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Ming Sound Tsao



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    ES04 - Liquid Biopsies in Lung Cancer (ID 772)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 203 BD
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      ES04.01 - Liquid Biopsies in Lung Cancer (Now Available) (ID 11366)

      15:20 - 15:40  |  Presenting Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract

      A liquid biopsy in cancer patients generally refers to the sampling and analysis of circulating tumor cells (CTC) or circulating tumor-derived (ct) DNA for the diagnosis and management of patients (1). This contrasts with the traditional tissue biopsy, which still represents the gold-standard to assess the accuracy of liquid biopsies. Liquid biopsy has significant advantage over tissue biopsy as it is more convenient to perform with minimal risk to the patients, thus potentially allows more frequent sampling to monitor disease progression or treatment efficacy (2,3). More recently, liquid biopsy also has been proposed as primary tool for early detection and diagnosis of cancer, or in cancer genotyping to make therapeutic decisions (4). While rapid advances in microfluidic and/or high throughput sequencing technologies have demonstrated the feasibility of quantitative analysis of CTC and ctDNA in advanced stage lung cancer patients, the adoption of these technologies as clinical diagnostics should conform with the accepted principles of laboratory medicine in analytical validity, interpretation, reporting, clinical validity and utility (5).

      Although circulating tumor cells has been validated and approved by the FDA as a useful prognostic method for many cancer types (6), CTC in lung cancer has not become a clinically useful clinical assay in non-small cell lung cancer (NSCLC), primarily due to the small number of CTC detectable in these patients. In small cell lung cancer patients, CTC has greater number (7), yet its clinical utility still needs to be established.

      In contrast to CTC, the clinical adoption of ctDNA in lung cancer has occurred rapidly, especially in the detection of T790M resistant mutation during first and second-generation EGFR TKI therapies (8). Since ctDNA represents only a small fraction (<1%) of cell-free (cf) DNA in the blood, most of which are derived from leukocytes, highly sensitive methods are required to detect ctDNA. In general, two methodological approaches are used to “detect” the presence of ctDNA: PCR amplification or hybrid capture of tumor-derived target DNA fragments +/- next generation sequencing. With these techniques, the detection of mutant ctDNA sequences in advanced lung cancer patients with EGFR mutated adenocarcinoma has achieved 60-85% sensitivity and >95% specificity, using tissue-based diagnosis as the reference. Many pre-analytical conditions may influence the reliability of results of ctDNA analyses. Additional biological factors (e.g. tumor stage/burden, type, heterogeneity) could also influence the sensitivity of detection of specific tumor genomic aberrations. Since lysis of white blood cells will dilute the ctDNA with leukocyte-derived DNA, it is imperative to collect blood in tubes containing EDTA or leukocyte stabilizing agents (e.g. Streck tube). For the former, blood needs to be processed within 2-4 hours or sooner after collection, while with the latter, they can be kept for up to 48 hours or longer. Plasma is also preferred over serum as clotting increases the amount of non-tumor cf DNA resulting from leukocyte lysis.

      With the current achievable sensitivity, ctDNA should not be used in treatment naïve patients as the primary method to determine the mutation status of EGFR or other actionable driver oncogenes, except when biopsy tissue is insufficient and re-biopsy is not feasible for timely molecular testing. However, despite its suboptimal sensitivity, extensive studies have established the clinical utility of ctDNA for testing T790M in patients with EGFR mutant lung adenocarcinoma, who have progressed on first/second generation EGFR TKI therapy (9). The ctDNA assay may include DNA derived from all tumors in the body, thus has the potential of better representation of total body mutation status than tissue biopsy, which usually targets only one of many tumor nodules in metastatic setting. However, the suboptimal specificity mandates that a negative result triggers a tumor tissue re-biopsy to exclude false negative result or to identify other resistant mechanisms, including small cell carcinoma transformation. Other candidate ctDNA assays being studied for their clinical utility in lung cancer include resistant mutations to ALK inhibitors, and tumor mutation burden as predictive biomarker for immune checkpoint inhibitor therapies.

      Liquid biopsy has generated great excitement among oncologists as it potentially may overcome many of the “tissue is the issue” limitations in current biomarker testing paradigm. However, it is crucial that we apply the same stringency of evidence on liquid biopsy as that has been applied to tissue-based biomarker testing, including the demonstration of clinical validity and utility in clinical trial patient samples. While promising data are rapidly being generated on the roles of ctDNA assay for monitoring and adjusting treatment, or in early detection of lung cancer or residual disease, significant research is still required before they become standards in routine clinical practice.

      References:

      1. Crowley E, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 2013;10: 472–484

      2. Sacher AG, et al. Application of Plasma Genotyping Technologies in Non-Small Cell Lung Cancer: A Practical Review. J Thorac Oncol. 2017;12:1344-1356

      3. Diaz LA, Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014;32: 579–86.

      4. Santarpia M, et al. Liquid biopsy for lung cancer early detection. J Thorac Dis. 2018;10(Suppl 7): S882-S897.

      5. Merker JD, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol 2018;36: 1631-41.

      6. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014 Sep;14(9):623-31.

