Virtual Library

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    ES02 - Quality Care in Lung Cancer (ID 770)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Nursing and Allied Professionals
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 206 BD
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      ES02.01 - Expanding PROs in Daily Practice (ID 11356)

      10:30 - 10:45  |  Presenting Author(s): Kahren White

      • Abstract

      Abstract not provided

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      ES02.02 - PRO: To Medicate: Managing Breathlessness (ID 11357)

      10:45 - 11:00  |  Presenting Author(s): Alexandre Chan

      • Abstract

      Abstract not provided

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      ES02.03 - CON: Not to Medicate: Managing Breathlessness (ID 11358)

      11:00 - 11:15  |  Presenting Author(s): Catherine L Granger

      • Abstract

      Abstract not provided

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      ES02.04 - Molecular Testing 101 for Nurses (ID 11359)

      11:15 - 11:30  |  Presenting Author(s): Beth Eaby-Sandy

      • Abstract

      Abstract not provided

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      ES02.05 - Structured Approach For Developing and Implementing and Advanced Practice Nursing Role in Lung Cancer (ID 11360)

      11:30 - 11:45  |  Presenting Author(s): Andrea Serena  |  Author(s): Solange Peters, Manuela Eicher

      • Abstract

      Abstract not provided

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    JTO - Meet the JTO Editor (ID 868)

    • Event: WCLC 2018
    • Type: Meet the JTO Editor
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 12:00 - 13:30, Room 206 BD
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      JTO.01 - Meet the JTO Editor (ID 12622)

      12:00 - 13:30  |  Presenting Author(s): Alex Adjei

      • Abstract
      • Slides

      Abstract not provided

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    MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD
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      MA22.01 - PARP Inhibitor Radiosensitization of Small Cell Lung Cancer Differs by PARP Trapping Potency (ID 13358)

      15:15 - 15:20  |  Presenting Author(s): Benjamin H Lok  |  Author(s): James H Laird, Jennifer Ma, Elisa De Stanchina, John Poirier, Charles M. Rudin

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in six SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. The dose modification factor (DMF), defined as the ratio of RT dose needed to achieve an equivalent level of survival with RT alone compared to that for RT plus drug, was calculated at 37% survival. Phosphorylated gH2AX sub-nuclear foci were assessed by immunofluorescence to quantify double-stranded DNA breaks (DSBs). Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models.

      4c3880bb027f159e801041b1021e88e8 Result

      Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays with a talazoparib dose of 20 nM demonstrating a DMF ranging from 1.61 – 2.88 in 4 cell lines with 0.2 nM demonstrating a DMF of 1.56 in 1 additional cell line. We confirmed radiosensitization in 3 of 3 cell lines by CSAs with DMF ranging from 1.40 – 2.20. To determine effects of PARP trapping on radiosensitization, we identified that concentrations of 200 nM talazoparib and 1600 nM veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization (DMF 3.3 with talazoparib vs DMF 1.0 with veliparib). This observation further correlated with an increased number of DSBs induced by talazoparib as compared to veliparib, where we found that talazoparib produced more residual DSBs than veliparib and DMSO with IR (gH2AX foci mean per cell: talazoparib 53.5, veliparib 33.5, DMSO 25.5) and without IR (40.0, 19.6, 14.6). Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models.

      8eea62084ca7e541d918e823422bd82e Conclusion

      PARP inhibition effectively sensitizes SCLC cell lines and PDXs to RT, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of RT in SCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.02 - Activation of MAPK Suppresses Neuroendocrine Transcription Factors and Causes Transdifferentiation of Small Cell Lung Cancer (ID 14051)

      15:20 - 15:25  |  Presenting Author(s): Yusuke Inoue  |  Author(s): William Lockwood

      • Abstract
      • Presentation
      • Slides

      Background

      Gene alterations involved in activating signaling through receptor tyrosine kinases/RAS/RAF/MEK/ERK pathway are extremely rare in small cell lung cancer (SCLC). In addition, EGFR expression is lost during the histological reprogramming of EGFR mutation-positive lung adenocarcinoma (LUAD) to SCLC, despite the cancer retaining the original EGFR mutation. These observations imply that signaling through mitogen-activated protein kinases (MAPKs) - critically important in non-small cell lung cancer - might be detrimental in SCLC biology. Here we investigated the impact of induction of two mutated oncogenic proteins, EGFRL858R and KRASG12V, the most common drivers of LUAD, on the phenotype and signaling profiles of SCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFRL858R or KRASG12V were aberrantly expressed in an inducible manner in three SCLC cell lines (H2107, H82, and H524). The effects of induction of these oncogenes were determined through cell viability analysis and Western blotting analysis particularly focusing on the regulation of master neuroendocrine transcription factors such as insulinoma-associated protein 1 (INSM1), POU class 3 homeobox 2 (BRN2), achaete-scute hologue 1 (ASCL1), and neurogenic differentiation factor 1 (NEUROD1). Genome-wide expression profiles were assessed in a longitudinal manner after oncogene induction and specific gene sets driven by MAPK activation in each SCLC cell line were defined.

      4c3880bb027f159e801041b1021e88e8 Result

      INSM1 and BRN2 were expressed in all the SCLC cell lines assessed. ASCL1 was expressed only in H2107 (classic type). Alternatively, NEUROD1 was expressed in the variant type SCLC cell lines, H82 and H524. Induction of mutant-EGFR or -KRAS resulted in different cell viability according to cell lines: H82 cells showed higher proliferation rate and the others showed lower proliferative ability. Furthermore, induction of these oncogenes caused transition from suspension to adherent phenotype in all the three cell lines. Importantly, EGFR/KRAS induction downregulated neuroendocrine transcription factors and these effects were more strongly observed after KRAS induction than after EGFR induction, which was concordant with the difference in degrees of phospho-ERK1/2 upregulation after induction of these mutant-oncogenes. Notably, treatment with SCH772984, an ERK1/2 inhibitor, rescued the repression of neuroendocrine factors by KRAS induction. Gene expression profiling is currently underway to reveal specific factors mediating ERK induced suppression of neuroendocrine programs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Activation of the RAS/RAF/MEK/ERK pathway causes phenotypic transition in SCLC growing in suspension to the adherent phenotype and suppresses neuroendocrine differentiation. Thus, ERK signaling has an fundamental role in repression of neuroendocrine differentiation programs and may be important in regulating histological transversion of SCLC to and from NSCLC with implications to drug resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.03 - SCLC Circulating Tumour Cell Derived Explants: The Clinical Characteristics of Patients Whose Samples Generate CDX (ID 12969)

      15:25 - 15:30  |  Presenting Author(s): Alexander John Vickers  |  Author(s): Louise Carter, Melanie Galvin, Mathew Carter, Lynsey Franklin, Karen Morris, Jacqueline Pierce, Kristopher Frese, Fiona Blackhall, Caroline Dive

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) prognosis is dismal, with minimal improvement in recent years. Work with SCLC cell lines and targeted therapies have been disappointing when translated into clinical practice. Circulating tumour cells (CTCs) represent a readily accessible liquid biopsy, which can be used to generate CTC derived explants (CDXs) for the study of SCLC biology and the investigation of biomarkers and therapeutics. These clinically relevant models appear to mirror patient response to therapeutics. Our aim was to assess if the patients whose samples generated a CDX represent the SCLC population, and determine if the clinical features of these patients offer insight into CTC biology.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was a single centre, retrospective analysis of 147 SCLC patients who had participated in The CHEMORES Study in which SCLC patients were asked to donate blood samples for the discovery and validation of novel biomarkers. Paired patient blood samples were taken for CTC enumeration using CellSearch Technology and for attempted CDX model generation. We obtained demographic and clinical information on these patients, and analysed the data for differences between patients whose blood samples generated a CDX and those whose did not.

