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Geoffrey Liu



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    MA14 - Survivorship, Socioeconomic and End-of-Life Considerations (ID 915)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 205 BD
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      MA14.06 - Predictors of Financial Toxicity, an Under-Recognized Patient-Reported Outcome (Now Available) (ID 13571)

      11:05 - 11:10  |  Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Background

      In contemporary cancer care, financial distress has been established as a clinically relevant patient-reported outcome (PRO) associated with worse mortality and quality of life, but remains under-recognized by health care providers. Our goal was to define predictors of patient financial toxicity (FT) in a public healthcare system.

      Method

      Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FT was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, an 11-item survey scored from 0-44 with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP) and extended insurance coverage (EIC) were collected. Associations between variables and COST score were evaluated using multivariable regression analyses.

      Result

      Of 249 patients approached, 200 (80%) participated. Median age of the cohort was 65 years; 44% were male, 36% immigrants, 67% employed or on pension, with median OOP between $1000-5000 CAD. Median COST score was 21 (range 0-44). FT was associated with age, with patients <65 years reporting greater FT than older patients (COST 18 vs. 25; P<0.0001). Employed patients or those receiving pension income reported less FT than unemployed patients (22 vs. 19; P=0.01). Less FT occurred in patients with EIC compared to those without (23 vs. 19; P=0.03). Patients with higher OOP reported more FT (P<0.0001). Patients on clinical trials reported less FT than others (25 vs. 20; P=0.04). In multivariable linear regression, younger age was a predictor of higher FT, when adjusting for income, employment status, OOP and EIC (P<0.0001).

      Conclusion

      Age is a predictor of FT in the Canadian (Ontario) public healthcare system, with younger lung cancer patients reporting greater financial distress. This study highlights priority patient populations where FT should be routinely assessed and appropriate resources for support offered.

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    MA17 - New Methods to Improve Lung Cancer Patients Outcomes (ID 918)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Nursing and Allied Professionals
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 205 AC
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      MA17.09 - Remote Symptom Reporting for Tele-Nursing Team in Thoracic Oncology Clinics: Environmental Scan and Stakeholder Engagement (Now Available) (ID 12226)

      14:30 - 14:35  |  Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Background

      50+% of cancer-related toxicities are under-reported. A real-time Remote (i.e., at-home) Symptom Reporting (RSR) system could help patients seek help when symptoms exceed thresholds, mitigating unplanned clinic/emergency room visits. A RSR system for solid-tumor patients undergoing chemotherapy is associated with improved health-related quality of life and survival (Basch et al, 2017). Adapting RSR into the thoracic cancer clinic environment requires assessments of potential implementation barriers, and tailoring of the RSR-system.

      Method

      Over a five month period, we performed an environmental scan to determine readiness of RSR implementation in our comprehensive thoracic oncology outpatient clinic. A qualitative assessment of potential RSR integration into the telephone triage environment was performed through one-on-one interviews and focus groups, followed by thematic analysis. Discussions were held with multiple stakeholders; key implementation champions were identified. We utilized the Canadian Institutes of Health Research Knowledge-to-Action Framework, Steps 2-4 as our guide.

      Result

      In the environmental scan, 125 telephone triage calls were logged over randomly-chosen days in a 6-week period. The mean ± SEM call duration was 5.4 ± 0.62 minutes. Mean time until response was 44.4 ± 3.8 minutes. Nurses spent on average 2.7 ± 0.2 minutes documenting into the electronic-patient-record. The mean duration from initial contact to completion was 24.1 ± 4.5 minutes. Resolution of the triage calls involved telephone advice alone (87%; n=109), unplanned clinic visits (6%; n=8), and emergency visits (6%; n=7).

      In the qualitative analyses, top stakeholder-identified issues were: lack of assessment standardization; wasted time transcribing paper triage notes to electronic records; and a high patient/family burden in terms on understanding when to seek help. There was universal interest in adopting a RSR system from administrative assistants, nursing administration, clinic nurses, physicians and trainees. Perceived benefits of RSR were: standardized, focused telephone assessments; tailored symptom assessments in the thoracic setting (i.e., dyspnea, coughing, hemoptysis); patient empowerment; and improved efficiency in patient contact, intra-team communication, and documentation. Key stakeholder RSR features were: a phone/web application that assesses symptom severity and indicates when to contact the triage team; one-touch feature to reach team; longitudinal symptom trend display for tele-nursing team; and embedding of the COSTaRS framework to facilitate tele-nursing interventions and documentation.

      Conclusion

      Integration of a RSR system integration was perceived favorably by stakeholders to increase nursing efficiency and improve health related patient outcomes, but success hinges on an identified set of key requirements.