      7. Hou JM, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30: 525-32.

      8. Rolfo C, et al. IASLC Statement Paper: Liquid biopsy for advanced non-small cell lung cancer (NSCLC). J Thorac Oncol 2018 Jun 6. [Epub ahead of print]

      9. Lindeman NI, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13: 323-358.

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    MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD
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      MA24.05 - Baseline Spatial Heterogeneity of T790M in Tyrosine Kinase Inhibitor Naïve EGFR-Mutant Lung Adenocarcinomas (Now Available) (ID 14171)

      11:00 - 11:05  |  Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      Despite a good initial response, most epidermal growth factor receptor EGFR-mutant lung adenocarcinomas develop resistance after treatment with 1st and 2nd generation tyrosine kinase inhibitors (TKIs). Approximately 50-60% of resistance can be attributed to the EGFRT790M mutation, which provides a higher affinity ATP binding site that outcompetes TKIs and restore constitutive kinase function. Although classically thought of as de novoacquisition, the presence of T790M has been shown to exist in some tumors before TKI-therapy. Obtaining a spatial map of T790M in TKI-naïve tumors can provide insight into development of this type of resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight cases of TKI-naive primary lung adenocarcinoma resections that were later found to be positive for T790M post-treatment with TKI were collected from 2004 to 2012. Initial pre-treatment tumor surgical resections were used for DNA extraction. Two tumor sections per case were divided into equal grid-like regions of approximately 8x8 mm2. The number of grids ranged from 16 to 32 per case, based on tumor size (0.8 cm to 6.5 cm). Digital droplet polymerase chain reaction was used to genotype the sensitizing EGFR-mutations and T790M mutations at each region. Allelic frequencies (AF) of the mutations were measured. Recurrence free interval, defined as surgical resection date to date of recurrence detection, and total duration of TKI-therapy were extracted from medical records.

      4c3880bb027f159e801041b1021e88e8 Result

      All eight cases of TKI-naïve EGFR-mutant lung adenocarcinomas were positive for T790M at baseline. T790M tumor burden, defined as the mean allelic frequency of T790M, ranged from 0.17% to 40.15% across the tumors. Three main patterns of distribution were observed. In two cases, T790M was present at low level (<1% AF) prevalence throughout the entire tumor. Five cases were characterized by the presence of distinct sub-clonal region, defined as T790M AF high in one or adjacent regions surrounded by regions with low or zero T790M AF. In one case, T790M was the predominant clone with T790M AF closely matching sensitizing EGFR-mutation AF. T790M tumor burden was not associated with either tumor size or recurrence free interval.

      8eea62084ca7e541d918e823422bd82e Conclusion

      T790M tumor cells exist prior to TKI-therapy in a majority, if not all, EGFR-mutated lung adenocarcinoma that developed T790M mutation as the resistance mechanism to EGFR TKI therapy, rather than by de novo acquisition during TKI-therapy exposure. However, pre-treatment T790M tumor burden did not appear to be associated with recurrence free survival, although this requires more cases for confirmation.

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    MA25 - Oligometastasis: Defining, Treating, and Evaluating (ID 929)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 203 BD
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      MA25.11 - Clinical and Molecular Predictors of Outcome in Patients with EGFR mutant NSCLC Brain Metastases treated with RT (Now Available) (ID 14529)

      14:40 - 14:45  |  Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      Brain metastases(BM) develop in ~45% of patients with EGFR mutant(EGFRm) non-small cell lung cancers(NSCLC). There are limited reports on clinical/molecular factors associated with BM outcomes after radiotherapy in EGFRm NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified patients with EGFRm NSCLC who presented with or developed BM and had their lung tumor resected. Clinical, demographic and TP53 status were collected from medical/pathology records. Whole-Exome Sequencing of the primary tumor was performed. Overall survival(OS) and intracranial progression(IP) were defined from start of BM treatment and correlated with clinical/molecular features. IP was defined from the date of BM treatment until any brain failure, either local(previously present BM) or distant(development of new BM). Categorical and continuous covariates were tested by Fisher exact or Mann-Whitney test, respectively. OS by Kaplan-Meier with groups compared by log-rank. For each model the Harrell Concordance Index(CI) was performed.

      4c3880bb027f159e801041b1021e88e8 Result

      From 41 eligible patients with BM, 9 were excluded due to sequencing quality. Of the 32 remaining patients, 20 (62%) had their BM treated with WBI (15 WBI alone and 5 TKIàWBI), 12 (38%) with TKI±SRS (9 TKI àSRS; 2 TKI alone and 1 SRS alone). Median age at BM was 59.5 years(y). Most of the cohort were female(81%), non-smoker(78%), non-Asian(62%) and 50% presented as stage III or higher at diagnosis. An EGFR exon 19 mutation was present in 72% of patients, 25% had 2 or more EGFRm, 15% with additional driver mutations and 53% with TP53 co-mutation. At a median follow-up of 1.21-y, no clinical/molecular factors(treatment, age, gender, ethnicity, smoking status, stage at presentation, EFGR exon 19 versus 21, number of EGFRm, additional driver mutations, TP53 co-mutation) correlated with survival. There was a trend for longer survival for patients treated with TKI±SRS(median 3.4y) compared to WBRT±TKI(median 1.4y); p=0.08 and for age at BM ≤59.5y(median 2.5y) compared to >59.5y (median 1.4y); p=0.2. Higher risk of IP was observed in younger patients (age as continuous variable) with HR of 0.94(95%CI 0.88-1.0), p=0.04; favoring older patients and remained significant after accounting for treatment modality on multivariate analysis p=0.03. No additional clinical/molecular factors correlated with IP.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our study, younger age at BM treatment was associated with higher IP. We also observed a trend for longer OS for younger patients(≤59.5y) and for patients treated with TKI±SRS. Our data suggest that younger patients with EGFR BM should undergo close intracranial follow up and that future studies to define the benefit of brain-directed multimodality treatment are warranted.

