sublobar resection might increase the risk of death in HGNEC patients. Therefore if the general condition of the patient permits, perioperative chemotherapy should be performed, and the extent of resection in the treatment of HGNEC should be lobectomy or more.

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      P1.12-06 - Pulmonary Neuroendocrine (Carcinoid) Tumors: CommNETs/NANETS Endorsement and Update of the ENETs Best Practice Consensus (ID 13029)

      16:45 - 18:00  |  Presenting Author(s): Simron Singh  |  Author(s): Emily K. Bergsland, Cynthia M. Card, Thomas A. Hope, Pamela L. Kunz, David T. Laidley, Ben Lawrence, Simone Leyden, Michael Michael, Lucy E. Modahl, Sten Myrehaug, Sukhmani Kaur Padda, Rodney F. Pommier, Robert A Ramirez, Michael Soulen, Jonathan Strosberg, Alia Thawer, Benjamin Wei, Bin Xu, Eva Segelov

      • Abstract

      Background

      The lung is the most common single site of origin of neuroendocrine cancers, and lung neuroendocrine tumor (LNET) incidence and prevalence is rising. There is a lack of both LNET-specific data and up to date clinical guidance. Management of LNETs often relies on extrapolation from other tumor sites. The Commonwealth Neuroendocrine Tumour Collaboration (CommNETS) and North American Neuroendocrine Tumor Society (NANETS) sought to consider current data and provide updated guidance on LNET diagnosis and management.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The latest best practice consensus on LNETs was published by the European Neuroendocrine Tumor Society (ENETS) in 2015. A review of content and methods using the AGREE II Rigour of Development subscale (www.agreetrust.org) confirmed the quality of the ENETS initiative, providing a basis for endorsement and update. A systematic literature search was conducted and a 22 member, multidisciplinary CommNETS/NANETS expert panel endorsed or modified recommendations from a patient-centered perspective. All statements were graded using Oxford criteria (CEBM.net).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 230 studies were identified for consideration by the panel. Recommendations were modified or added to reflect clinical data not available in 2015. Out of the 52 ENETS statements, 40% were endorsed, 58% were modified or updated, one was removed and four were added. Themes identified in the consensus update include new statements, practice changing modifications, augmented grades of recommendation and statement refinements, each addressing specialties ranging from epidemiology, pathology and diagnosis to treatment and follow-up (Table 1). The importance of LNET directed research and patient-centered care throughout the treatment trajectory is also emphasized, along with directions for future research.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Ongoing collaboration is essential for future development of updated LNET clinical guidance and to direct research efforts in a patient-centered context. Our consensus update demonstrates international collaboration to develop guidance on clinical management of malignancies for which limited data are available.

      Table 1. Themes in CommNETS/NANETS Lung NET Consensus Update

      New statements

      Epidemiology

      Highlights marked increase in the incidence and prevalence of lung NETs

      Radiation Therapy

      Guidance on use of palliative EBRT for patients with symptomatic locally advanced or metastatic disease

      Medical Therapy

      Recommendation of pre-surgical prophylaxis with SSAs for patients with carcinoid syndrome

      Indicates lack of benefit of anti-angiogenics in lung NET

      Practice changing statement modifications

      Diagnosis

      Indicates limited clinical value of chromogranin A in lung NET diagnosis and disease state characterization

      Surgery

      Indicates that cytoreductive surgery of the liver may be expanded to patients with non-aggressive tumors, including those with more limited extra-hepatic disease

      Statements with augmented recommendations

      Surgery

      The grades of recommendation for complete anatomic resection and systematic nodal dissection for peripheral tumors and for preference of lung parenchymal-sparing surgery over pneumonectomy were each augmented to Grade B

      Medical Therapy

      The grades of recommendation for PRRT and mTOR inhibitors statements were augmented to Grades B and A, respectively

      Statement refinements

      Pathology

      Refined to reflect new standards for classification (WHO 2015) and staging (UICC/AJCC 8th edition)

      Tailored to highlight need for endobronchial biopsy or surgical resection for sufficient sampling to differentiate TC from AC

      Diagnosis

      Radiological imaging statements were modified to simplify guidance and clarify differences in requirements for diagnostic compared to liver imaging, and to guide application of various nuclear imaging techniques