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    MA18 - Modelling, Decision-Making and Population-Based Outcomes (ID 920)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 201 F
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      MA18.07 - Awareness of the Harms of Continued Smoking Among Lung Cancer (LC) Survivors (Now Available) (ID 12024)

      14:05 - 14:10  |  Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Background

      Continued smoking after a LC diagnosis is associated with poorer cancer outcomes including increased risk of treatment-related side-effects, reduced treatment efficacy and poorer prognosis. Smoking cessation is an integral part of LC survivorship by improving both cancer and non-cancer outcomes. To enhance survivorship education, clinicians should understand patient awareness of the harms of continued smoking.

      Method

      LC survivors from Princess Margaret Cancer Centre, Toronto (2014-2017) were surveyed with respect to self-awareness of the harms of continued smoking on cancer-related outcomes. Univariable and multivariable logistic regression models assessed factors associated with awareness and whether awareness was associated with cessation among current smokers at diagnosis.

      Result

      Of 553 patients, 181 were lifetime never-smokers. Among those smoking during the peri-diagnosis period (n=177), 65% quit after diagnosis. Among all, few patients were aware that smoking negatively impacts treatment-related outcomes [complications from cancer surgery (only 41% aware), radiation side-effects (30%), quality-of-life on chemotherapy (44%) and treatment efficacy (36%)]; half were aware that smoking negatively impacts cancer prognosis (51% aware) and risk of developing second primaries (50%). Compared to ex-smokers/never-smokers at diagnosis, current smokers at diagnosis were less aware of the impact of smoking on radiation side-effects (22% vs 31% aware, P=0.01), prognosis (44% vs 55%, P=0.02) and risk of second primaries (42% vs 55%, P=0.007). Among sociodemographic variables, only those speaking English at home were consistently found more likely unaware that smoking negatively impacts these outcomes (ORs=1.52-2.20, P<0.04). Patients with early stage disease were more likely unaware that smoking negative impacts radiation side-effects (OR=1.60, 95%CI[1.09-2.35], P=0.02); while patients on curative treatment (OR=1.53[1.08-2.17], P=0.02) and those exposed to second-hand smoke (SHS) were more likely unaware that smoking impacts quality-of-life on chemotherapy (OR=1.64[1.05-2.58], P=0.03). Exposure to SHS, treatment intent and stage were not associated with awareness of impact on prognosis or second primaries (P>0.11). Among smokers in the peri-diagnosis period, awareness of the impact of smoking on surgical complications (aOR=2.09 [0.96-4.54], P=0.06), quality-of-life while receiving chemotherapy (aOR=2.60[1.17-5.79], P=0.02) and on treatment efficacy (aOR =2.24[0.97-5.20], P=0.06) were each associated with subsequent quitting, adjusted for marital status, pack-years, self-rated health and SHS exposure.

      Conclusion

      Many LC patients are unaware of the harms of continued smoking on cancer outcomes, particularly those smoking at diagnosis. Awareness of some of these outcomes was associated with subsequent tobacco cessation. Patient education on the health benefits of smoking cessation may increase quit rates and improve outcomes for LC patients.

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      MA18.09 - Predictors of Health Utility Scores (HUS) in Advanced EGFR-Mutated NSCLC. (Now Available) (ID 13087)

      14:25 - 14:30  |  Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Background

      Advanced NSCLC patients with EGFR mutations (EGFRm) are currently treated with first - to third-generation tyrosine kinase inhibitors (TKIs). In the advanced setting, quality of life is an important goal; we therefore evaluated determinants of HUS in this population.

      Method

      In a prospective, observational study, patients with advanced EGFRm NSCLC completed EQ-5D surveys at outpatient visits generating HUS (range 0-1). Patients were allowed to enrol at any point in their disease course. Baseline clinical characteristics and outcome data were extracted from chart review. Patient imaging was reviewed and health states (stable/progressing) at each encounter recorded. Univariable analyses conducted using ANOVA and multivariable regression analyses with generalized estimating equations identified factors associated with HUS.

      Result

      From November 2014 to July 2017, 782 encounters (follow-up visits) were collected for 244 patients. Median age at first encounter was 64 years (range:29-96); 54% were female and 54% Asian. Median time from diagnosis of stage IV NSCLC to first encounter was 23 months (range:0-67). The median number of HUS collected per patient was 2 (range:1-14). For patients with multiple visits the median time between completed questionnaires was 1.8 months (1-18). 105 patients (43%) presented with or developed brain metastases during the study period. In a univariable analysis, regardless of treatment line, mean HUS (mHUS) on osimertinib was 0.85 (standard deviation (SD):0.15) (n=33 patients; 114 encounters) compared to mHUS=0.80 (SD:0.17) on gefitinib (n=147, 351 encounters); mHUS=0.72 (SD:0.16) on chemotherapy (n=32, 76 encounters); and mHUS=0.79 (SD=0.15) on other TKIs (n=49, 133 encounters); p<0.001. In a multivariable analysis, disease progression (p=0.04) and ECOG performance status >0 (p<0.001) were associated with lower HUS. In contrast, treatment with osimertinib (when compared to a reference group of first-generation TKIs, gefitinib/erlotinib) was associated with improved HUS (p=0.01), while line of therapy and number of metastatic sites of disease were not associated with HUS. In addition, brain metastases had no significant impact on HUS (p=0.33).