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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 3
    • Now Available
    • 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 (Now Available) (ID 12144)

      13:30 - 13:35  |  Author(s): Ming Sound Tsao

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

      13:40 - 13:45  |  Author(s): 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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      MA27.07 - Lung Adenocarcinoma Harboring BRAF G469V Mutation is Uniquely Sensitive to EGFR Tyrosine Kinase Inhibitors (Now Available) (ID 12771)

      14:10 - 14:15  |  Author(s): 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.

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    MTE01 - Preclinical Models of Lung Cancer (Ticketed Session) (ID 811)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 206 F
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      MTE01.02 - Lung Patient Derived Xenograft and Organoid (Now Available) (ID 11547)

      07:30 - 08:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract

      Establishment of preclinical lung cancer models that closely match patient tumor biology is imperative for developing therapeutic strategies with the most translational relevance. Non small cell lung cancer (NSCLC) cell lines grown under 2D conditions or as cell line-derived xenografts (CDXs) are the most widely used models. They have been complemented with murine models engineered to develop lung cancer after introduction of specific genetic alterations (GEMMs). Lung cancer cell lines are readily amenable to mechanistic studies and economical high-throughput drug screening. However, for many NSCLC cell lines, the spectrum of mutations and copy number alterations have drifted considerably relative to patient tumors 1. This finding, in conjunction with long-term adaption to heterologous in vitro growth conditions, raise concerns about the extent to which cell line biology and potential drug responses may have deviated from clinical tumors. GEMMs are powerful tools for studying specific oncogenic mechanisms in isolation in vivo, but these models lack the intratumoral heterogeneity of patient tumors, which is thought to play a major role in the development of drug resistance. Furthermore, ideally, GEMMs should be constructed using the appropriate cell of origin context, which is challenging, as there are differences in the compositions of human and murine airways, and the cellular origins for most forms of lung cancer have not been established.

      NSCLC patient-derived xenografts (PDXs) overcome some of the limitations of these other models. They show much less genetic drift than cell lines, and their mRNA expression and the phospho-tyrosyl proteome more closely match patient tumors 1, 2. We have established a large collection of NSCLC PDXs from surgically resected tumors and endobronchial ultrasound-guided (EBUS) and CT-guided biopsies. Tumor specimens were initially implanted in the subcutaneous flanks of NSG mice (NOD SCID gamma, non-obese diabetic severe combined immunodeficiency, gamma). The PDX tumors have been viably cryopreserved and can be serially passaged in NOD SCID mice. Most of our collection comprises the major histologic subtypes of NSCLC [52 adenocarcinomas (LUAD) and 62 squamous cell carcinomas (LUSC)]. They, along with the primary patient tumors, are being molecularly profiled at multiple levels so that they can be optimally used for personalized medicine studies and novel integrated approaches to understand NSCLC pathogenesis, prognosis, and treatment. These levels include copy number variations, exome mutations, DNA methylation, mRNA and miRNA expression, and proteomics. In general, the PDX models recapitulate the mutation spectrum, copy number variations, and gene expression of matched patient histologies. They also recapitulate sensitivity and resistance to known targeted therapeutics (e.g. EGFR inhibitors), and thus, can be used to dissect mechanisms underlying differential drug responses. Such studies are ongoing, including investigation of potentially new biomarker-targeted therapeutic combinations. We have also found that not all patient tumor fragments engraft successfully, and that successful engraftment correlates with poor prognosis of the patient 3. We are using this relationship to discover a new molecular fingerprint to predict clinical outcome, as well as understand the bases that distinguish less and more aggressive tumor behavior.

      In parallel, we have developed methods to grow organoids from primary patient tumors and PDX models in 3D culture using Matrigel (PDO and XDO, respectively). For LUAD, both the PDO and XDO success rate of establishing bona fide organoid models is ~20%. Our stringent criteria include a minimum capacity of 10 passages and a split ratio of at least 1:3. LUSC has been more difficult to establish as organoid models, with a success rate of 17%, and only from PDXs, so far. Using these methods, we have established 4 models of each histology, which we have confirmed form tumors when transplanted into mice. Molecular profiling indicates that the organoids maintain the same mutation spectrum and copy number variations of their parental tumor tissue. These models offer distinct advantages over PDXs and cell lines. As compared to standard 2D cultures, they recapitulate the appropriate tissue histology, and thus, possibly clinically relevant growth control mechanisms, even while growing ex vivo. This notion is further supported by the ex vivo conditions supporting gene expression patterns, which allows the organoids to be segregated into their respective tumor histologies when using signatures derived from patient or PDX material. Given the low cost, rapid growth rates, and ease of in vitro manipulation, these models are ideally suited for rapid discovery and testing of new therapeutic strategies that can be matched to specific patient molecular profiles.

      In summary, generation of molecularly profiled PDX and organoid models offer great opportunity for translational and personalized medicine in NSCLC.

      1. Gao, H. et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat. Med. 21, 1318-1325 (2015).

      2. Wang, D. et al. Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors. Int. J. Cancer 140, 662-673 (2017).

      3. John, T. et al. The ability to form primary tumor xenografts is predictive of increased risk of disease recurrence in early-stage non-small cell lung cancer. Clin. Cancer Res. 17, 134-141 (2011).