      Bronchoscopy statements were simplified to highlight efficacy and safety of bronchoscopy

      Surgery

      Surgery for localized disease statements modified to reflect equivalence of sublobar resection and lobectomy, especially for typical carcinoid tumors

      Endobronchial resection statements were revised to reflect need to limit procedure to high risk patients or as a bridge to surgery

      Medical Therapy

      Follow-up statement was revised to better define and direct post-treatment surveillance for lung NETs patients who receive medical therapy

      AC; atypical carcinoid; EBRT, external beam radiotherapy; NET, neuroendocrine tumor; PRRT, peptide receptor radionuclide therapy; SSA; somatostatin analog; TC, typical carcinoid

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-06a - Rovalpituzumab Tesirine Maintenance Therapy Following 1st Line Platinum‑Based Chemotherapy in Small Cell Lung Cancer (ID 13432)

      16:45 - 18:00  |  Presenting Author(s): Philip Komarnitsky  |  Author(s): Ho-Jin Lee, Manan Shah, Shekman Wong, Sanja Gauthier, Juliann Dziubinski, Stacy Osbaugh, Fan Zhang

      • Abstract
      • Slides

      Background

      Small Cell Lung Cancer (SCLC) embodies 15-20% of lung cancers. Patients are staged with either limited or extensive disease (ED); the standard front-line treatment for the latter is chemotherapy with carbo- or cisplatin combined with etoposide or irinotecan. Response rates are high with limited duration. Recurrence may be attributable to chemo-resistant tumor initiating cells (TICs). Delta-like protein 3 (DLL3) is an inhibitory Notch receptor ligand identified as a novel target in SCLC TICs. DLL3 is highly expressed in SCLC but not normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate composed of a DLL3-targeting IgG1 monoclonal antibody tethered to a DNA cross-linking toxin. Rova-T has shown activity in recurrent/relapsed ED SCLC patients1. Given DLL3 expression in TICs, exploration of Rova-T front-line maintenance strategies in ED SCLC is warranted. The postulated mechanism of action of Rova-T and its clinical activity indicate potential to improve progression-free and overall survival in this setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a Phase 3, randomized, double-blind, placebo-controlled, international study (NCT03033511, no patients enrolled yet as of 7 February 2017). Approximately 740 ED SCLC patients will be enrolled to include ~480 patients with high DLL3 expression. Eligibility: patients ≥ 18 years; histologically or cytologically confirmed ED SCLC with ongoing clinical benefit (complete/partial response or stable disease) after 4 cycles of 1st line platinum-based therapy; definitively treated CNS metastases allowed; > 3 but ≤ 9 wks between the administration of the last cycle of platinum-based chemotherapy and randomization; available tumor tissue for DLL3 expression testing; ECOG performance score 0-1. Patients will be randomly assigned 1:1 to receive 0.3 mg/kg Rova-T or placebo on Day 1 of each 6-wk cycle, omitting every 3rd cycle. Primary objectives: determine if Rova-T improves progression-free and overall survival. Secondary objectives: assess Rova-T antitumor activity by determining objective response rate, clinical benefit rate, duration of response, and changes in patient reported outcomes.

      1. Rudin et al., Lancet Oncol, 2016.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-06b - Rovalpituzumab Tesirine vs Topotecan in Patients with Advanced Small Cell Lung Cancer Following 1st Line Chemotherapy (ID 13438)

      16:45 - 18:00  |  Presenting Author(s): Philip Komarnitsky  |  Author(s): Ho-Jin Lee, Manan Shah, Shekman Wong, Scott Gulbranson, Juliann Dziubinski, Laura Caffrey, Poonam Tanwani, Monica Motwani, Fan Zhang