      Conclusion

      Progressive disease and worse performance status associate with lower HUS in patients with EGFRm NSCLC. Patients treated with osimertinib had the highest HUS when compared with a reference group of first-generation EGFR TKIs regardless of line of therapy. These results may help in the choice of EGFR-TKI, especially in patients with a poor performance status.

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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.12 - Discussant - MA 21.09, MA 21.10, MA 21.11 (Now Available) (ID 14630)

      16:30 - 16:45  |  Presenting Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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): Geoffrey Liu

      • 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.

      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.

      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.

      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: 2
    • 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): 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.

      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.

      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+).

      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): Geoffrey Liu

      • 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.

      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.

      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.

      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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    MS29 - Selection into Screening Programs: Interplay of Risk Algorithms, Genetic Markers and Biomarkers (ID 807)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 F
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      MS29.03 - Polygenic Risk Score for Risk Assessment (Now Available) (ID 11527)

      14:05 - 14:20  |  Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background: Genome-wide association studies uncovered multiple lung cancer susceptibility genes, and consortium efforts greatly increased our ability to investigate the genetic architecture of histological subtypes. However the clinical utility of these genomic discoveries remains unclear. Method: We therefore constructed a risk prediction model with polygenic risk score (PRS) based on 18,316 lung cancer patients and 14,025 controls with European ancestry, via 10-fold cross-validation with elastic net penalized regression. Model calibration was assessed, and was validated with UK biobank data (N=336,911 unrelated participants with European ancestry). To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (NLST, N=50,772 participants). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. Added value of PRS to the risk prediction model was assessed by Net Reclassification Index. Results: A PRS was constructed based on 128 independent lung cancer variants using regularized penalized regression. The lung cancer ORs for individuals at the bottom 5% and top 5% of the PRS distribution were 0.49 (95%CI=0.43-0.56, P=2.7e-26) and 2.23 (95%CI=1.93-2.58, P=2.3e-27) in the training set, and 0.46 (95%CI=0.34-0.64, P=2.50e-6) and 1.33 (95%CI=1.08-1.64, P=7.10e-3) in the testing set, versus those at 40 to 60% as the referent group. The OR per standard deviation of PRS was 1.43 (95%CI=1.39-1.47. P=7.8e-138) for overall lung cancer risk in the training set and 1.24 (95%CI=1.18-1.30, P=2.59-e19) in the testing set. When considering age as the time scale, PRS separated out the curve of 5-year absolute risk and cumulative risk. When simulating the PRS distribution in the NLST population, we estimated 47.4% of cases occurred in the top 20% of the individuals with highest lifetime cumulative risk. Discussion: Including well-established genomic information in the risk model can contribute to the risk stratification of the population.

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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): Geoffrey Liu

      • 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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    OA11 - Thymic and Other Thoracic Tumours: Targeted Therapies, Biomarkers and Neo/Adjuvant Radiotherapy (ID 919)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 205 BD
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      OA11.06 - Two BRM Promoter Polymorphisms Do Not Predict Susceptibility or Prognosis of Thymoma (Now Available) (ID 12745)

      14:25 - 14:35  |  Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Background

      Brahma (BRM) is a critical protein subunit in chromatin remodeling, and insertions/deletions at its two polymorphic promotor sites (BRM-741 and BRM-1321) have been reported as susceptibility and/or prognostic markers in lung, head and neck, esophageal, pancreatic, and liver cancers. There is also early evidence of potential association with immune-related diseases such as ulcerative colitis and rheumatoid arthritis. As epigenetic silencing of BRM can be pharmacologically reversed, BRM polymorphisms in cancer might have therapeutic implications. Thymoma is a unique cancer in that it has immunological disease associations. We evaluated whether BRM-741 and BRM-1321 polymorphisms influence overall risk, survival, and time-to-progression of thymoma.

      Method

      Thymoma cases and matched healthy controls were recruited in a comprehensive cancer centre. Study participants’ peripheral blood samples were collected and genotyped for BRM promoter polymorphisms. Multivariable logistic regression assessed risk of thymoma in case-control analyses. Association of BRM variants with overall survival (OS) and time-to-progression or recurrence (TTP) was assessed by multivariable Cox regression.