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (Now Available) (ID 14530)

      10:50 - 11:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53

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

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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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  |  Author(s): Ming Sound Tsao

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-94 - Diagnostic Patterns of Non-Small Cell Lung Cancer at Princess Margaret Cancer Centre (Now Available) (ID 14178)

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      Accurate classification of lung cancer subtypes has become critical in tailoring lung cancer treatment. Our study aimed to evaluate changes in diagnostic testing and pathologic subtyping of advanced non-small cell lung cancer (NSCLC) over time at a major cancer centre.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A review of patients diagnosed with advanced NSCLC at the Princess Margaret Cancer Centre between 2007-2009 and 2013-2015 was performed. Diagnostic method, sample type and site, pathologic subtype, and use of immunohistochemical (IHC) staining and molecular testing were abstracted.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 238 patients were reviewed in 2007-2009 and 283 patients in 2013-2015 (Table 1). Over time, the proportion of patients diagnosed with adenocarcinoma increased from 60.9% to 73.1% while NSCLC-not otherwise specified (NOS) diagnosis decreased from 18.9% to 6.4%, p<0.0001. There was a decrease in use of diagnostic bronchoscopy (26.9% vs 18.4%) and an increase with mediastinal sampling procedures including endobronchial ultrasound (9.2% vs 20.5%), p=0.0001. A substantial reduction in cases reported as NSCLC-NOS was observed among bronchoscopy, image-guided, and mediastinal sampling procedures. The reduction in NSCLC-NOS was also predominantly seen in cytology samples, from 22.0% to 4.0% (p<0.0001).

      IHC use increased over time from 41.6% to 76.3% (p<0.0001). Patients with larger samples and IHC analysis were more likely to have biomarker testing performed (both p<0.01). Within the group diagnosed with NSCLC-NOS, the use of IHC increased non-significantly from 64% (29/45) to 94% (16/18). With the exception of bronchoscopy samples, use of IHC increased significantly with each method of diagnosis and sample type.

      table 1. patient demographics and diagnostic sampling characteristics.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Customizing treatment based on pathologic subtype and molecular genotype has become key in treating advanced lung cancer patients. Greater accuracy of pathologic diagnosis is being achieved including through use of routine IHC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.03 - Biology (Not CME Accredited Session) (ID 952)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.03-03 - Upfront Next Generation Sequencing in NSCLC: A Publicly Funded Perspective (Now Available) (ID 11826)

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      A growing number of targeted drug treatments in non-small cell lung cancer (NSCLC) have led to the need for molecular profiling beyond the standard of care (SOC) EGFR/ALK. Here we present actionable targets, impact on patient treatment, clinical trial opportunities and costs using the Illumina TruSight Tumor 15 panel (TST15) for NSCLC samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue-based next generation sequencing using the TST15 was reflexively performed on all newly diagnosed cases of non-squamous NSCLC at the University Health Network (Toronto, Canada) from February 2017-February 2018. The panel identifies hot spot mutations in KRAS, EGFR, TP53, PIK3CA, BRAF, ERBB2, FOXL2, GNA11, GNAQ, KIT, NRAS, PDGFRA, RET, AKT1 and MET, but not fusions, copy number variations (CNV) nor MET exon 14 skipping mutations. Patient age, stage, pathologic subtype, and genotyping results were collected prospectively. Treatment changes as a result of TST15 and clinical trial opportunities (clinicaltrials.gov) were identified. Incremental testing costs were based on direct laboratory costs, but not personnel and administration costs.

      4c3880bb027f159e801041b1021e88e8 Result

      Testing included 342 samples from 336 patients. The TST15 panel identified 409 mutations from 342 samples. Sample demographics include: male: 53, and stage 1/2/3/4: 34/8/15/43%. Incremental actionable targets beyond EGFR and ALK were identified in 3.5% of patients (ERBB2 2.3%, BRAF V600E 1.2%). Most mutations occurred in TP53 (43%), EGFR (24%) and KRAS (26%). Co-mutations occurred in 32% (TP53, KRAS, EGFR) of samples. To date, one patient has had a treatment change as a result of TST15 beyond targeting EGFR. Above SOC clinical trial options were identified for 88% of stage IV and 26% of stage III patients. 3.6 samples were needed to identify one actionable mutation, predominantly in EGFR, at an estimated cost of $1919 CAD per target.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Extended genotyping with TST15 in NSCLC identifies an additional 3.5% of patients with actionable mutations above SOC and improves clinical trial options for patients. Despite this, impact on patient treatment beyond targeting EGFR is minimal. To enhance the number of targets and minimize costs, affordable population-based comprehensive testing with a panel that includes fusions/CNV is needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.03-04 - Next Generation Sequencing in Lung Cancer Using the Oncomine Comprehensive Assay: The Canadian Publicly Funded Experience (Now Available) (ID 12181)

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      Standard of care (SOC) diagnostics for patients with stage IV non-small cell lung cancer (NSCLC) in Canada includes EGFR and ALK testing. Other genomic alterations are not tested routinely; however, access to enhanced molecular testing may broaden treatment options, clinical trial access, and improve outcomes for patients. This study uses the Oncomine Comprehensive Assay (OCA) v3, a next generation sequencing (NGS) panel in NSCLC to evaluate actionable targets, clinical trial eligibility, treatment impact, costs, turnaround time, and patient preference.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Consecutive consenting stage IV NSCLC outpatients at the Princess Margaret Cancer Centre without EGFR/ALK/KRAS/BRAF derangement diagnosed at the University Health Network (UHN) in Toronto, Canada will be enrolled to undergo OCA testing on diagnostic samples. The selected platform (OCA v3, ThermoFisher) includes 161 genes including hotspots, fusions, and copy number variations. Patient age, pathologic subtype, genotyping results and treatment history will be collected. Primary endpoints include incremental actionable targets identified and clinical trial opportunities (clinicaltrials.gov) added through incremental testing beyond SOC. Secondary endpoints include treatment changes as a result of OCA testing, costs from the perspective of the Canadian public healthcare system, patient willingness-to pay, and test turnaround time.