      4c3880bb027f159e801041b1021e88e8 Result

      231 paired blood samples were taken from 147 patients, with 45 CDXs successfully generated from 34 patients. CTC number was significantly higher in samples which generated a CDX than those which didn’t, p=0.001. Successful progression samples had a significantly lower CTC number than successful baseline samples, p=0.026. There was no significant difference in age, gender, pack year history, performance status, stage, chemosensitivity or the presence of liver or brain metastases between patients whose samples did and did not generate a CDX. Metastatic burden was significantly higher in patients whose samples generated a CDX, p=<0.001. Progression free (PFS) and overall survival were significantly shorter in patients whose samples generated a CDX, p=<0.001

      8eea62084ca7e541d918e823422bd82e Conclusion

      CTC number correlates with CDX success, although a specific CTC phenotype may be more important. CTCs at progression may have a more aggressive phenotype than those at baseline. CDXs appeared to represent the SCLC population which is important when translating knowledge gained by studying CDXs into clinical practice. CTCs may play a role in the widespread metastatic dissemination of SCLC and thus survival of patients. Shortened PFS in the absence of difference in chemosensitivity may be due to outliers with particularly long PFS in the unsuccessful group. Further genomic and phenotypic analysis of subpopulations of CTCs may provide further insight.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.04 - Discussant - MA 22.01, MA 22.02, MA 22.03 (ID 14617)

      15:30 - 15:45  |  Presenting Author(s): Céline Mascaux

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA22.05 - Impact of Tumor Spread Through Air Spaces (STAS) in Lung Neuroendocrine Tumors (NETs) (ID 14221)

      15:45 - 15:50  |  Presenting Author(s): Katsura Emoto  |  Author(s): Rania Gaber Aly, Takashi Eguchi, Kyuichi Kadota, Natasha Rekhtman, Kay See Tan, Prasad S. Adusumilli, William D Travis

      • Abstract
      • Presentation
      • Slides

      Background

      We have previously reported the prognostic significance of STAS in lung adenocarcinoma and squamous cell carcinoma. The aim of this study was to investigate the incidence and prognostic impact of STAS in lung NETs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We evaluated all tumor slides (range 2-7, median 3) for presence of STAS from patients with p-Stage I-III primary lung NETs [n=628, typical carcinoid (TC, n=305), atypical carcinoid (AC, n=38), large cell neuroendocrine carcinoma (LCNEC, n=93) and small cell lung carcinoma (SCLC, n=57)]. Patients with combined NETs were excluded from this analysis (n=19). Cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were analyzed by competing risks approach.

      4c3880bb027f159e801041b1021e88e8 Result

      STAS was identified in 25% of NETs (15% in TC, 37% in AC, 43% in LCNEC, and 46% in SCLC). Prognostic analysis in TC cohort was not conducted due to the small number of events (<5 events). Patients with STAS positive tumors were associated with higher CIR than STAS negative tumors in the total (AC-LCNEC-SCLC) cohort as well as individual AC, LCNEC and SCLC cohorts (Figure 1, A-D). STAS was also associated with higher LC-CID in all cohorts except for AC (Figure 1, E-H). In multivariable analysis, STAS was a significant risk factor for recurrence and lung cancer specific-death, independent of stage and histologic subtype. Stratified by stage, STAS was an independent predictor of recurrence (subhazard ratio [SHR] 2.39, 95% CI 1.26-4.54, p= 0.007) and lung cancer-specific death (SHR 2.42, 95% CI 1.21- 4.84, p= 0.012) in LCNEC. In SCLC, STAS was also an independent risk factor of lung cancer-specific death (SHR 4.06, 95% CI 1.33- 12.35, p= 0.014).

      stas net figure abstract iaslc 2018 isa.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      STAS is a significant prognosticator in individual NET subtypes; AC, LCNEC, and SCLC. STAS is an independent poor prognostic factor in LCNEC and SCLC for lung cancer-specific death.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.06 - Preinvasive Multifocal Neuroendocrine Lesions with Primary Typical Carcinoid Lung Tumors: A Negative Prognostic Factor? (ID 12432)

      15:50 - 15:55  |  Presenting Author(s): Niccolo Daddi  |  Author(s): Valentina Tassi, Elisa Scarnecchia, Frances Allison, Jacopo Vannucci, Rosanna Capozzi, Valeria Liparulo, Kazuhiro Yasufuku, Marc De Perrot, Andrew Pierre, Özgür Mete, Renato Colella, Stefano Ascani, Piero Ferolla, Gail Elizabeth Darling, Shaf Keshavjee, Francesco Puma, Thomas Kenneth Waddell

      • Abstract
      • Presentation
      • Slides

      Background

      Impact on survival in patients with surgically resected multifocal neuroendocrine lesions (MNET), such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) or tumorlets, along with primary typical lung carcinoid (TC) is unclear. Aim of this study is to analyze whether synchronous preinvasive multifocal neuroendocrine lesions of the lung with primary TC tumors (MTNET+TC) may represent a negative prognostic factor.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective study, prospectively collected, for TC from two institutional databases was evaluated with a lifelong follow-up from surgery. Patients who did not receive surgery, underwent bronchial resection or lung transplant were excluded. Pathology specimens were all reclassified according the 2015 WHO and the eight AJCC Staging system. Kaplan-Meier(KM) method and Log-rank test reports significance between TC and were MTNET+TC were used. Hence a 1:1 propensity score matching analyses was done by adjusting the imbalance and comparing the overall survival and progression free rate between matched groups with a Cox proportional hazards regression model. A p value of 0.05 or less was considered significant.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 1983 to December 2013 a total of 234 patients was outlined from the databases (TABLE). A total of 41 patients (17.5%) with MNET+TC were identified. Overall KM progression free survival achieved at 5 and 10 years respectively MNET+TC 93.2% and 83.8% compare to TC 98.4% and 96.1% (p =0.00039). Thirty-six MNET+TC were matched pairs vs. TC alone. Univariate Cox proportional hazards model for matched patients MNET+TC compared to TC was 2.78 (95% CI=0.84-9.3, p=0.095). Difference in progression free rate between matched groups was p<0.001.

      table_net_daddi.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Synchronous multifocal neuroendocrine preinvasive lesions (MNET) with primary typical carcinoid (TC) lung tumors can be a negative prognostic factor. Careful search of MNET should be always performed in clinical and pathological staging of a suspected primary TC. The increased risk of progression of MNET+TC warrants an accurate and lifelong follow-up.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.07 - Prognostic Value of Distant Organ-Specific Metastases in Newly Diagnosed Lung Neuroendocrine Tumors: A Population-Based Study (ID 12684)