      Result

      Of 237 cases of histologically diagnosed thymoma and 948 age- and gender-matched healthy controls, thymoma patients had median age of 53 (range: 17-84) years; 121 (51%) were male; 76 (32%) had a history of myasthenia gravis. Median follow-up time was 7 years. 79% of patients were recurrence- and progression-free at 10-year follow-up (95% CI: 74-86%), and 81% of patients were alive at 10 years post-diagnosis (95% CI: 75-87%). Frequency of homozygous variants for either gene was not significantly different between thymoma cases and controls: homozygous BRM-741genotype (OR=1.0; 95%CI:0.6-1.8; P=0.95), homozygous BRM-1321 (OR=0.59; 95%CI:0.3-1.0; P=0.07) or double homozygous variants in both loci (OR=0.69; 95%CI:0.3-1.4; P=0.29). No association between BRM-741/BRM-1321 and OS and TTP was detected (For homozygous BRM-741, OS P=0.74, TTP P=0.93; for homozygous BRM-1321 OS P=0.39, TTP P=0.93). Consistently, there was also no association between double homozygous variants and OS and TTP (Double homozygous, OS P=0.64, TTP P=0.48). Heterozygous variants were also not associated with either risk or outcome.

      Conclusion

      Results of this study do not support use of BRM promoter polymorphisms as susceptibility or prognostic markers for thymoma. Molecular biologic mechanisms of risk and prognosis remain elusive in malignant thymoma.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-42 - Real-World Evaluation of Tolerability in Older Adult Patients (≥75 Years Old) with EGFR-mutated NSCLC (Now Available) (ID 13289)

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • Abstract
      • Slides

      Background

      NSCLC patients carrying EGFR mutations are diagnosed across a wide age distribution. Although EGFR tyrosine kinase inhibitors (TKIs) are generally well tolerated, there remains a paucity of real-world data on toxicity and health utility scores (HUS) in older patients.

      Method

      A longitudinal observational study evaluated health-related quality of life (HRQoL) using HUS through the EQ-5D questionnaire, and common EGFR-TKI toxicities using PRO-CTCAE in NSCLC outpatients carrying EGFR mutations. Patients were classified into two groups: older (>75 years) and younger (<75 years). Patient characteristics and outcomes were extracted from chart review; patients were classified as having stable or progressive disease according to imaging findings. HUS and PRO-CTCAE results were compared descriptively.

      Result

      Of 240 patients and 774 encounters, 52 patients (22%; comprising 157 encounters) were aged ≥ 75 years. Gender and race were similarly distributed in both age groups: 63% of older patients and 70% of younger (<75 years) were female; 56% of older patients and 53% of younger patients were Asian. Use of gefitinib in older patients was much higher than other drugs: among 147 patients who received gefitinib, 27% (40 patients) were older, compared to 15% (5/33) for osimertinib and 15% (3/20) for erlotinib. Of patients receiving afatinib (n=11) and chemotherapy (n=32), none were ≥ 75 years. The following table describes HUS and PRO-CTCAE results by treatment and age group for stable patients.

      Older Adults (75 years)

      Younger Adults (<75 years)

      N

      HUS, mean (SD)

      PRO-CTCAE*, median [IQR]

      N

      HUS, mean (SD)

      PRO-CTCAE*, median [IQR]

      Stable on gefitinib

      34

      0.83 (0.20)

      4.5 [0,16]

      77

      0.80 (0.15)

      4 [0,15]

      Stable on osimertinib

      5

      0.80 (0.23)

      13.5 [0,17]

      22

      0.87 (0.12)

      0 [0,13.5]

      Stable on erlotinib

      3

      0.82 (0.08)

      0 [0,9]

      11

      0.80 (0.14)

      0 [0,16]

      *Higher PRO-CTCAE indicates more severe toxicities/symptoms.

      Conclusion

      In a real-world evaluation, patients 75 years or older comprised almost a quarter of all patients with EGFR-mutant advanced NSCLC. Afatinib and chemotherapy were not used at all in this population. Gefitinib was used most commonly, with similar toxicities and health utilities between older and younger patients. Osimertinib and erlotinib were used too infrequently in this study for conclusive age comparisons.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-11 - PRO-CTCAE Toxicities in Advanced NSCLC Patients with EGFR Mutations: A Real World Assessment (ID 12998)

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • Abstract
      • Slides

      Background

      The Patient Reported Outcomes of the CTCAE (PRO-CTCAE) tool has not been evaluated in a real-world study of EGFR-mutation positive patients treated with TKIs/chemotherapies. We evaluated its role in capturing clinically-significant toxicities.