      4c3880bb027f159e801041b1021e88e8 Result

      The study activated in February 2018 with 7 patients enrolled as of April 2018. Results of the value of incremental OCA testing beyond standard of care in the Canadian public healthcare system will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      While OCA testing in patients with advanced NSCLC may identify more actionable targets than selected genotyping, its cost effectiveness in the Canadian healthcare system is unknown and will be determined through this study.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.09 - Pathology (Not CME Accredited Session) (ID 958)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.09-01 - Tumor-Associated Immune Cell Infiltration Patterns in Early Stage Squamous Lung Carcinoma (Now Available) (ID 13456)

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      With the recent clinical success of immunotherapy in non-small cell lung carcinoma, the character of the inflammatory infiltrate associated with these tumors is now the subject of increasing interest. Molecular studies have suggested that tumors can be stratified by the character of their inflammatory infiltrate. We now describe the detailed histological appearances of a multi-institutional series of early stage squamous carcinomas and correlate them with mutation burden, PDL1 expression patterns and clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histologic sections of from 250 tumors were evaluated by two pathologists independently for squamous subtype (WHO classification), percentage and character of intratumoral inflammatory cells, percentage and character of para-tumoral infiltrate and presence or absence of scalloping at tumor cell/stromal interface by inflammatory cells along the edges of tumor cell nests, a feature possibly related to existing immune reaction. The ratios of infiltrating inflammatory cells to tumor cells were estimated in 10% increments by microscopic inspection. Quantity and character of infiltrates was assessed by Kaplan-Meir testing for effect on survival and by Pearson bivariate testing for relationships among variables.

      4c3880bb027f159e801041b1021e88e8 Result

      The character and extent of inflammatory infiltrates were highly heterogeneous. The infiltrates could be divided into intratumoral and paratumoral patterns according to their location in relation to microscopic tumor cell nests. Intratumoral infiltrates could be further subdivided into two patterns: one consisted exclusively lymphocytes, usually few in number; a second polymorphous pattern contained many inflammatory cell types including polymorphonuclear leukocytes (PMNs). In paratumoral tissue, three patterns could be discerned: lymphocytic, plasmacytic and polymorphous. Inflammatory cell infiltrate quantity or character did not correlate with survival for either intratumoral or paratumoral infiltrates and there was no evident relationship to mutational burden or to PDL1 expression by IHC. Scalloping at the tumor cell stromal interface was also not prognostically significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The inflammatory infiltrates in early stage squamous lung carcinoma are highly heterogenous and are not associated with outcome. However, the complexity of tumor infiltrating inflammatory cells is worthy of further evaluation in future immunotherapeutic trials.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.09-02 - Comprehensive Assessment of PD-L1 Immunohistochemistry on Paired Tissue and Cytology Specimens in Non-Small Cell Lung Cancer   (Now Available) (ID 13248)

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      Molecules targeting Programmed Death Receptor 1 (PD-1) and its ligand (PD-L1) are now part of the therapeutic arsenal for patients presenting with advanced stage non-small cell lung carcinoma (NSCLC). PD-L1 staining assessed by immunohistochemistry (IHC) is currently used as a predictive biomarker to select patients likely to respond to PD-1/PD-L1 inhibitors. Despite recent data, it is still not clear if cytology specimens provide reliable and valid PD-L1 results, when compared to tissue specimens. In this project, we aimed to compare PD-L1 IHC results on tissue (biopsy and surgery) and cytology specimens from the same patient. We also wanted to assess the performance of two IHC kits as well as the intra and interobserver agreement in evaluating cytology specimens.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort comprising 46 patients with a diagnosis of NSCLC was selected. Each patient had a surgical specimen with a corresponding cytology sample (cell block), including 20 pleural effusions, and/or a biopsy, for a total of 182 specimens. IHC was performed using 28-8 and SP263 PD-L1 kits. PD-L1 staining was measured as the percentage of tumor cells with membranous staining (tumor proportion score, TPS) as rated blindly by four evaluators. Sixty slides were then blindly reevaluated for documenting intraobserver agreement. PD-L1 TPS was grouped as <1%, 1-49% and >50%. Fleiss and Cohen’s kappas were used to evaluate TPS concordance between tissue and cytology specimens and to assess the inter and intraobserver agreement.

      4c3880bb027f159e801041b1021e88e8 Result

      Respectively for 28-8 and SP263 kits, 37.5 and 25.0% of the 32 patients with a cytology sample had a PD-L1 TPS of >50% with a good agreement between the kits (k=0.73, CI95% 0.50-0.97). The agreement between the cytology and surgical specimen was good (28-8: k=0.76, CI95% 0.46-1.0, SP263: k=0.75, CI95% 0.42-1.0) and was slightly lower between the 26 patients with a biopsy and a cytology specimen (28-8: k=0.71, CI95% 0.31-1.0, SP263: k=0.67, CI95% 0.19-1.0). For the evaluation of PD-L1 TPS in cytology specimens, the interobserver agreement was good (28-8: k=0.71, CI95% 0.60-0.82, SP263: k=0.63, CI95% 0.52-0.74) and the intraobserver agreement was excellent (k=0.93, CI95% 0.85-1.0).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We showed that PD-L1 TPS evaluated in cytology samples have a good concordance with biopsy and surgical specimens. We also demonstrated that the evaluation in cytology specimen is feasible as the inter and intraobserver agreement was good to excellent. Overall, our results support the use of PD-L1 IHC on cytology specimens, however, this will need to be correlated with the clinical response to immunotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.11 - Screening and Early Detection (Not CME Accredited Session) (ID 960)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.11-19 - MicroRNAs as Liquid Biopsy Biomarkers for Early Detection in Lung Cancer. (ID 14050)