      15:55 - 16:00  |  Presenting Author(s): Min Fan  |  Author(s): Junmiao Wen, Jiayan Chen, Di Liu, Xinyan Xu, Junhua Zhang, Yu Gu, Lv Huang

      • Abstract
      • Presentation
      • Slides

      Background

      Lung neuroendocrine tumors (Lung NETs) are rare neoplasms with inferior outcomes for patients with distant metastases. AJCC cancer staging system for the classification of NETs was first introduced in 2010. However, the prognostic impact of metastatic sites for lung NETs are poorly explored. We aimed to fill this gap of our knowledge using the SEER database.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinical-pathological characteristics, specific metastatic sites and outcomes of stage IV lung NETs (according to AJCC 7th edition) were extracted from the SEER database from 2010-2014. Overall survival (OS) and Lung cancer-specific survival (LCSS) were estimated by the Kaplan-Meier method and comparisons conducted using log-rank tests and Cox regression models.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 2337 stage IV lung NETs patients were identified. The 5-year OS and LCSS were 10.7% and 18.3%, respectively. Among them, 2159 patients had specific organ metastases (liver, lung, bone or brain) at diagnosis. Liver was the most common metastatic site (1183, 50.6%), followed by bone (801,34.3%), lung (701,29.9%) and brain (616,26.4%). Patients with isolated lung metastases (1-, 5-year OS: 63.2%, 43.2%; 1-, 5-year LCSS: 74.0%, 62.9%,) had significantly better outcomes comparing to other patterns of metastases. The outcomes of patients with any brain metastases was most unfavorable (1-, 5-year OS: 20.3%, 2.1%, p<0.001; 1-, 5-year LCSS: 26.8%, 7.7%, p<0.001). Multivariate Cox regression analysis on OS and LCSS revealed that age > 60 years (p<0.001), male gender (p<0.001), poorer differentiation (p<0.001) and brain metastases (p<0.001) were independently poor prognostic factors for stage IV lung NETs patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The prognostic impact of metastatic site was unambiguous in stage IV patients with lung NETs. Comparing other metastatic patterns, brain metastases was associated with significant worse survival outcomes. Nearly twenty-fold difference in 5-year survival was revealed between isolated lung and brain metastases. For advanced lung NETs patients, brain metastases might be considered as a distinct category of dismal outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.08 - Discussant - MA 22.05, MA 22.06, MA 22.07 (ID 14618)

      16:00 - 16:15  |  Presenting Author(s): Giuseppe Pelosi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA22.09 - Should Stereotactic Radiosurgery be Considered for Salvage of Intracranial Recurrence in Small Cell Lung Cancer? (ID 14092)

      16:15 - 16:20  |  Presenting Author(s): Brooklyn Mazure  |  Author(s): Neil Guest, Ariel Letcher, Sunita Ghosh, Zsolt Gabos, Karen P Chu, Brock Debenham, Tirath Nijjar, Diane Severin, Rufus Scrimger, Wilson Roa, Don Yee, Alysa Fairchild

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic cranial irradiation (PCI) remains a standard of care for small cell lung cancer (SCLC) to improve overall survival (OS) and prevent recurrence in limited (LS) and extensive stage (ES) disease. Intracranial recurrence (IC) after PCI affects 12-33%. Limited published data describe outcomes of salvage reirradiation (ReRT). Our purpose was to review outcomes after IC post-PCI or therapeutic whole brain radiotherapy (WBRT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Consecutive patients with pathologically-confirmed SCLC assessed (01/2013-12/2015) at a tertiary cancer centre (catchment 1.5M) were retrospectively reviewed. Demographics, treatment and outcomes were abstracted and summary statistics calculated. Kaplan-Meier estimates and univariate and multivariate analysis (MVA) via the Cox proportional hazard model were performed.

      4c3880bb027f159e801041b1021e88e8 Result

      Median age was 66.1yrs, 53% female, and 80% ECOG 0-2 (N =372). Median survival (MS) was 24 months (95%CI 18.3-29.7 mos) for 103 LS, and 7 months (95%CI 6.1-7.9 mos) for 269 ES patients. 72/103 LS received PCI (69.9%), 84.7% of whom had radical thoracic radiotherapy (RT). 54/269 ES patients presented with brain metastases (BM); 98/215 of the remaining received PCI, and 72 of those thoracic RT (84.7% 25-30Gy/10). PCI dose was 25Gy/10 in 95.9%. PCI patients had better performance status (PS), and were more likely to receive chemotherapy (CT) and thoracic RT (all p<0.013). 18.8% (32/170) recurred post-PCI (13 LS; 19 ES) at a median of 11.5 mos. 45/54 presenting with BM received WBRT (83.3% 20Gy/5), 14 of whom recurred. MS after PCI was 28 mos vs 12 mos for LS and ES, respectively. For LS patients with IC post-PCI, MS was 20 mos vs 38 mos without IC (p=0.03). On MVA, interval between brain RT predicted OS after PCI (HR 0.87; p<0.001), while stage (HR 3.56; p=0.008) and cranial RT dose predicted IC (HR 0.65; p=0.047). At IC, 56.5% (26/46) had <5 BM, median 1.7cm (range 0.5-5cm), 39.1% had no extracranial disease, 6 were asymptomatic, and 50% had ECOG 0-2. 30/46 had ReRT: 27 WBRT and 3 stereotactic radiosurgery (SRS). In retrospect, 17/46 would have been candidates for salvage SRS: 5 LS post-PCI; 8 ES post-PCI; and 4 ES post-WBRT.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This cohort seems to challenge the belief that in-brain progression is always: diffuse; associated with clinical deterioration; and synchronous with systemic failure. With potential for OS >6 months, repeat WBRT risks meaningful neurocognitive toxicity. Further data are required; however, approximately 1 in 3 SCLC patients who recur after PCI or WBRT appear clinically appropriate for salvage SRS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.10 - Prevalence and Risk Factors of Brain Metastases in Limited Stage Small Cell Lung Cancer Immediately Before Prophylactic Cranial Irradiation (ID 13185)

      16:20 - 16:25  |  Presenting Author(s): Zhengfei Zhu  |  Author(s): Xiao Chu, Xi Yang

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastasis (BM) and improves overall survival (OS) in limited-stage Small Cell Lung Cancer (LS-SCLC) patients with complete or partial remission after receiving chemoradiotherapy. However, cranial magnetic resonance imaging (CMRI) before scheduled PCI is not mandatory, and its necessity remains controversial. Therefore, we conducted this study to evaluate LS-SCLC patients’ BM rate revealed by CMRI immediately before PCI.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      283 consecutive LS-SCLC patients diagnosed at our center between 2014 and 2017 were evaluated, all have negative base-line CMRI. Patients received platinum-based chemotherapy plus concurrent or sequential thoracic radiation. 119 complete or partial responders were identified. All received another CMRI immediately before PCI and constituted the cohort of interest. Logistic regression was employed to assess the relationship between pre-PCI BM risk and the following variables: age, gender, smoking history, lymph node stage or time from treatment initiation to pre-PCI MRI (TTPCI). Cox regression was employed to evaluate relations between these risk factors and OS. Two-sided P value <0.05 was considered statistical significant.