      Method

      A longitudinal observational study evaluated common EGFR-TKI toxicities using PRO-CTCAE, measured on a five-point scale (1=no symptoms to 5=very severe symptoms) in outpatients with EGFR-mutated (EGFRm) advanced NSCLC.

      Result

      Toxicity information was collected for 709 follow-up visits (encounters) from 232 patients. Median age was 64 (range:29-96), 161 (69%) were female and 124 (53%) were Asian. 85 (37%) already had brain metastases at first encounter. 485 encounters were observed from patients stable on treatment, and 187 from patients progressing or with documented progression on their current treatment. 24 patients were treated with osimertinib (97 encounters, 97% in second/subsequent-line), 136 with gefitinib (324 encounters, 95% in first line therapy), 42 were receiving other EGFR-TKIs (118 encounters, 53% in second/subsequent-line), and 29 with chemotherapy (73 encounters, 96% second/subsequent-line). The table below summarizes the treatment-related PRO-CTCAE toxicities self-graded as moderate-to-very-severe by EGFRm patients.

      Proportion of patients reporting highest grade of toxicity as grade 3-5, by PRO-CTCAE

      Gefitinib

      Osimertinib

      Other EGFR TKI

      Chemotherapy

      Diarrhea

      17%

      18%

      24%

      8%

      Constipation

      12%

      4%

      12%

      16%

      Decreased appetite

      10%

      7%

      14%

      26%

      Nausea

      6%

      3%

      4%

      24%

      Vomiting

      1%

      2%

      3%

      16%

      Fatigue

      18%

      12%

      23%

      42%

      Numbness and Tingling

      6%

      7%

      10%

      16%

      Skin Rash

      23%

      12%

      20%

      9%

      Visual Disorders

      (includes dry eye)

      4%

      0%

      3%

      4%

      Total PRO-CTCAE Score, MEDIAN [IQR]

      4 [0,16]

      0 [0,15]

      6 [0,17]

      10 [0,21]

      Conclusion

      Osimertinib therapy had the most favorable self-reported toxicity profiles of all the therapies in EGFRm patients, followed by gefitinib. Chemotherapy generated the greatest toxicities. The use of PRO-CTCAE was well-accepted by patients in a clinical setting. This confirms trial data supporting favorable toxicities with osimertinib compared to other therapies for EGFRm NSCLC patients.

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      P1.13-15 - Detection of EGFR Mutations in cfDNA and Development of Resistance (ID 12634)

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • Abstract

      Background

      Peripheral blood sampling for T790M in patients (pts) failing initial EGFR-TKIs is now standard practice. The value of longitudinal sampling in pts is unknown.

      Method

      A study of cell free (cf) DNA analysis in pts with EGFR mutated(m) non-small cell lung cancer (NSCLC) is ongoing at the Princess Margaret Cancer Centre. The ThermoFisher OncomineTM lung assay detecting single nucleotide variants and indels to a limit of 0.05-0.1% variant allele frequency (VAF) was used. Patient clinical details and outcomes were collected prospectively.

      Result

      From Oct 2016-Feb 2017, 73 pts with EGFRm NSCLC enrolled and first blood samples were analysed. Most (92%) had mutations in del19 or L858R, including 1 pt with del19/S768I. Uncommon EGFRm were present in 6 (G718X, L861Q, exon20ins). Detectable levels of cfDNA were found in 50 pts (68%). Of 64 pts either starting an EGFR-TKI (n=11,17%), receiving a TKI without progression (PD) (23, 36%) or with PD on a TKI (30, 47%), the presence of the primary EGFRm (n=39, 61%) strongly associated with pre- 1st TKI or PD, p=0.03. Of 53 pts receiving a TKI, the presence of T790M in 31 (58%) associated with PD (p=0.04). Where pts had no radiologic PD evident, the median progression free survival (PFS), taken from blood draw, was 2.1 months (mths) versus 10 mths (HR 2.22, 95% CI: 0.89-5.54 p=0.08) when the primary EGFRm was detected. If T790M was present in cfDNA, the median PFS was 3.0 months versus 9.7 mths, (HR 4.59, 95% CI: 1.43-14.73 p=0.005). In univariable regression analyses the %VAF of the primary EGFRm correlated with PFS (HR 1.15, 95%CI: 1.02-1.29, p=0.02) with a trend in the %VAF of T790M (HR 1.16 95% CI:0.99-1.37, p=0.08). T790M was detected in 3 of 4 pts with T790M -ve tissue, and other co-occurring EGFRm were found in 10 pts including K745R in a pt receiving first-line osimertinib. TP53 (n=10), KRAS (1), PI3KCA(1) and ALK(2)gene mutations were also detected. Interestingly, in 1 pt receiving chemotherapy with T790M+ disease, both the primary EGFRm and T790M were detected in blood at the time of PD.