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      microRNAs (miRNAs) control the expression of key driver genes associated with tumorigenesis in several cancer types and can be detected as stable circulating molecules in body fluids. Deregulated miRNAs have been identified as potential biomarkers in plasma from cancer patients. In lung cancer, the most promising clinical application of circulating miRNAs is early disease detection, since late diagnosis is a major clinical problem associated with patient death.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      38 plasma samples from patients with lung adenocarcinoma and squamous cell carcinoma and 21 healthy controls from a screening population were profiled for an 800 miRNA set using the Nanostring nCounter® platform. Validation was performed in an independent sample set of 40 patients and 40 controls, paired by age and sex, using TaqMan® quantitative real-time PCR. Statistical analyses were performed using the Mann Whitney test, and miRNA signatures identified by Elastic net, improved Maximizing R Square Analysis (MARSA) and C-Statistics. Bioinformatic approaches were applied for external data validation against other miRNA expression datasets.

      4c3880bb027f159e801041b1021e88e8 Result

      A subset of 149 miRNAs was significantly over-expressed in patient plasma compared to controls with fold change ≥2, p≤0.01 and FDR<0.05. In addition, three distinct miRNA signatures with 12 unique miRNAs were identified in the discovery set (hsa-miR-16-5p, hsa-miR-92a, hsa-miR-106b-5p, hsa-miR-148b-3p, hsa-miR-155-5p, hsa-miR-217, hsa-miR-378e, hsa-miR-451, hsa-miR-484, hsa-miR-1285-3p, hsa-miR-1285-5p and hsa-miR-664a-3p). All signatures were validated in the independent sample set, being able to distinguish patients from controls. Interestingly, miRNAs identified herein control the expression of tyrosine kinase, transcription factors and immune system related genes associated with lung tumorigenesis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      By using a highly specific and sensitive assay and stringent criteria on sample selection and data analyses, we were able to identify known and novel miRNAs that are significantly deregulated exclusively in plasma from patients with a diagnosis of lung adenocarcinoma or squamous cell carcinoma. Our results contribute to the identification of circulating plasma miRNAs as potential biomarkers for early disease detection in lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.11-23 - Risk Perception Among a Lung Cancer Screening Population (ID 13045)

      16:45 - 18:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      To make lung cancer screening feasible, populations with the highest risk of developing cancer need to be targeted. Furthermore, factors which motivate individuals to participate in lung cancer screening programs should be integrated into recruitment strategies. Among these motivators, an individual’s perception of their lung cancer risk is an important consideration. This paper analyzes factors associated with risk perception in subjects enrolled in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan), and assesses the relationship between subjects’ risk perception and actual calculated risk.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The PanCan low-dose screening CT study recruited individuals from the general population who were current or former smokers age 50-75 having at least a 2% risk of developing lung cancer over 6 years as calculated by the PanCan model. Risk perception was captured at baseline with a 5-point Likert scale question asking the subject to assess their personal chances of being diagnosed with lung cancer compared with other smokers of the same age. Multivariate linear regression analysis was used to assess the relationship between risk factors and risk perception. Baseline risk variables in the model include demographics, smoking history, symptoms, medications, occupation, previous chest imaging, history of COPD, medical comorbidities, and family history of cancer.

      4c3880bb027f159e801041b1021e88e8 Result

      2514 patients were included in the analysis. Median age was 62.3, 55.3% were male, median pack-year smoking history was 50 years (range 2.2-230), and median calculated lung cancer risk was 3.4% over 6 years (range 2-38.2). Calculated lung cancer risk increased by 0.08% (SE 0.02, p-value=0.001) for each increase in Likert risk perception category. On multivariable analysis, the following variables were associated with risk perception category: cigarettes smoked per day (+0.003 increase in category / cigarette, p=0.083), presence of dyspnea (+0.192), presence of wheeze (+0.272), known COPD (+0.110), no family history of cancer (-0.476) and no family history of lung cancer (-0.385) (all p<0.001). Increased perception of risk was associated with intent to quit smoking within 6 months (p<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this lung cancer screening study, risk perception was positively associated with calculated risk for lung cancer, despite a minimum 2% risk in the cohort. Individual factors and family history of cancer predicted risk perception. Risk perception was also associated with a willingness to quit smoking. Self-risk perception and associated factors could be used to tailor recruitment strategies to screening programs. The link between risk perception and willingness to quit smoking could aid integrated tobacco cessation programs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.03 - Biology (Not CME Accredited Session) (ID 969)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.03-06 - Differentially Expressed microRNAs in Lung Adenocarcinoma Invert Effects of Copy Number Aberrations of Prognostic Genes (ID 14319)

      12:00 - 13:30  |  Author(s): Ming Sound Tsao

      • Abstract

      Background

      Significant associations between chromosomal copy number aberrations (CNAs) and differential gene expression have been found across many cancers. However, significantly downregulated genes have been often found to reside within chromosomal regions with increased number of copies and vice versa, creating a paradoxical signal. This phenomenon was usually ignored as a noise, but can potentially be a consequence of interference of other regulatory mechanisms controlling mRNA transcription.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To explore existence of such paradoxes in lung adenocarcinoma (LUAD), we performed integrative analysis of 1,937 tumour and normal tissue samples, comprising copy number aberrations, gene expression and microRNA expressions data and conducted meta-analysis of 9 microRNA expression studies.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified and validated 75 “paradoxical” genes whose differential expression consistently contrasted with aberrations of their copy numbers. Of these, 41 genes (p < 0.001) are prognostic and form a clinically relevant signature. Interestingly, differential expression of 19 microRNAs that are frequently deregulated in LUAD, explains observed paradoxes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that deregulation of paradoxical genes is crucial in LUAD and their expression pattern is maintained epigenetically, defying gene copy number status. Our work highlights importance of large integrative analysis of diverse biological data and the need to examine phenomena that contrast the established knowledge.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.03-18 - Collagen Type XI Promotes Lung Adenocarcinoma Dissemination Via Integrin α2 and DDR1 (ID 14009)