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) represents ~15% of lung cancers. Standard therapy most often consists of a platinum-based therapy + a second agent (etoposide). Initial response rates are high but not durable. Treatment for relapsed patients is limited, but includes topotecan. However, efficacy of topotecan is suboptimal and there is a high unmet need in this population. Delta-like protein 3 (DLL3) is an atypical Notch receptor family ligand identified as a target in SCLC and neuroendocrine carcinomas (NECs). DLL3 is highly expressed in SCLC and NECs but not normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate composed of a DLL3-targeting IgG1 monoclonal antibody tethered to a toxic DNA crosslinker. Rova-T has antitumor activity in relapsed SCLC patients, and was well-tolerated1. Thus, we are investigating Rova-T vs topotecan as a 2nd line therapy in advanced SCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a Phase 3, randomized, open-label, multicenter study (NCT03061812) to assess efficacy, safety, and tolerability of Rova-T vs topotecan. Approximately 411 patients will be enrolled and randomized 2:1 between 2 arms. Arm A regimen: 0.3 mg/kg Rova-T intravenous (IV) on Day 1 + 8 mg dexamethasone orally, twice daily on Day -1, 1 and 2 of a 42-day cycle; administered for 2 cycles with up to 2 additional cycles permitted. Arm B: 1.5 mg/m2 topotecan (or per local label) IV on Days 1-5 of each 21-day cycle; administered until disease progression. Patient eligibility: ≥ 18 years; confirmed, advanced/metastatic SCLC with first disease progression following frontline standard therapy; DLL3-high tumor expression; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug or topotecan, irinotecan, or other topoisomerase I inhibitor. Efficacy endpoints include progression free survival, overall survival, objective response rate, duration of response, and patient-reported outcomes.

      1. Rudin et al., Lancet Oncol, 2016.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-07 - Time to the End of Thoracic Radiotherapy Affects to Survival Outcomes Greater than Radiation Dose in Limited Stage Small Cell Lung Cancer (ID 13607)

      16:45 - 18:00  |  Presenting Author(s): Sung-Ja Ahn  |  Author(s): Jae-Uk Jeong, Wan Jeon, Young-Chul Kim, In-Jae Oh, Cheol-Kyu Park, Mee Sun Yoon, Ju-Young Song, Taek-Keun Nam, Woong-Ki Chung

      • Abstract
      • Slides

      Background

      Early thoracic radiotherapy (TRT) concurrent with chemotherapy and radiation doses of 45 Gy given 1.5 Gy bid still has taken a seat as a standard treatment option for limited-stage small cell lung cancer (LS-SCLC). We aim to search the association between radiation parameters and survival outcomes in LS-SCLC patients who undertaken more than 45 Gy of TRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      One hundred and one patients with LS-SCLC who completed TRT between August 2005 and March 2014 were reviewed retrospectively. Median age was 64 years (43-80) and male to female was 88 vs. 13. Stage IIIA was 30 and IIIB was 55, respectively. TRT was performed using 3-dimensional conformal radiation therapy (3DCRT) and delivered using 2Gy single fraction per day in 73.2% of patients. The median dose TRT was 50 Gy (45-65), and all patients received concurrent chemoradiotherapy. PCI was combined in 56 (55.4%) patients.

      4c3880bb027f159e801041b1021e88e8 Result

      The median survival for all patients was 26.9 months. Local failure occurred in 41 patients (40.5%), and distant metastasis was noted in 54 patients (53.4%). The 3-year local control, progression-free survival (PFS), and overall survival (OS) rates were 52.0%, 29.5%, and 56.4%, respectively. On univariate analysis, the American Joint Committee on Cancer stage (p<0.001), timing of TRT (≤2 vs, >2 cycles, p=0.017), tumor response (CR vs. PR, p=0.015), the duration from the start date of chemotherapy to the end of TRT (SER) (≤70 vs >70 days, p=0.025), and PCI (p=0.003) were the significant predictors of OS and stage (p<0.001) and PCI (p=0.017) were the significant predictors in PFS. Multivariate analysis revealed that stage (hazard ratio [HR], 3.61; 95% CI, 2.15-6.07) was the only significant factor in PFS and stage (HR, 2.49; 95% CI, 1.56-3.98), SER (HR, 1.93; 95% CI, 1.22-3.07), PCI (HR, 0.52; 95% CI, 0.33-0.84), and tumor response (HR, 1.76; 95% CI, 1.12 – 2.77) were the significant predictors in OS. There was one fatal radiation pneumonitis. Grade 3 radiation pneumonitis and esophagitis was shown in 7 (6.9%) vs. 7 (6.9%) patients, respectively. Grade 3 and 4 leukopenia was shown in 30 (29.7%) vs. 11 (10.8%) patients and febrile neutropenia was 9 (8.9%) vs. 1 (0.9%) patients, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      SER less than 70 days was a significant predictors of OS in LS-SCLC patients who received more than 45 Gy of TRT concurrently with chemotherapy. We could not find any significant positive survival benefits of TRT dose or BED escalation in our patients groups.