      Conclusion

      In addition to the emergence of resistance mutations, the presence of the primary EGFRm in pts receiving EGFR-TKIs may associate with a shorter PFS and therefore may be useful in longitudinal analyses of cfDNA to direct therapy.

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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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      P2.01-46 - Investigating the Effects of Prior Malignancy on NSCLC Trial Eligibility (Now Available) (ID 12617)

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • Abstract
      • Slides

      Background

      Up to 18% of patients with non-small cell lung cancer (NSCLC) who are candidates for participation in a clinical trial are excluded due to a prior malignancy. Common reasons include the need for another anti-cancer therapy and potential impact on clinical trial endpoints. We evaluated the proportion of trials that exclude patients with a prior history of malignancy, and estimate the potential impact of the prior malignancy from a cohort of NSCLC patients treated with first line systemic therapy.

      Method

      Clinical trials of palliative systemic therapy for NSCLC registered on or after January 1st 2014 from clinical trials.gov were reviewed to determine the proportion of trials that included a prior malignancy as an exclusion criterion. Patients with NSCLC and a prior malignancy, treated with first line palliative systemic treatment between January 1st 2010 and January 1st 2016 at the Princess Margaret Cancer Centre (PMCC), Toronto, Canada were identified from a cancer registry. A list of prespecified criteria of ways in which a prior malignancy may impact safety or a clinical trial endpoint was defined. These included: requirement for non-NSCLC anticancer therapies, other cancer detected on imaging, biopsy or tumour markers, disease progression or death from other malignancy, clinician uncertainty as to presence of synchronous other cancers. The proportions of patients with one or more of these criteria were assessed.

      Result

      66% of 359 clinical trial protocols contained an exclusion criterion for prior malignancy. 112 patients with advanced NSCLC and a prior malignancy were identified at PMCC, the median age was 71, 49% were male, the median time between prior cancer and NSCLC diagnosis was 74 months. 21% of patients were enrolled on a clinical trial. 52(59%) of the 88 patients not enrolled on a clinical trial did not meet any of our predetermined criteria, which may impact safety or a clinical trial endpoint due to other malignancy.

      Conclusion

      A prior history of a malignancy is a common exclusion in NSCLC clinical trials. Preliminary results suggest the majority of patients in our study did not appear to have a complication that would have impacted safety or clinical trial endpoints. Further analyses to explore appropriate exclusion criteria for prior malignancies, which may minimize need to exclude patients from clinical trials, are underway.

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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): Geoffrey Liu

      • 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.

      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.

      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.

      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.

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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): Geoffrey Liu

      • 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.

      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.

      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.

      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.

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.06-23 - Association of Two BRM Promoter Polymorphisms and Tobacco Exposure with Malignant Pleural Mesothelioma (MPM) Risk and Survival (ID 12738)

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • Abstract

      Background

      Brahma (BRM) is a critical ATPase subunit of the SWI/SNF chromatin remodeling complex. Homozygous 6-7bp insertion variants at two polymorphic promotor sites (BRM-741/BRM-1321) cause epigenetic suppression of BRM expression and they have been reported as susceptibility and/or prognostic markers in many malignancies, including non-small cell lung cancer. As epigenetic silencing of BRM can be reversed pharmacologically, targeting BRM polymorphisms has significant therapeutic potential. We evaluated BRM-741/BRM-1321 polymorphisms’ association with risk and prognosis of malignant pleural mesothelioma (MPM). While the effect of tobacco in MPM remains controversial, its interaction with genetic polymorphisms in MPM is largely unknown. We evaluated associations between BRM polymorphisms-tobacco exposure and MPM.

      Method

      MPM and age-distribution matched asbestos-exposed controls were recruited as part of an asbestos-exposure surveillance program. Participants were genotyped for BRM polymorphisms. Multivariable logistic regression assessed risk of MPM in case-control analyses. Association of BRM variants with overall survival (OS) was assessed by multivariable Cox regression. Secondary subset analyses were performed, stratified by smoking status.

      Result

      Of 265 MPM cases, 146 (55%) were ever-smokers; 51 (19%) were female; median age was 66 (range:21-84) years. Median OS was 18 months; median follow-up time was 15 months. Compared to 795 controls, there were no significant associations of BRM with risk (P>0.10, all comparisons). In contrast, compared to the wild-type genotype, the homozygous variant of BRM-741 and BRM-1321 were associated with lower OS, with adjusted hazard ratio (aHR)=2.56 [95%CI:1.7-3.8] and 2.07 [95%CI:1.4-3.1], respectively. Compared to patients carrying the double wild-type, patients homozygous at both loci had lower OS (aHR=2.70 [95%CI:1.7-4.4]).