      12:00 - 13:30  |  Author(s): Ming Sound Tsao

      • Abstract

      Background

      Our previous studies showed that non-small cell lung cancer (NSCLC) stroma is an important actor of lung tumorigenesis. We found integrin α11, a fibrillar collagen receptor expressed on cancer-associated fibroblasts (CAF), to be strongly up-regulated in NSCLC stroma and to promote NSCLC growth in vivo. Collagen XI is a fibrillar collagen that expression is increased in NSCLC and is correlated with integrin α11 expression. The purpose of the present study is to determine whether integrin α11-mediated lung tumorigenesis is induced via collagen XI and how that collagen may affect lung carcinoma cell invasion.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To study the effects of collagen XI, collagen XI has been incorporated in a matrix of collagen I at a ratio 1:3 (collagen I/XI). For tumor cell invasion, lung adenocarcinoma H1975 cells were allowed to form spheroids before being embedded in a collagen I or a mix of collagen I/XI matrix. Area of dissemination and migration pattern has been analyzed 48 hours later. In order to identify the collagen receptor interacting with collagen XI, we used cell attachment and ELISA assay. Knockout of integrin α2 and DDR1 has been performed using the CRISPR-Cas9 strategy in H1975 cell line.

      4c3880bb027f159e801041b1021e88e8 Result

      We showed that high collagen XI expression is associated with high risk of recurrence in the UHN cohort of 165 NSCLC patients (hazard ratio= 1.97, 95% confidence interval 1.09-3.56, P<0.026). Surprisingly, CAF embedded in a mix of collagen I/XI matrix failed to reorganize the collagen matrix as efficient as embedded CAFs in only collagen I matrix and displayed inhibition of migration in presence of collagen XI. In contrast, collagen XI greatly enhanced invasion of lung adenocarcinoma H1975 cells in a mix collagen matrix with a different invasion pattern compared to H1975 cell invasion in collagen I. Although integrin α11 expression correlates with collagen XI expression in NSCLC, this integrin bound poorly to collagen XI. Instead we found integrin α2 and DDR1 to interact with collagen type XI (Kd=5nM and Kd=24nM, respectively). Knockout of integrin α2 or DDR1 in H1975 cells suppressed collagen XI-increased invasion in a collagen I/XI matrix, indicating that both collagen receptors are required to mediate collagen XI effect on lung adenocarcinoma dissemination.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We showed that the presence of collagen XI in NSCLC stroma could enhance lung adenocarcinoma dissemination via integrin α2 and DDR1. Thus, targeting these two collagen receptors may be a new strategy to improve the outcome of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.03-19 - The Lysyl Oxidase like-1 Promotes NSCLC Tumorigenecity Through Increased Matrix Reorganization and Stiffness (ID 14048)

      12:00 - 13:30  |  Author(s): Ming Sound Tsao

      • Abstract

      Background

      The importance of the stroma in tumorigenicity has been increasingly recognized in the past few years and targeting tumor stroma has become a new strategy for the development of new therapies. The lysyl oxidase like-1 (LOXL1) is a matrix cross-linking enzyme, essentially secreted by cancer-associated fibroblasts (CAFs) in the stroma. We previously showed that LOXL1 expression strongly correlated with integrin α11 expression, a collagen receptor that promotes NSCLC tumorigenecity, suggesting that LOXL1 may also contribute to lung tumor growth and metastasis by modifying the stromal collagen matrix.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Primary CAFs (CAF094) isolated from a NSCLC resection specimen and immortalized with hTERT were infected with full length LOXL1 (LOXL1 overexpression), LOXL1 shRNA (LOXL1 knockdown) or with their respective controls, using a lentiviral system. To investigate the impact of LOXL1 on collagen matrix reorganization, we allowed CAFs expressing different levels of LOXL1 to contract collagen matrices. Contracted collagen matrices have then been submitted to second harmonic generation to analyze collagen fibers. We established the role of LOXL1 in lung carcinoma invasion and growth using an in vitro organotypic model and an in vivo xenograft model, respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      LOXL1-overexpressing CAFs embedded in collagen lattices displayed greater ability to reorganize the collagen matrix than those with lower LOXL1 expression. Furthermore, analysis of the collagen matrix demonstrated that LOXL1 contributed to more linear and dense collagen fibers organization. As a consequence of collagen matrix reorganization, invasion of the lung carcinoma H661 cell line significantly increased in an organotypic model in presence of LOXL1-overexpressing CAFs. Moreover, we showed that loss of Loxl1 in mice inhibited subcutaneous growth of the lung adenocarcinoma H4006 cell line compared to the mouse wild-type counterparts.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrated that overexpression of LOXL1 in NSCLC tumor stroma results in an increased of tumor growth and invasion, due to a change in the matrix reorganization. Thus, LOXL1 appears as an interesting target to improve the outcome of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P3.03-29 - The Prognostic Effect of Tumor Mutation Burden and Smoking History in Resected EGFR Mutant Non-Small Cell Lung Cancer (Now Available) (ID 13199)