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      P1.12-08 - The Effect of Cisplatin Versus Carboplatin on Cancer Outcomes for Small Cell Lung Cancer Patients in a Population-Based Cohort (ID 14373)

      16:45 - 18:00  |  Presenting Author(s): David E Dawe  |  Author(s): Trevor Aquin, Shantanu Banerji, Oliver Bucher

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) is associated with high rates of mortality and treatment involves chemotherapy. In non-small cell lung cancer, using cisplatin results in superior response and survival compared to carboplatin, but causes more toxicity. Little research regarding this drug choice in SCLC exists, but available studies suggest equivalent survival. Nevertheless, many oncologists continue to use cisplatin preferentially.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using the population-based Manitoba Cancer Registry, we identified SCLC cases diagnosed from 2004 to 2013 in Manitoba and completed a retrospective chart review for those treated with chemotherapy. Demographics, tumour response, and treatment toxicity were compared between cisplatin and carboplatin treated groups. Overall survival (OS) and progression free survival (PFS) were evaluated using multivariate Cox proportional hazard methods. Likelihood of completing chemotherapy (at least 4 cycles) was assessed using multivariable logistic regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 531 patients identified, 139 (26.2%) received carboplatin and 392 (73.8%) received cisplatin as part of first line chemotherapy. More patients who received carboplatin had poor performance status (13.7% v 7.4%), elevated LDH (58.3% v 42.3%), and extensive stage disease (69.8% v 54.1%), all p<0.01. Unadjusted median OS was 224 v 322 days for carboplatin and cisplatin. Multivariable adjusted analysis for OS using cisplatin patients not completing treatment as the reference comparator showed hazard ratios for carboplatin completers – 0.65 (0.43-0.98), cisplatin completers – 0.69 (0.47-1.00), and carboplatin incompleters – 1.00 (0.64-1.55), p = 0.13. For PFS carboplatin completers – 1.07 (0.60-1.90), cisplatin completers – 0.83 (0.51-1.36), and carboplatin incompleters – 0.96 (0.64-1.46), p = 0.59. There was not significant difference between carboplatin and cisplatin in likelihood of completing chemotherapy, when adjusted for other patient characteristics - 0.75 (0.47-1.22), p=0.26 Those treated with carboplatin had significantly less neutropenia (57.6% v 74.7%), nephrotoxicity (2.9% v 13.5%), neurotoxicity (0.7% v 12.0%), and nausea/vomiting (28.1% v 42.6%) associated with treatment, all p<0.01.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a real world, population-based setting, carboplatin appears to be an equally effective treatment option for SCLC, facilitating equivalent survival while avoiding toxicity. Clinicians may wish to re-examine their preference for cisplatin.

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      P1.12-09 - The Effect of Site of First Chemotherapy on Small Cell Lung Cancer Patient Outcomes (ID 13082)

      16:45 - 18:00  |  Presenting Author(s): David E Dawe  |  Author(s): Rebekah Rittberg, Trevor Aquin, Susan Green, Oliver Bucher, Shantanu Banerji

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) ischaracterized by a rapid doubling time and high responsiveness to chemotherapy (CT) with a rapid relapse. Due to the sensitivity of SCLC to CT, it is one of the few malignancies treated in acutely ill patients admitted to hospital with a poor performance status (PS). However, there is little available information on the outcomes and toxicity experienced by patients with SCLC who require initial CT as an inpatient.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort study was conducted evaluating patients consecutively diagnosed with SCLC in Manitoba from 2004 to 2013 treated with platinum-doublet CT. Patient demographics, staging, treatment, CT toxicities, Eastern Cooperative Oncology Group(ECOG) PS, treatment response, and survival were collected using the Manitoba Cancer Registry and chart review. Outcomes of progression free survival (PFS) and overall survival (OS) were evaluated based on site of first CT (inpatient versus outpatient) and PS.