      There was a significant differential effect of BRM polymorphisms on risk of MPM, by smoking status (interaction P<0.001): among ever-smokers, BRM homozygous variants in BRM-741, BRM-1321, or both conferred lower risks (adjusted odds ratios, aORs were between 0.18-0.28; each P<0.001), while for never-smokers, there was significantly greater risk conferred by carrying the homozygous variants (aORs between 2.7-4.4). Likewise, a similar differential effect by smoking status was seen in prognosis (interaction P<0.001): there was no association between BRM polymorphisms and OS in ever smokers (P>0.1, all comparisons), but in never-smokers, the aHR of carrying homozygous variants of BRM-741, BRM-1321 or both were 7.7 [95%CI:3.8-16], 4.0 [95%CI:2.1-7.7], and 8.6 [95%CI:3.7-20], respectively.

      Conclusion

      Never-smokers who develop malignant pleural mesothelioma have an increased chance of carrying BRM homozygous variants in their germline DNA, which results in substantially worse prognosis. In contrast, in smokers, there may be a protective effect, with no difference in overall survival.

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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): Geoffrey Liu

      • 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.

      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.

      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.

      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.

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

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • 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.

      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.

      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).

      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.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-13 - Real-World Study of Osimertinib in EGFR T790M-Mutated Non-Small Cell Lung Cancer (NSCLC): ASTRIS Canadian Cohort Analysis (ID 12986)

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • Abstract
      • Slides

      Background

      ASTRIS is an open-label, single-arm, multinational, real world study of osimertinib for patients with advanced/metastatic epidermal growth factor receptor-mutated (EGFRm) T790M-positive non-small cell lung cancer (NSCLC) who previously received therapy with an EGFR tyrosine kinase inhibitor (EGFR-TKI) (NCT02474355). Data cut-off (DCO) for the second interim analysis was 20 October 2017, with 3014 patients enrolled (full analysis set), including 99 patients in Canada.

      Method

      Adult patients with locally advanced/metastatic EGFRm NSCLC, not amenable to curative surgery/radiotherapy, with confirmation of T790M and prior EGFR-TKI therapy were enrolled. Patients were included with World Health Organization performance status of 0 to 2, as well as those with asymptomatic stable central nervous system (CNS) metastases. Patients received osimertinib 80 mg once daily until loss of clinical benefit. The primary efficacy outcome was overall survival (OS), with secondary outcomes of investigator-assessed response rate (RR), progression-free survival (PFS), and time to treatment discontinuation (TTD).

      Result

      From study start (14 January 2016) to DCO (20 October 2017), 99 patients were enrolled at 12 Canadian centres. Median age was 64 years (30-89 years). Patients were 68% female, 57% Asian, and had ECOG 0/1/2 of 22%/65%/13%. Twenty-five patients had CNS metastases at screening. Gefitinib was the most commonly used previous EGFR-TKI (gefitinib, erlotinib and afatinib were 80%, 14%, and 14%, respectively). Thirty-nine percent had previous chemotherapy; 6% previous immunotherapy; 46% previous radiotherapy. All patients had T790M: 75% tissue, 7% blood and 18% cytology. Biomarker testing methods varied, with the majority (61%) identified by Entrogen EGFR kit. At DCO, 45 patients had discontinued treatment. OS data were immature. Median PFS was 11.0 months (95% CI, 8.9-13.3). Median TTD was 14.9 months (95% CI, 11.2-not calculated). RR was 67.0% (95% CI, 56.7-76.2); sub-analyses showed RR of 69.9% (58.0-80.1), 66.7% (22.3, 95.7) and 55.6% (30.8, 78.5) for patients with T790M by tissue, blood and cytology, respectively. Serious adverse events (AEs) were reported for 18% of patients. AEs leading to dose modifications and discontinuations were reported for 12% and 5% of patients, respectively.

      Conclusion

      The Canadian results from this real world study of osimertinib in advanced/metastatic EGFRm T790M-positive NSCLC, which includes heavily pretreated patients and various approaches to biomarker testing, were comparable to outcomes reported in the phase III study AURA3 (NCT02151981). These findings provide further support for osimertinib as standard of care for EGFRm T790M-positive NSCLC.

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    P2.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 964)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.15-10 - Determinants of Health Utility Scores (HUS) in Patients with ALK Rearranged Non-Small Cell Lung Cancer. (ID 14025)

      16:45 - 18:00  |  Author(s): Geoffrey Liu

      • Abstract
      • Slides

      Background

      Despite an increasing number of available treatment options for patients with advanced ALK-rearranged (ALKr) NSCLC, the goals of care remain to improve survival whilst maintaining quality of life. With rapidly changing management and prognosis, understanding the impact of treatments on quality of life becomes important. We evaluated factors affecting health utility scores (HUS) in this generally younger cohort of patients with NSCLC.