      4c3880bb027f159e801041b1021e88e8 Result

      25 out of 119 (21%) LS-SCLC patients developed pre-PCI BMs, TTPCI (2.83 to 13.03 months) was revealed as an independent risk factor for pre-PCI BM (risk ratio: 1.653, 95% CI: 1.312 – 2.084, P < 0.001, Table 1). Patients with pre-PCI BM have significantly shorter OS (hazard ratio: 1.653, 95% CI: 1.312 – 2.084, P < 0.001, Table 1).

      table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      A considerable portion of LS-SCLC patients developed BM after definitive chemoradiotherapy and immediately before PCI. We recommend mandatory CMRI before PCI in these patients. Earlier scheduled PCI may reduce BM rate in selected LS-SCLC patients, further studies are warranted to determine the optimal PCI timing for LS-SCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA22.11 - Risk of Hippocampal Metastases in Small Cell Lung Cancer: Implications for Hippocampal Sparing Cranial Irradiation (ID 12791)

      16:25 - 16:30  |  Presenting Author(s): Rachel Effeney  |  Author(s): Lekshmi Nair, Michelle Murphy, Craig Hukins, Margot Lehman, G Tao Mai

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) decreases the incidence of brain metastases (BMs) and can improve overall survival. However whole brain radiation therapy is associated with a decline in neurocognitive function. Hippocampal-sparing whole brain radiation therapy (HS-WBRT) aims to minimise damage to neural progenitor cells (NPCs) within the hippocampus and reduce the toxicity of PCI, although there may be an increased risk of treatment failure in the hippocampal region. The incidence of hippocampal metastases was investigated in patients with BMs from SCLC to evaluate the feasibility of HS-WBRT in this population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with SCLC presenting between 2000 and 2016 with BMs at presentation or during their disease course without previous cranial irradiation were identified from a prospectively maintained database. Hippocampal metastases (HMs) were defined as metastases within the hippocampus and a 5-mm radial expansion (hippocampus avoidance zone, according to the Radiation Therapy Oncology Group 0933 atlas). The rate of hippocampal metastases and associated clinical features were analysed.

      4c3880bb027f159e801041b1021e88e8 Result

      One hundred and twenty eligible patients with a total of 754 brain metastases were identified. In 67 (55.8%) patients BMs were detected at diagnosis of SCLC and in 53 (44.2%) patients BMs developed later without previous PCI. The median number of metastases was 3, and 27 (22.5%) patients had a single BM. There were 22 (18.3%) patients with hippocampal metastases. A total of 23 (3.1%) metastases involved the hippocampal avoidance area. On logistic regression analysis, the number of brain metastases was an independent risk factor for HMs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The overall incidence of hippocampal metastases in our cohort of SCLC patients is high. As HS-WBRT may increase the risk of treatment failure in the spared region, prospective randomised trials are encouraged.

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      MA22.12 - Discussant - MA 22.09, MA 22.10, MA 22.11 (ID 14622)

      16:30 - 16:45  |  Presenting Author(s): Houda Bahig

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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      MA27.01 - Establishment of PDX From Tumors Characterized by EGFR Mutations or ALK Fusion Genes from Resections, Biopsies and Pleural Fluids (ID 12144)

      13:30 - 13:35  |  Presenting Author(s): Sebastiao Martins-Filho  |  Author(s): Michael Cabanero, Nhu-An Pham, Erin L Stewart, Deepti Ravi, Devalben Patel, Judy McConnell, Alexandria Grindlay, Frances Allison, Ming Li, Frances A Shepherd, Ming Sound Tsao, Kazuhiro Yasufuku, Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Background

      Patient-derived xenograft (PDX) models allow for cancer tissue expansion, providing an effective method to evaluate tumor biology and mechanisms of response or resistance. Our study aims to establish models in patients enriched for lung adenocarcinoma (LUAD) with EGFR mutations or ALK fusion genes which respond initially to oral targeted therapy, but typically develop resistance and disease relapse within 2 years. The PDXs will be evaluated for their potential to model therapy outcomes, to determine resistance mechanisms and to evaluate novel therapy strategies to overcome resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From August 2015 to January 2018, we collected 109 samples from patients with EGFR- or ALK-driven LUAD and from never-smoker LUAD patients with unknown mutation status. Five samples with low tissue viability (i.e. necrotic) or very low tumor content (<100 malignant cells) were excluded. Adequate samples were implanted into the subcutaneous tissue of NOD-SCID mice. At this time, 16 samples have reached the study endpoint (tumor growth ≥1.5cm3) and 60 showed no tumor-growth following implantation (median follow-up: 8m). Results are currently pending for 18 models.

      4c3880bb027f159e801041b1021e88e8 Result

      Samples were collected from surgical resections (31, 36%), CT-guided biopsies (12, 14%), EBUS (19, 22%) and pleural fluid effusions (24, 28%). Most patients were female (51/86, 59%), never smokers (62/85, 73%), and had stage III or IV cancer (55/79, 70%). Mutations in EGFR and ALK were found in 55/81 (68%) and 12/84 (14%) primary cancers, respectively. Early-passage xenograft engraftment (XG) was observed in only 16 (19%) PDXs, including 9/55 (16%) EGFR- and 1/12 (8%) ALK-mutant cancers. The phenotype and molecular changes (EGFR and ALK) were consistent within the PDX model and its corresponding patient sample. Samples collected from surgical-resection specimens showed a trend towards higher engraftment rates (p=0.084). Conversely, the presence of EGFR or ALK mutations showed a trend towards non-engraftment (noXG, p=0.075). Patient smoking status and tumor stage did not influence engraftment rate. To identify reasons for no tumor-growth, we conducted histological analysis in the subcutaneous fat-pads (nodes in the implant sites) of 28 noXG mice. Interestingly, we identified small non-palpable foci of carcinoma in 8 animals (4 EGFR+ and 2 ALK+).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Environmental or molecular factors may impair engraftment rates of EGFR+ and ALK+ LUAD samples in PDX models. Nevertheless, these models recapitulate the primary disease and could be useful for population-based drug-screening studies.

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      MA27.02 - Hypofractionated Radiotherapy Normalizes Tumor Vasculature in Non-Small Cell Lung Cancer Xenografts Through p-STAT3/HIF-1 Alpha Pathway (ID 14322)

      13:35 - 13:40  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Xiong Chun Jin, Fan Tong, Chunhua Wei, Hui Lu

      • Abstract
      • Presentation
      • Slides

      Background

      Our study aimed to investigate specific biological effect of hypofractionated radiotherapy (HFRT) on tumor angiogenesis, when compared with conventional radiotherapy (CRT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Firstly, models of nude mice as well as dorsal skinfold window chamber (DSWC) bearing H460 and HCC827 (NSCLC cell lines) were established. Tumors suffered irradiation with doses of 0 Gy (control group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). After irradiation, xenograft volumes were recorded every other day. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; α-SMA and CD34 immune-histochemical staining was employed to detect the micro-vessel density (MVD) and coverage rates of pericyte on tumor vessels; pimonidazole hydrochloride was used to detect hypoxia; western blotting and RT-PCR were used to detect the expression levels of p-STAT3, HIF-1α, SDF-1 and VEGFA. Then, S3I-201, the STAT3 inhibitor, was used to further verify the mechanism of the effect of HFRT on vascular normalization.