      4c3880bb027f159e801041b1021e88e8 Result

      530 patients received CT for SCLC with 82 patients (15%) receiving their first CT as an inpatient. Sixty-three percent of inpatients received the full CT course, compared to 81% of outpatients, (p=0.0006). Outpatients had a greater likelihood of responding to CT (p=0.0043). Neutropenia, febrile neutropenia, thrombocytopenia, nephrotoxicity and fatigue were all experienced less often by the inpatient cohort, (p<0.0001), (p=0.0040), (p<0.0001), (p<0.0001) and (0.0068). For inpatients, OS at 12, 24 and 60 months was 22%, 9% and 7%, versus outpatient OS of 43%, 20% and 9%, (each p<0.0001). Median PFS and OS were longer for outpatients, 212 versus 161 days, (p=0.0035) and 321 versus 192 days, (p=0.0003). Patients with poorer ECOG PS had shorter PFS and OS; with a median PFS for PS 0, 1-2, 3-4 of 316, 203 and 147 days, (p<0.0001) and median OS for PS 0, 1-2 and 3-4 of 498, 303 and 179 days, (p<0.0001). On multivariate analysis, ECOG PS was an independent predictor of outcome, (p=0.0005) while site of first CT was not significant when ECOG PS was included, (p=0.3494).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although SCLC patients initially treated as inpatients had shorter PFS and OS, some experienced long term survival, including a 7% five-year survival. CT toxicities were not more common for inpatients. This validates that administration of CT in hospital can be considered as these patients may have a meaningful long-term response to therapy if properly selected. As previously identified in the literature, this data demonstrated that patients with poorer ECOG PS have shorter PFS and OS.

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      P1.12-10 - Patterns of Curative Chemo-Radiotherapy Regimen and Impacts on the Outcome of Limited Stage SCLC in a Canadian Institution: 2010 – 2015 Diagnoses (ID 13367)

      16:45 - 18:00  |  Presenting Author(s): Anifat A. Elegbede  |  Author(s): Michelle Dean, Gwyn Bebb

      • Abstract
      • Slides

      Background

      Curative intent chemotherapy and radiotherapy (ChemoRT) is the widely recommended treatment for limited stage (LS) small cell lung cancer (SCLC) follow by prophylactic cranial irradiation (PCI) in those who responded to the initial therapy. LS-SCLC is however characterized by high relapse rate with only about 20% surviving to 2 years. Our objective is to examine the characteristics, treatment patterns and overall survival of LS-SCLC for patients diagnosed within a 5-year period at the Tom Baker Cancer Centre, Canada, prior to wide adoption of emerging treatment options including surgery and immunotherapy in the curative and palliative settings respectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using the Glans-Look Lung Research (GLR) database, we defined the clinical and demographic features of patients diagnosed with LS-SCLC from 2010 to 2015, determined the rate of systemic treatment uptake, and investigated the impact of PCI, curative intent, and palliative treatments on overall survival. We summarized our findings with descriptive statistics (including Fisher’s Exact test) and Kaplan Meier survival curves using SPSS. Statistical significance was set at p value < 0.05 and 95% confidence intervals.

      4c3880bb027f159e801041b1021e88e8 Result

      About a third (107/349, 31%) of patients diagnosed with SCLC from 2010 to 2015 were LS-SCLC, with median age of 67 years. Over the 5-year period, systemic treatments uptake rates and patterns fluctuates. Overall, > 50% received ChemoRT and 65% of the ChemoRT group also received PCI. Curative concurrent RT dose 45 – 55Gy, 25 fractions schedule was more common (55%). Few stage T1a-2a, N0-1 LS-SCLC had surgery (5%). Thirty eight percent of those who received initial curative intent treatments further received some palliative treatments for disease recurrence or progression {8% (2/26) initial Surgery ± Adjuvant & 92% (24/26) ChemoRT}. The median overall survival for the cohort was 24 months (p < 0.001). There were more than 50% survival at 60 months for patients treated with curative 15 fractions concurrent ChemoRT (p < 0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Most patients received ChemoRT while a few had surgery. Concurrent 15 fractions ChemoRT may offer better survival benefits than the 25 fraction schedule. The impact of PCI on LS-SCLC and other survival outcomes will be presented.