      Method

      An ongoing prospective observational/real-world cohort study at the Princess Margaret Cancer Centre is enrolling patients with advanced NSCLC. Patients are asked to complete the EQ5D questionnaire at each outpatient visit. During the period from November, 2014 to March, 2018, patients with ALKr who participated were analyzed. Baseline clinical characteristics, oncological treatment, and outcomes were extracted from chart review. Factors associated with HUS were identified using ANOVA.

      Result

      272 encounters (follow-up visits) in 43 ALK+ patients were analysed. The median age at diagnosis was 56 years (range: 31-79 years). Half the patients in our sample were female (49%), and the majority were never-smokers (84%); 44% of the cohort were Asian. During the study period, 24 patients (56%) presented with or developed brain metastases. The median number of HUS collected per person was 4 (range: 1-20). Among patients who were stable on treatment, there were no statistically significant differences in mean HUS (mHUS) between different ALK inhibitors: mHUS [SD, standard deviation] were: mHUS of crizotinib=0.82 [0.08] (n=25, 92 encounters); mHUS of ceritinib=0.79 [0.14] (n=17, 102 encounters); and mHUS of other ALK inhibitors=0.80 [0.17] (n=12, 25 encounters), which included mHUS of alectinib=0.79 [0.20] (n=8, 10 encounters). The number of previous lines of treatment did not impact HUS (p=0.85). Patients stable on treatment who received prior whole brain radiation (n=14) had lower mHUS compared to those who never had WBRT (mHUS=0.78 [0.14] vs. 0.84 [0.10]; p=0.05), which may partly explain differences in mHUS by sex (64% of patients who had received WBRT were female vs 41% who did not receive WBRT): males=0.84 [0.10] vs females=0.78 [0.14], p=0.04. In 11 stable patients who had received radiation to bone metastases mHUS was 0.75 [0.16] vs. 0.84 [0.09] in those who did not (p=0.006).

      Conclusion

      In this study, mean HUS were similar across different ALK inhibitors. Female patients and those receiving whole brain radiation or radiation to bone had lower HUS. This highlights specific factors that influence health-related quality of life in this subset of patients with advanced NSCLC

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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: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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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): Geoffrey Liu

      • 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.

      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.

      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).

      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.

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    P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)

    • 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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      P3.04-20 - Correlation of Immune-Related Adverse Events and Response from Immune Checkpoint Inhibitors in Patients with Advanced NSCLC (Now Available) (ID 14138)

      12:00 - 13:30  |  Author(s): Geoffrey Liu

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) are associated with a unique set of toxicities termed immune-related adverse events (irAEs). The association between response to ICI therapy and development of irAEs has been documented in various cancer types.

      Method

      Stage IV non-small cell lung cancer (NSCLC) patients treated with ICIs at the Princess Margaret Cancer Centre between 2013 and 2016 were followed for treatment response, treatment duration, survival, and toxicity. The relationship between treatment outcomes and occurrence of irAEs was examined.

      Result

      A total of 97 advanced NSCLC patients were followed. Most patients (81%) received anti-PD-1 agents, 17% received anti-PD-L1 agents, and 2% received combination anti-PD-L1 plus anti-CTLA-4 therapy. Median follow up for the cohort was 5.1 months (0.3-38.1 months) from treatment start. Demographic and tumour characteristics were balanced between the groups. IrAEs occurred in half of patients (51%) on ICIs and grade≥3 irAEs in 7%. The most commonly observed irAEs were arthralgia (13%), diarrhea/colitis (12%), and skin rash (11%). Discontinuation of treatment due to irAEs occurred in 10% of patients, half of whom experienced grade≥3 irAEs.

      The overall response rate to ICIs was 23%, with the majority occurring by week 8 of treatment (16/22). Response was non-evaluable in one patient and this was excluded from response analysis. Patients with grade≥3 irAEs were more likely to have response to treatment compared to those with grade I/II irAEs and no irAEs (67% vs 17% vs 23%, p=0.035), Table 1. Smoking status was not associated with response rate or frequency of irAEs. Median survival was not reached in those with grade≥3 irAEs, 15.7 months in those with grade I/II irAEs, and 7.4 months in those with no irAE (p=0.16). Duration of treatment did not differ significantly among the groups.

      table 1. relationship between immune-related adverse events (irae) and response to treatment.jpg

      Conclusion

      The occurrence of grade≥3 irAEs may be associated with treatment response in advanced NSCLC patients undergoing ICI therapy.

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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): Geoffrey Liu

      • 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.

      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.

      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).

      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.

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