      4c3880bb027f159e801041b1021e88e8 Result

      Compared to CRT groups, the growth suppression effect of HFRT on tumor tissue was enhanced, accompanied by stronger effect on decrease in MVD, vascular normalization and improvement of tumor hypoxia. RT-PCR and western blotting exhibited that HFRT promoted the vascular normalization by activating STAT3/ HIF-1α signaling pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Compared to CRT, the pathway of p-STAT3/HIF-1α and its downstream angiogenic factors (VEGFA and SDF-1) might play important roles in forming of a window-period of vascular normalization in NSCLC, which contributed to the specific biological effect of HFRT on tumor vasculature.

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      MA27.03 - Multi-Omic Characterization of TKI-Treated Drug-Tolerant Cell Population in an EGFR-Mutated NSCLC Primary-Derived Xenograft (ID 13370)

      13:40 - 13:45  |  Presenting Author(s): Erin L Stewart  |  Author(s): Michael Cabanero, Vibha Raghavan, Jeffrey Bruce, Paul Guilhamon, Rajat Singhania, Nhu-An Pham, Shu Yi Shen, Tiantian Li, Ming Li, Natasha B Leighl, Frances A Shepherd, Trevor J. Pugh, Daniel De Carvalho, Mathieu Lupien, Geoffrey Liu, Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      Sixty to eighty percent of advanced stage lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutated tumors respond to first generation EGFR tyrosine kinase inhibitors (TKIs). However, cure is not yet achievable with any EGFR TKI monotherapy, as patients eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of epigenetically modified drug tolerant cells (DTCs) may be important for tumor cells surviving TKI. We hypothesize that molecularly characterizing DTCs in vivo and comparing them to the untreated tumor in a patient-derived xenograft (PDX) model may delineate mechanisms of tolerance that closely mimic those occurring in patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      DTCs were produced via chronic exposure to erlotinib in a lung adenocarcinoma PDX harbouring an exon 19 deletion. Histological, genomic, transcriptomic (including single-cell RNA-seq), and epigenetic characterizations were performed on DTCs and compared to untreated baseline (BL) tumors.

      4c3880bb027f159e801041b1021e88e8 Result

      Compared to BL, DTCs exhibit decreased levels of proliferation (Ki67 by immunohistochemistry (IHC) and increased expression of senescence/quiescence (p21) and anti-apoptosis (BCL-XL) immunohistochemistry (IHC) markers, while maintaining EGFR pathway signaling (pEGFR, pAKT, pERK, pS6 IHC). Whole exome-sequencing provides evidence that DTCs likely do not represent mutationally distinct subclones from the bulk tumor. Instead, DTCs exhibit a number of differentially expressed genes compared to BL tumors that are involved in cell cycle arrest, senescence/quiescence, differentiation, vesicles, and inflammation. Genes with epigenetic differences (chromatin openness and/or promoter methylation) are involved in similar cellular processes. A minor (<2%) subpopulation of transcriptomically-defined DTC-like cells in the BL tumors are very similar to the DTCs, supporting the hypothesis that DTCs may exist prior to treatment. A number of transcription regulators are found to have differential gene expression and epigenetic regulation as well as DNA-binding motifs found in regions of chromatin uniquely open in DTCs or baseline tumors. These transcription regulators are involved in cell maintenance, proliferation, and differentiation, and may play key roles in promoting DTC phenotype.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this specific EGFR mutant PDX model sensitive to first generation TKIs, DTC-like cells are found in the BL untreated tumors, and its resultant phenotype after exposure to TKI appears to be involved in cell cycle, differentiation, senescence/quiescence, proliferation and maintenance. PDX models may provide insights into therapeutic strategies to target DTCs, and further improve the survival of EGFR-mutated NSCLC patients.

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      MA27.04 - Discussant - MA 27.01, MA 27.02, MA 27.03 (ID 14583)

      13:45 - 14:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA27.05 - Drug Loaded Mesenchymal Stem Cells for Targeted Lung Cancer Treatment in Mice (ID 11827)

      14:00 - 14:05  |  Presenting Author(s): YAOJIONG Wu  |  Author(s): Xusheng Wang

      • Abstract

      Background

      Mesenchymal stem cells (MSCs) are cells residing in many tissues of our body. Due to their low immunogenicity, allogeneic MSCs have been used extensively for immune regulation and many other conditions. Over 90% of culture expanded MSCs are entrapped in the lungs after intravenous infusion. Taking this advantage, in this study, we utilized MSCs as a vehicle for targeted delivery of drugs to the lungs to treat lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      For enhanced cellular uptake, docetaxel (DTX) was loaded in PLGA-PEG nanoparticles (NPs). Lung cancer was induced in KrasG12D mice, who expressed a form of constitutively activated Kras protein in lung cells upon local administration of cre-advenovirus (AdCre) solution. The size of lung cancer was assessed by PET-CT and tissue analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      The amount of DTX uptake by MSCs at 1, 3, 7, 12, and 24 hours was measured by LC-MS, and the result showed that DTX intake reached peak at 12 hours with ~36 μg in 106 MSCs, compared to 15 μg DTX in equal number of fibroblasts, indicating that MSCs had higher NPs-DTX uptake capacity than fibroblasts. To visualize MSCs in vivo, MSCs were labeled with luciferase (Luci). 106 MSCs-Luci loaded with NPs-DTX were injected intravenously in mice. In vivo imaging system (IVIS) analysis showed a predominant accumulation of the cells (drug) in the lungs at 24 hours after injection. The effect of MSCs/NPs/DTX in inhibiting lung cancer development was evaluated in KrasG12D mice. Five days after lung cancer induction, the mice received an intravenous injection of 106 MSCs loaded with NPs-DTX (~25 μg), NPs-DTX (~200 μg) alone, or PBS every 5 days. 30 days after tumor induction, PET-CT analysis detected large masses in the lungs in PBS treated mice, compared to much smaller masses in MSCs/NPs/DTX-treated or NPs-DTX-treated mice. In consistence, the tumor weight was significantly lower in MSCs/NPs/DTX-treated or NPs-DTX-treated animals than PBS-treated mice, and similar reductions in tumor weight were found in MSCs/NPs/DTX-treated or NPs-DTX-treated mice.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Thus our data indicate that MSC loaded with DTX can provide targeted therapy for lung cancer to achieve equal cancer inhibition with much lower doses of DTX thus reducing side effects of the drug. As allogeneic MSCs do not cause obvious immune rejection, our study suggests a novel approach for targeted lung cancer therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.06 - Therapeutic Silencing of Oncogenic KRAS With a Mutant-Specific Short Interfering RNA (ID 12227)

      14:05 - 14:10  |  Presenting Author(s): Chad Victor Pecot  |  Author(s): Amanda Van Swearingen, Bjoern Papke

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic mutations in RASgenes are well established drivers of cancer. In particular, lung, pancreatic and colorectal cancers carry high rates of oncogenic mutations in KRAS. Promising preclinical strategies with RNA interference (RNAi) have been developed to target oncogenic RAS function, yet a clinically effective anti-RAS therapy remains to be achieved. While genetic knock-down of mutant KRASwith RNAi is one promising approach, current methods are not selective and also decrease normal RAS, raising concerns about potential normal tissue toxicity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We took a novel in silico approach to develop a library of siRNAs that are theoretically capble of silencing mutant KRAS sequences yet spare the wild-type sequence. We utilized a 3T3 model system to test our library of siRNAS against various human KRAS G12 and G13 mutations compared with the wild-type sequence. Dose titrations were performed to assess the unique affinity of our lead candidate for mutant v. WT. Using a KRAS mutant orthotopic lung model, we assessed in vivo silencing and therapeutic effects following delivery of our lead candidate when packaged into a nanoliposome.

      4c3880bb027f159e801041b1021e88e8 Result

      Here we describe a custom designed short interfering RNA (siRNA) oligonucleotide (KRAS-m) that displays a higher affinity for the most frequent subsets of oncogenic KRASmRNAs than for wild-type KRASmRNA. Using 3T3 cells stably expressing wild-type or various KRAS mutations, we observed that KRAS-m preferentially suppressed expression of G12C, G12D, G12V and G13D missense mutations compared to wild-type KRAS. Additionally, KRAS-m impaired proliferation of lung cancer cells in 2D as well as 3D spheroids embedded in extracellular matrix. In order to optimize in vivo stability and minimize toxicity, a 2’O-methylation strategy was utilized and several equipotent modifications were found. To overcome future clinical limitations of delivering siRNA to tumors, we evaluated a lipid nanoparticle platform (LNP) clinically-proved to be safe and highly efficient at delivering systemic RNAi. Biodistribution studies in a syngeneic, orthotopic metastasis model of KRAS (G12D) lung adenocarcinoma revealed substantial uptake of LNP-siRNAs in lung tumors and metastasis. Time-kinetic studies in this model revealed a single delivery of LNP-KRAS-m siRNA significantly silenced KRAS protein expression in tumors for at least 3 days. Compared with LNP-control siRNAs, following two deliveries of LNP-KRAS-m siRNAs model led to significant reductions in disease burden.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Taken together, our data indicate a novel strategy to target oncogenic KRAS-driven lung tumors using a mutant-specific siRNA capable of targeting many of the most common KRAS mutations.

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      MA27.07 - Lung Adenocarcinoma Harboring BRAF G469V Mutation is Uniquely Sensitive to EGFR Tyrosine Kinase Inhibitors (ID 12771)

      14:10 - 14:15  |  Presenting Author(s): Hirotsugu Notsuda  |  Author(s): Nhu-An Pham, Ming Li, Ni Liu, Vibha Raghavan, Zhenhao Fang, Christopher B Marshall, Nadeem Moghal, Mitsuhiko Ikura, Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      BRAF mutations occur in 2-5% of non-small cell lung cancers with ~50% being non-V600E. Previous studies reported that two BRAF G469 mutations, G469V and G469A increase kinase activity and MAPK activation, thus are likely oncogenic. Patients with non-V600E mutations are mostly not sensitive to approved BRAF inhibitors vemurafenib or dabrafenib. We established a lung adenocarcinoma (LUAD) patient derived xenograft (PDX) that is epidermal growth factor receptor (EGFR) wild type and non-amplified, but harbors BRAF G469V mutation, yet is sensitive to gefitinib. We performed functional studies to characterize the oncogenicity and sensitivity of BRAF G469 mutations to EGFR tyrosine kinase inhibitors (TKIs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PDX12 was established in NOD-SCID mice from a resected stage IIIA LUAD. The XDC12 cell line was established from PDX12. NCI-H1395 and -H1755 LUAD cell lines with BRAF G469A mutation were obtained from ATCC. BRAF mutant driver activity was characterized by shRNA knockdown of BRAF in LUAD cell lines and the ability of the mutants to promote IL3-independent growth when expressed in Ba/F3 cells. PDX12 responsiveness to TKIs was evaluated by tumor volume shrinkage while cell line sensitivity was quantified using the MTS assay. Drug effects on signaling were assessed by phospho-immunoblotting. Computational modeling was used to predict how the mutations promote BRAF activation and sensitivity to EGFR-TKIs, while purified BRAF proteins were used to validate predictions.

      4c3880bb027f159e801041b1021e88e8 Result

      Knockdown of BRAF by shRNA inhibited growth of all BRAF mutant cell lines, while ectopic BRAF G469V and G469A expression in Ba/F3 cells promoted IL3-independent MAPK activation and growth, supporting both mutations being oncogenic drivers. The XDC12 cell line was sensitive to EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib), but resistant to the BRAF inhibitor dabrafenib, which correlated with inhibition of MAPK phosphorylation. By contrast, H1395 and H1755 cell lines with BRAF G469A mutations were resistant to both the EGFR-TKIs and the BRAF inhibitor. Similarly, only Ba/F3 cells expressing BRAF G469V, but not G469A, were sensitive to EGFR-TKIs. Consistent with the in vitro data and our initial PDX findings with gefitinib, multiple EGFR-TKIs induced tumor shrinkage in PDX12 in vivo.

      8eea62084ca7e541d918e823422bd82e Conclusion

      BRAF G469V/A mutations are oncogenic drivers but are insensitive to BRAF inhibitors. However, only BRAF G469V, but not G469A mutation, is sensitive to EGFR-TKIs. Thus, two different driver alterations affecting the same BRAF codon can lead to distinct drug sensitivities.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.08 - Discussant - MA 27.05, MA 27.06, MA 27.07 (ID 14581)

      14:15 - 14:30  |  Presenting Author(s): Gwyn Bebb

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA27.09 - Dual Inhibition of BCL-XL and MCL-1 is Required to Induce Tumour Regression in Lung Squamous Cell Carcinomas Sensitive to FGFR Inhibition (ID 12645)

      14:30 - 14:35  |  Presenting Author(s): Marie-Liesse Asselin-Labat  |  Author(s): Clare E Weeden, Casey Ah-Cann, Aliaksei Holik, Delphine Merino, Guillaume Lessene

      • Abstract
      • Presentation
      • Slides

      Background

      Fibroblast growth factor receptor 1 (FGFR1) gene amplification has been described in 20% of lung squamous cell carcinoma (SqCC), suggesting that FGFR tyrosine kinase inhibitors may constitute a new therapeutic approach for patients carrying this genetic alteration. However, a recently completed clinical trial reported low response rates to FGFR therapy, indicating the need for refined biomarkers. We have recently described that high levels of FGFR1 RNA expression better predicts response to FGFR inhibitors, yet the treatment results in tumour cell stasis as opposed to cell death. BH3-mimetics are a class of anticancer agents that block the BCL-2 family of pro-survival proteins to induce cell death and were recently approved for clinical use in blood cancers. We therefore hypothesized that combining BH3-mimetics with FGFR-targeted therapy may enhance the killing of SqCC cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We developed patient-derived xenograft models of lung squamous cell carcinoma and evaluated the activity of specific inhibitors of BCL-XL (A1331852), BCL-2 (ABT-199), MCL-1 (S63845) or FGFR (BGJ398) as single agents or in combination in vitro and in vivo. Genetic knockout of BCL-XL was also performed using CRISPR/Cas9. We evaluated compounds synergy in vitro using BLISS assay and in vivo efficacy using mRECIST.