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      P1.12-11 - 2010 – 2015 Extensive Stage SCLC Diagnoses in a Canadian Institution: Baseline Characteristics That Impact on the Overall Survival (ID 13430)

      16:45 - 18:00  |  Presenting Author(s): Anifat A. Elegbede  |  Author(s): Michelle Dean, Gwyn Bebb

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) represents only about 13 – 15% of lung cancers but has posed significant challenges due to minimal progress in therapeutics development prior to the recent advent of immunotherapy. Our objective is to establish baseline characteristics and overall survival of Extensive SCLC (ES-SCLC) based on the current conventional therapy for patients diagnosed within a 5 year period at the Tom Baker Cancer Centre, Canada. This information will be crucial in assessing the effectiveness of novel anti-immune checkpoint treatment strategies.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using the Glans-Look Lung Research (GLR) database, we defined the clinical and demographic features of patients diagnosed with ES-SCLC from 2010 to 2015, determined the rate of systemic treatment uptake, and investigated the impact of prophylactic cranial irradiation and palliative treatments on overall survival. We summarized our findings with descriptive statistics (including Fisher’s Exact test) and Kaplan Meier curves using the SPSS. Statistical significance was set at p value < 0.05 and 95% confidence intervals.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 2010 to 2015 SCLC diagnoses, 68% (242/349) were ES-SCLC with median age of 68 years. Close to 90% received some form of palliative treatment. Chemotherapy (CT) was a major component of palliative treatments {89% overall, (190/214): 41% CT only, 22% CT & thoracic radiotherapy (RT) and 38% CT & RT-Other sites}. About a third (32%) of patients who received 1st line CT also had a 2nd line (range between 1 – 4 lines). Prophylactic cranial irradiation (PCI) uptake rates were 38% and 11% for CT only and CT & RT respectively. The median overall survival for ES-SCLC within the cohort was 7 months (p < 0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In contrast to advanced stage non-small cell lung cancers, there was high rate of sytemic treatment uptake for ES-SCLC. Overall however, < 20% (41/242) followed through with PCI. Other outcome findings will be presented and discussed.

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      P1.12-12 - A Systematic Review and Meta-Analysis of Early and Late Survival Following Anti-Cancer Therapies for Small Cell Lung Cancer (ID 13476)

      16:45 - 18:00  |  Presenting Author(s): Gavin S Jones  |  Author(s): Kelly Elimian, David Raymond Baldwin, Tricia McKeever, Richard Hubbard

      • Abstract
      • Slides

      Background

      Treatments for small cell lung cancer (SCLC) have not changed significantly in contrast to non-small cell where it is more individually tailored. Current guidelines generally have a one size fits all approach to chemotherapy. We conducted the largest systematic review and meta-analysis in SCLC to evaluate early and median survival by different study factors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We searched EMBASE and MEDLINE for randomized controlled trials and observational cohort studies which reported survival following platinum doublet chemotherapy for SCLC. We calculated overall survival at 30 and 90 days along with the median survival.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 10,487 titles, 161 were included. Cisplatin + etoposide (n=87 (49.4%)), carboplatin + etoposide (n=36 (20.5%)) and cisplatin + irinotecan (n=23 (13.1%)) were predominantly reported. The commonly reported cause of death within 30 days was neutropaenic sepsis (n=27), disease progression (n=11) and cardiovascular (n=8). Across both stages 30-day survival was 98% (95% CI 98-99%) whilst 90-day was 95% (95% CI 94-96%). Thirty and 90-day survival showed similar patterns to study factors as median survival (summarised in Table 1).

      Limited stage median survival was 18.1 months (95% CI 17.0-19.1). Studies that administered thoracic radiotherapy and PCI had better survival than those that did not. Studies giving carboplatin + etoposide or included poorer PS (0-3) individuals had inferior survival. PCI timing did not show survival differences.