      12:00 - 13:30  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      Although EGFRm NSCLC occurs mainly in non-smoking patients, most series report 20%-35% of cases in current or previous smokers. Broad molecular profiling of EGFRm NSCLC in smokers has not been reported.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgically resected primary EGFR exon 19, 20 and 21 mutated NSCLC tumors from 106 patients were molecularly profiled by whole exome sequencing using the Illumina HiSeq2000 platform. Alignment and variant discovery analysis was performed according to GATK best practices workflow; 74 sequenced to a mean coverage of 65.1x. Demographics and outcomes were compared for smokers and non-smokers (non-S), and by mutation profile.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 53 non-smokers and 21 smokers (5 current/recent within 10 years), 70% were female, 51% non-Asian, 40.5% >65 years of age and 58.1% had EGFR exon 19. Of the 74 patients, 51% were stage I, 19% stage II and 30% stage III+. Smoking was associated with male sex (p= 0.011) and non-Asian ethnicity (p=0.00002) but not age, stage or EGFR exon 19/20/21 subtype. Multiple “driver” mutations occurred in tumors of 23.8% smokers and 26.4% non-S. TP53/EGFR co-mutation occurred in 52.4% smokers and 47.2% non-S. There was no significant difference seen for TMB in smokers: median TMB in smokers 3(1.4-7.46) versus 2.7(0.96-3.95) in non-S (p=0.11). The strongest prognostic factor for OS and DFS was stage (I, II, III+) (p<0.0001 for each compared to stage I). Smoking history did not have a significant effect on survival: HR 1.61 (CI 0.78-3.32, p=0.2) or probability of relapse: HR 0.9 (CI 0.46-1.77, p=0.77). Smoking within 10 years of NSCLC diagnosis was not associated with shorter OS/DFS. Neither EGFRm subtype nor TP53/EGFR co-mutation was associated with probability of relapse or OS. High TMB was significantly associated with shorter survival: HR above vs below the median 2.37 (CI 1.12-5.01, p=0.024), but not probability of relapse: HR 1.67 (CI 0.88-3.19, p=0.12). A subset analysis found the effect of TMB on survival was significant in patients >65 years (p=0.004), but not in patients <65 years (p=0.95).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Stage remains the strongest prognostic factor for survival and probability of relapse in completely resected EGFRm NSCLC. TMB appears to have an effect on survival outcomes, unlike smoking status, and this effect may be greater in patients older than 65 years.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.09 - Pathology (Not CME Accredited Session) (ID 975)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.09-26 - Concordance of Surgical Resections and Fine Needle Biopsy-Derived Cell Block Sections for PD-L1 22C3 Immunohistochemistry   (ID 13499)

      12:00 - 13:30  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 982)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.16-07 - The Impact of Clinical and Molecular Profile of Resected EGFR-Mutant Non-Small Cell Lung Cancer on the Risk of Developing Brain Metastases (Now Available) (ID 13339)

      12:00 - 13:30  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Background

      Brain metastases are common in non-small cell lung cancers (NSCLC) with activating EGFR mutations (EGFRm), occurring in 44%-63% of patients. To date, there are no known clinical or molecular factors to predict the risk of brain metastases in these patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this retrospective single-institution study, we identified 106 patients with EGFRm NSCLC who underwent surgery for primary lung tumor. Clinical and demographic data was collected from electronic records. Whole Exome Sequencing (WES) of the primary tumor was performed utilizing the Agilent SureSelect Exome v6+COSMIC baits followed by sequencing on the Illumina HiSeq2500 platform. Development of brain metastases was correlated with clinical/pathologic features, EGFR mutation type, co-mutation of EGFR and other frequently mutated genes; and non-synonymous tumor mutation burden (TMB). Statistical analysis used Fisher exact test for categorical variables, Mann-Whitney test for continuous variables of association with the risk of developing brain metastases, and Gray’s test for the probability of brain metastases over time.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 106 patients who underwent surgical resection of primary EGFRm NSCLC, WES was successful for 73: 51 (70%) females, 52 (71%) never smokers, 38 (52%) stage I, 14 (19%) stage II and 21 (28%) stage III; 42 (57%) EGFR exon 19 mutation, 30 (41%) exon 21, 1(1%) Exon 20 insertion mutation.

      Twenty-five patients (34%) developed brain metastases. Patients with brain metastases were younger (median age 61 vs. 65 years, p=0.021), had more advanced stages (p=0.012), with a trend towards higher rates in females (p=0.066). One patient with brain metastases had de-novo EGFR T790M mutation in the primary tumor. No difference was seen regarding smoking history, EGFR mutation type, TP53 co-mutation, and median TMB. The 5-year probability of brain metastases increased with increasing stage (14% stage I; 43% stage II, [HR=3.00], 44% stage III, [HR=3.13], p=0.03), and a trend towards higher probability among females (33% vs. 19%; HR=0.39 for males, p=0.074), and younger patients (37% <65 years vs. 15% >65, HR=0.37 in older patients, p=0.042). There was no difference in probability of brain metastases based on smoking history, ethnicity, EGFR type (33% exon 19 vs. 22% exon 21, p=0.28), TP53 co-mutation (31% vs. 27% without TP53, p=0.59), or TMB (24% TMB≤2.87 vs. 32% TMB>2.87non-synonymous mutations/Mb, p>0.99).

      8eea62084ca7e541d918e823422bd82e Conclusion

      While our findings suggest that younger age, advanced stage, and female sex may be associated with the development of BM in EGFRm NSCLC, we could identify no molecular predictor of BM based on EGFR subtype, TP53 co-mutation or TMB.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PL04 - Take Action - Key Messages from WCLC 2018 and Goals for 2019 (ID 852)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 15:15 - 16:30, Plenary Hall
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      PL04.02 - Biomarkers (Now Available) (ID 11656)

      15:25 - 15:35  |  Presenting Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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