      4c3880bb027f159e801041b1021e88e8 Result

      Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We identified a greater reliance of lung SqCC cells on BCL-XL compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitor alone gives a survival benefit in combination FGFR therapy in vivo. In contrast, triple BCL-XL, MCL-1 and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our work therefore provides a rationale for the simultaneous inhibition of MCL-1, BCL-XL and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.

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      MA27.10 - EGFR-Targeted Therapy Alters the Tumor Microenvironment In EGFR-Driven Lung Tumors: Rationale for Combination Therapies (ID 11863)

      14:35 - 14:40  |  Presenting Author(s): Yijun Jia  |  Author(s): Tao Jiang, Xuefei Li, Chao Zhao, Caicun Zhou, Sha Zhao

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer patients harboring EGFR mutations have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). However, these patients develop resistance eventually. With the promising implementation of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize this immuneapproach in the context of targeted therapies. Although many clinical trials have attempted to study combining EHGR-TKIs with PD-1/PD-L1 inhibitors in NSCLC cases, the clinical benefit is still undefined. Therefore, we carry out this study to investigate the immune response of EGFR-TKIs in EGFR-driven lung tumors, aiming to explore factors may influence the efficacy of this combination strategy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We investigated the early and long-term antitumor effects of first-generation TKI gefitinib and third-generation TKI osimertinib respectively in mice with EGFRL858R andEGFR19DEL/T790M-driven lung tumors.The changes of immune texture in tumors were dynamically tested in different treatment groups by flow cytometry and immunohistochemistry.

      4c3880bb027f159e801041b1021e88e8 Result

      Upon treatment of gefitinib and osimertinib, we saw significant tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFR19DEL/T790M-driven tumors did not respond to gefitinib, but did show a significant tumor response to third-generation TKI osimertinib treatment. Accompanied with obvious tumor shrinkage, we saw a significant increase of infiltrating CD11b+ myeloid cells and CD3+ lymphocytes throughout treatment. We further analyzed subpopulation of CD11b+ myeloid cells and CD3+ lymphocytes. Results showed that EGFR-TKIs may demonstrated anti-tumor activity by raising cytotoxic CD8+ T cells, activating dendritic cells, eradicating Foxp3+ Tregs and inhibiting M2-like polarization at early stage. However, these immune benefits occurred temporarily and gradually disappeared with treatment went on. On the other hands, the proportion of myeloid-derived suppressor cells(MDSCs), particular mononuclear-MDSCs were consistently elevated responding to sensitive EGFR-TKIs treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Together, results of our study provide novel insights into the immune response to EGFR-TKIs in vivo and provides rationale for potential combinations of EGFR-TKIs and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.And additional therapies aiming to eliminate certain immunosuppressive components should be considered when applying this combination strategy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.11 - Genomic Sequencing and Editing Revealed the GRM8 Signaling Pathway as Potential Therapeutic Targets of Squamous Cell Lung Cancer (ID 12246)

      14:40 - 14:45  |  Presenting Author(s): Panpan Zhang  |  Author(s): Shaolei Li, Yue Yang

      • Abstract
      • Slides

      Background

      Lung cancer is the leading cause of cancer death worldwide. Squamous cell carcinoma (LUSC) is one subtype of non-small-cell lung cancer (NSCLC), and ranks at the second of lung cancer incidence. Although targeting receptor tyrosine kinases (RTKs) had already brought better clinical outcomes to NSCLC patients carrying corresponding mutations, very few mutated targets had been identified in LUSC subtype, probably because of the lack of mutation hotspot and functional validation of mutated candidate.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The whole exome (WES) and whole genome (WGS) sequencing and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from 11 groups of LUSC primary tumors and corresponding patient-derived xenografts (PDXs).

      4c3880bb027f159e801041b1021e88e8 Result

      The WES data revealed high homologies on the mutation types and signatures among primary tumor and different passages of PDX tumor samples. Nine significant genes carrying single nucleotide variations (SNVs) and three carrying copy number variations (CNVs) were identified as targeting candidates from WES and WGS data based on the mutation frequency and driver gene analysis. The oncogenic or tumor suppressor functions of those 12 candidates were validated through CRISPR-Cas9 loss-of-function system in tumor cells derived from PDX tissues carrying corresponding mutations and in normal bronchial epithelial cell-line. Furthermore, using CRISPRa transcriptionally activating system, one novel candidate, Metabotropic glutamate receptor 8 (GRM8) was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.12 - Discussant - MA 27.09, MA 27.10, MA 27.11 (ID 14582)

      14:45 - 15:00  |  Presenting Author(s): Dave Barbie

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      Abstract not provided

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    MS04 - Joint GLCC/IASLC Session: Exploring Hot Topics for Advocates (ID 783)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Advocacy
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 206 BD
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      MS04.01 - Collecting Data in the Real World - How Can Patient Groups Work with Researchers in Defining and Collecting Real-World Evidence? (ID 11415)

      10:30 - 10:45  |  Presenting Author(s): Taofeek Owonikoko

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      Abstract not provided

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      MS04.02 - How Is Lung Cancer Screening Evolving to Be More Efficient and Effective? (ID 11416)

      10:45 - 11:00  |  Presenting Author(s): David Raymond Baldwin

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      Abstract not provided

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      MS04.03 - Exploring Smoking Stigma, Negativity and Lung Cancer - What Can Be Done? (ID 11417)

      11:00 - 11:15  |  Presenting Author(s): Stefania Vallone

      • Abstract
      • Presentation
      • Slides

      Abstract

      Misinformation or false myths about cancer generate fear and a negative perception of a person affected by this disease. Lung cancer patients experience a higher level of cancer-related stigma than other cancer patients, because the general negative attitude about smoking, recognized as one of the main risk factors, contributes to the stigmatization of people who live with this condition. Although the relation between tobacco use and lung cancer is established, worldwide lung cancer patients are affected by a noteworthy and unjustified stigma and considered responsible of their disease in a different way from other cancer patients. For it, they are often reluctant to disclose the disease, because of fear to be discriminated, and patients' stories show that stigma could be harmful and detrimental to them and their loved ones and may cause limitations in working toward a cure. The lack of public empathy and support adds an emotional burden to an already frustrating situation that can affect quality of life and may contribute to depression, anxiety, poor self-esteem, guilt, shame, blame, negatively impacting psychological adjustments and interpersonal communication. Low public support for lung cancer is not restricted to popular perceptions and attitudes, but can also be seen in research funding. Lung cancer remains an underfunded disease and despite the higher mortality, it received less funding compared to other common cancers, such as breast cancer.

      What can be done?

      Stigma impacts all spheres of a person’s life and patients, caregivers, advocates and healthcare professionals have started years ago actively working in this area developing programs and campaigns that can help to change this situation, partly persisting because smoking is still considered more as a bad habit rather than a serious addiction. It’s important to motivate and encourage smokers to quit rather than blaming them, and even when the lung cancer has already been diagnosed, smoking cessation is important for a better quality of life. Providing smoke-free policies and tailored and effective campaigns is essential for improving the people awareness about the issue that smoking contributes to a number of diseases and cancers even if most people associate it exclusively with lung cancer. But, lung cancer is not just a smoker's disease, there are additional factors to consider and the education of patients, the general public and the health care personnel on these topics plays a valuable role. To help dispel stigma it is crucial the dissemination of correct and up-to-date information, the commitment of celebrities, patient families and friends, doctors in campaigning and advocating on their behalf, sharing the stories of lung cancer patient’s in order to increase the visibility of this disease and to generate a movement able to create a support network more sympathetic with these people, because they need and deserve care and support, not an evaluation of the possible causes of the disease. Raising the awareness is one of the main goals of any Lung Cancer Advocate worldwide and in conjunction with Lung Cancer Awareness Month, observed annually in November, many advocacy groups improve their efforts independently or in cooperation for promoting public campaigns about prevention, screening, new treatments and other issues. With the purpose of harmonizing the action, some years ago the International Association for the Study of Lung Cancer (IASLC) proposed and lead a unified effort among a consortium of non-profit lung cancer patient organizations and individuals to produce a coordinated public awareness campaign for Lung Cancer Awareness Month (LCAM) in November in order to reach the maximum amount of impact on media coverage, policy makers and public support.

      Reducing stigma is also one of pillar of the global action of GLCC (Global Lung Cancer Coalition) that in 2010, commissioned a research carried out by Ipsos MORI, which surveyed over 16,000 people in 16 countries, and found some evidence that sympathy levels were influenced by rates of smoking in each country. Between 10% and 29% of people admitted to feeling less sympathetic towards lung cancer sufferers because of its association with smoking.

      In 2017, GLCC commissioned a new multi-national study to Populus agency to undertake an online survey of adults across 25 countries for understanding attitudes towards lung cancer among the public. The results confirmed that 21% of people, out of least 1,000 adults per country still agree that they have less sympathy for people with lung cancer than other forms of cancer.

      In conclusion, in lung cancer there is a strong need to overcome many challenges to ensure that all of the patients may have the same hope and equal chances to fight against this disease. Lung cancer patients and caregivers still face a number of significant challenges and more has to be done to increase public awareness, to provide diagnostic tools and access to safe and effective treatments, to support efficient research and to combat the stigma. We’ve come a long way, and we certainly have a long way to go. We should work all together to effectively diminish the stigma that surrounds lung cancer and move forward in a positive way.

      References:

      1) Lung cancer stigma, depression, and quality of life among ever and never smokers Janine K. Cataldo, Thierry M. Jahan, and Voranan L. Pongquan

      2) Public attitudes about lung cancer: stigma, support, and predictors of support Jared Weiss,1Briana J Stephenson, Lloyd J Edwards, Maureen Rigney, and Amy Copeland

      3) Lung cancer in never smokers: clinical epidemiology and environmental risk factors Jonathan M. Samet, Erika Avila-Tang, Paolo Boffetta, Lindsay M. Hannan, Susan Olivo-Marston, Michael J. Thun and Charles M. Rudin

      4) Global Perception of Lung Cancer: An Ipsos MORI report for the Global Lung Cancer Coalition

      5) Based on WHO data (2005) on prevalence of tobacco used by country (full data and further information can be found at http://www.who.int/mediacentre/factsheets/fs297/en/index.html

      e353dbe42c8654f33588d4da0b517469

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      MS04.04 - E-Cigarettes - What Do Lung Cancer Advocates Need to Know? (ID 11418)

      11:15 - 11:30  |  Presenting Author(s): Carolyn Dresler

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      Abstract not provided

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    MS06 - Practical Issues in the Management of Oligometastatic NSCLC (ID 785)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Oligometastatic NSCLC
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 BD
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      MS06.01 - The Role of Radiation in Treating the Mets (ID 11423)

      13:30 - 13:45  |  Presenting Author(s): Hak Choy

      • Abstract
      • Presentation
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      Abstract not provided

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      MS06.02 - The Role of Interventional Pulmonology and Radiology (ID 11424)

      13:45 - 14:00  |  Presenting Author(s): Kwun M Fong

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      Abstract not provided

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      MS06.03 - The Role of Surgical Resection (ID 11425)

      14:00 - 14:15  |  Presenting Author(s): Boris Sepesi

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      Abstract not provided

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      MS06.04 - Systemic Therapy for Oligomets: Before, During, or After Local Therapies? (ID 11426)

      14:15 - 14:30  |  Presenting Author(s): Ross Camidge

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      Abstract not provided

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      MS06.05 - The Special Case of Brain Metastases: Systemic Therapy, Radiation or Both? (ID 11427)

      14:30 - 14:45  |  Presenting Author(s): Laurie Gaspar

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      • Presentation
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      Abstract not provided

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    MS09 - Tumour Board - Tissue Acquisition and Staging (ID 788)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 206 BD
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    MS18 - Management of SCLC Patients Not Represented in Clinical Trials (ID 797)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 206 BD
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      MS18.01 - Treatment of Patients with Poor Performance Status (ECOG 3-4) (ID 11477)

      13:30 - 13:50  |  Presenting Author(s): Luiz H. Araujo

      • Abstract
      • Presentation
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      Abstract not provided

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      MS18.02 - Treatment of Elderly Patients with SCLC (ID 11478)

      13:50 - 14:10  |  Presenting Author(s): Karen Kelly

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      • Presentation
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      Abstract not provided

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      MS18.03 - Treatment of SCLC transformed from EGFR Mutant Adenocarcinoma (ID 11479)

      14:10 - 14:30  |  Presenting Author(s): Nicolas Marcoux

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      • Presentation
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      Abstract not provided

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      MS18.04 - Retreatment with Platinum and Etoposide and Treatment Beyond Second Line (ID 11480)

      14:30 - 14:50  |  Presenting Author(s): Charles Butts

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      Abstract not provided

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    MS24 - Global Perspectives on Tobacco Control (ID 802)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 206 BD
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      MS24.01 - Tobacco Control Impacting the Effectiveness and Cost of Cancer Care (ID 11501)

      10:30 - 10:45  |  Presenting Author(s): Graham Warren

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS24.02 - Legal Action Against the Tobacco Industry in Europe (ID 11502)

      10:45 - 11:00  |  Author(s): Wanda De Kanter

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      Abstract not provided

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      MS24.03 - The Importance of Physician Involvement in Tobacco Control (ID 11503)

      11:00 - 11:15  |  Presenting Author(s): Jacek Jassem

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      Abstract not provided

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      MS24.04 - Challenges of Tobacco Control in China (ID 11504)

      11:15 - 11:30  |  Presenting Author(s): Caicun Zhou

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      Abstract not provided

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    MTE06 - Symptom Management in Mesothelioma (Ticketed Session) (ID 816)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Mesothelioma
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 206 BD
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      MTE06.01 - Role of Pleurectomy in Palliation of Symptoms (ID 11556)

      07:00 - 07:30  |  Presenting Author(s): John G Edwards

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      Abstract not provided

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      MTE06.02 - How to Register Toxicity and Guide Patients (ID 11557)

      07:30 - 08:00  |  Presenting Author(s): Liz Darlison

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      Abstract not provided

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