      Extensive stage median survival was 9.6 months (95% CI 8.9-10.3). This was augmented in studies that gave irinotecan + cisplatin and were conducted in Asia. There were no survival differences by cisplatin/carboplatin or median participant age.

      median survival world lung.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      Neutropenic sepsis accounts for the majority of 30-day deaths and was mostly reported with cisplatin + etoposide. Our findings broadly support guideline recommendations but suggest certain sub-populations e.g. Asian individuals, benefit from targeted treatment with irinotecan + cisplatin. Age should be re-considered as a treatment-deciding factor in extensive stage.

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      P1.12-13 - Impact of Chronic Obstructive Pulmonary Disease on the Survival of Patients with Extensive-Disease Small Cell Lung Cancer (ID 13719)

      16:45 - 18:00  |  Presenting Author(s): Eun Joo Kang  |  Author(s): Jung Sun Kim, Suk Young Lee, Ju Won Kim, Yoon Ji Choi

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) is a highly fatal lung malignancy. Cigarette smoking is an important cause of SCLC, and most patients have heavy smoking history. Also, smoking is an established risk factor of chronic obstructive pulmonary disease (COPD). Therefore, patients who are diagnosed with SCLC have high chance to coincide with COPD. However, the coincidence rate of COPD and SCLC are not known well. Moreover, the impact of COPD on the mortality of patients with SCLC, especially for patients with extensive diesase (ED) is not reported yet. Therefore, we conducted investigation of clinical features and survival differences between patients who were diagnosed with SCLC with COPD or patients without COPD.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed medical records of patients who were diagnosed with SCLC-ED and received treatment between 2002 and 2016 at the Korea University Hospital. Among the 182 patients who were diagnosed with SCLC-ED and received palliative chemotherapy, 125 patients who had pulmonary function test report and previous or current smoking history were included. According to the global initiative for chronic obstructive lung disease (GOLD) classification, COPD was defined as FEV1/FVC <0.70.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 125 patients, COPD was present in 69 (55.2 %) patients. Among the patients with COPD, 48 (69.5%) patients did not know the COPD before the diagnosis of SCLC. Patients in the COPD group were older (mean age ± standard deviation, 68.9 ± 8.2 versus 65.6± 8.4 years; p=0.03). The mean FEV1(L) and predicted percent of FEV1 were 1.7L (67.9%) in COPD group and 2.9L (81.2%) in non-COPD group. Gender, body mass index, amount of smoking, ECOG performance status and neutrophil to lymphocyte ratio were not different between the two groups. Median overall survival of all patients was 8.6 months (95% confidential index [CI], 7.7-9.5). Median overall survival of the first-line chemotherapy between patients with COPD and patients without COPD was not statistically different (p=0.382). Median progression-free survival of the first-line chemotherapy between the two groups also were not different (p=0.372). In the analysis of COPD group, FEV1(L) and predicted percent of FEV1 did not affect survival among the patients with COPD (p=0.289).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, the presence of COPD at the diagnosis of SCLC-ED does not affect survival outcome in patients who were treated palliative chemotherapy. Even though the patients have severe obstructive pulmonary disease, active chemotherapy has to be considered with priority for the patients with SCLC-ED.

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      P1.12-14 - Survival of Patients with Small-Cell Lung Cancer Undergoing Surgical Resection (ID 13768)

      16:45 - 18:00  |  Presenting Author(s): Shinji Kikuchi  |  Author(s): Junko Okamura, Kentaro Araki, Takahiro Yanagihara, Kojiro Nakaoka, Yusuke Kitazawa, Naohiro Kobayashi, Yukinobu Goto, Yuko Minami, Masataka Onizuka, Hideo Ichimura, Yukio Sato

      • Abstract

      Background

      Small-cell lung cancer (SCLC) prognosis remains poor despite improvements in diagnosis and therapy. Current standard treatment for limited stage SCLC is concurrent chemo-radiotherapy, however recent retrospective studies indicate that surgery is an important treatment modality. We analyzed the overall survival and prognostic predictors of survival in patients who underwent surgical resection.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed the clinical course of 42 SCLC patients who had undergone complete surgical resection in our hospital between May 1989 and October 2017. Stages were determined or reclassified according to the eighth version of the TNM staging system.

      4c3880bb027f159e801041b1021e88e8 Result

      The mean age at pulmonary surgery was 68.0 years, 37 (88.1%) patients were male, and 2 (4.8%) were never smokers. Preoperative diagnosis of cancer was achieved in 18 (42.9%) patients. The surgical procedures included wedge resection in 6 (14.3%) and lobectomy in 36 (85.7%). There were no perioperative deaths and major postoperative complications. Thirty-two patients (76.2%) received adjuvant chemotherapy and three patients (7.1%) underwent prophylactic cranial irradiation. Pathological stages were 2 cases in IA1, 5 in IA2, 1 in IA3, 6 in IB, 3 in IIA, 8 in IIB, 13 in IIIA, 3 in IIIB, 1 in IVA. The pathology of primary tumor demonstrated 30 (71.4%) pure SCLC and 12 (28.6%) combined SCLC. The overall 5-year survival rate was 57.2% after an average follow-up of 58.7 months. A significantly good survival was observed using univariate analysis in patients with female (p=0.048), preoperative normal serum level of CEA (p=0.013), normal serum level of SCC (p<0.001), pR0 resection (p=0.02), adjuvant chemotherapy (p<0.001), and histological pure SCLC (p=0.002). In preoperative factor, multivariate Cox proportional hazard model analysis revealed that overall survival was shorter in patients with increased SCC levels and cN1or 2.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We conclude that pulmonary resection for early-stage SCLC is a safe and effective treatment strategy, and adjuvant chemotherapy may be useful in patients undergoing surgery in a practical management. Increased SCC levels and cN1 or 2 were identified as prognosis-related criteria for a poor prognosis of resected early SCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-15 - Distinctive Clinical Characteristics of SCLC in Never-Smokers (ID 13328)

      16:45 - 18:00  |  Presenting Author(s): Idrees Mian  |  Author(s): Samantha Nichols, Amy Abernethy, Ken Carson, Kathleen Maignon, Aracelis Torres, Jeremy Snider, Garrett M Frampton, Gerald Li, Elad Sharon, Eva Szabo, Anish Thomas

      • Abstract
      • Slides

      Background

      Epidemiologic data suggest that 3% of patients with SCLCs are never-smokers. A large population study is required to describe the characteristics and outcomes of SCLC in never-smokers. Defining SCLC subgroups based on clinical characteristics, specifically smoking status, may lead to treatment advances in this historically recalcitrant cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a multicenter analysis using the Flatiron Health electronic health record-derived database, a nationally representative database comprising patient-level structured and unstructured data curated via technology-enabled abstraction. The cohort consisted of patients with clinician confirmed SCLC diagnosed on or after January 1, 2013. Genomic data from a clinico-genomic database developed by Flatiron and Foundation Medicine was used for a subset of patients that had received next-generation sequencing on the FoundationOne panel. Clinical and genomic characteristics were compared between smokers and never-smokers using descriptive statistics while the presence of other cancers was confirmed via chart review for never-smokers. Association of patient characteristics with overall survival was assessed using a univariate Cox proportional hazards model.

      4c3880bb027f159e801041b1021e88e8 Result

      103 of 4655 (2.2%) SCLC patients were never-smokers. Characteristics of these patients were: female 65%, male 35%; Asian 4.85%, Black 4.85%, White 62.1%; extensive-stage (ES) 68.9%, limited-stage (LS) 20.4%, unknown 10.7%. Compared with smokers (n=4552), never-smokers were more likely to be 80+ years (p=0.040), female (p=0.013), Asian (p<0.001), and present with ES (p=0.038). Based on univariate analyses, poor prognostic factors in never-smokers included sodium < 140 mEql/L (HR=1.95; p=0.028) and ES (HR=2.62; p=0.013). 26 (25%) patients had confirmed history of multiple primary malignancies. Three patients had prior history of organ transplant and two patients had history of pulmonary fibrosis. Survival of never-smokers (8.0 months for ES and 20.6 months for LS) appeared similar to historical data from smokers with SCLC. In the subset of 251 SCLC patients where tumor mutation data was available, never-smokers (n=18, 7.2%) were less likely to have a detectable alteration in TP53 (44.4% vs 95.3%; p<0.001) or RB1 (27.8% vs 76.8%; p<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion