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G. Liu



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    MA17 - Genetic Drivers (ID 409)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      MA17.06 - Landscape of Somatic Mutations Involving Lung Cancer Associated Genes in Non-Small Cell Lung Cancer (NSCLC) Patient-Derived Xenografts (ID 6084)

      14:56 - 15:02  |  Author(s): G. Liu

      • Abstract
      • Presentation
      • Slides

      Background:
      Patient-derived tumor xenografts (PDXs) have high fidelity to their histological origins, and maintain the molecular heterogeneity and genetic aberrations of the donor patient tumors more faithfully than established in non-small cell lung cancer (NSCLC) cell lines. This study evaluated whether our panel of PDX models recapitulate known cancer-related gene mutations.

      Methods:
      Whole-exome sequencing was completed on 103 NSCLC PDX models, 47 adenocarcinoma (AdC) and 56 squamous (SqCC), with a mean coverage of 84x. After filtering for contaminating mouse reads, the exome data were aligned using the Burrows-Wheeler Aligner, processed using the standard GATK pipeline, and mutations were identified using MuTect. Additional filtering using dbSNP, ExAC and ESP was performed for cases without corresponding normal adjacent lung exome data (n = 80). The identified mutations were compared to 1260 frequently mutated cancer-related genes, which were compiled from a panel of cancer-related mutated genes (555) and a panel of lung cancer-specific mutated genes (1082).

      Results:
      High rates of somatic mutations were observed in both AdC (mean of 12.4 mutations/megabase) and SqCC (mean of 11.7 mutations/megabase) PDX models. Compared to the rates observed in primary lung cancers in The Cancer Genome Atlas studies (mean of 8.9 mutations/megabase in AdC; 8.1 mutations/megabase in SqCC), these values appear higher, but may be inflated due to the lack of data from corresponding normal tissues. AdC models had a total of 953 mutated genes (median: 57 genes/model; range: 5-307), while SqCC models were characterized by 1007 mutated genes (median: 55 genes/model; range: 21-354). Specific mutation frequencies were compared to those determined in a recent study involving genomic alterations in human primary lung AdC and SqCC (Nature Genetics 2016; 48; 607–616). This comparison, based on mutated genes common in both studies, demonstrated significant correlation of the frequencies in 791 genes in AdC (ρ=0.78; p<2.2×10[-16]), as well as in 799 genes in SqCC (ρ=0.73; p<2.2×10[-16]). Three genes that were reported as significantly mutated in both AdC and SqCC primaries, and had higher mutation frequencies in SqCC, were also observed to be higher in our SqCC PDX models (TP53: 48.9% in AdC vs. 55.4% in SqCC; CDKN2A: 4.3% vs. 7.1% and PIK3CA: 2.1% vs. 23.2%); however, the statistical significance of these differences needs to be tested.

      Conclusion:
      Mutation landscapes in cancer genes are recapitulated in AdC and SqCC PDX models. The fidelity of these landscapes in matched patient primary tumour samples is being investigated.

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    OA21 - Palliative and Supportive Care for Lung Cancer Patients (ID 405)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Palliative Care/Ethics
    • Presentations: 1
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      OA21.02 - ALK-Rearranged Non-Small Cell Lung Cancer is Associated with a High Rate of Venous Thromboembolism (ID 4290)

      11:10 - 11:20  |  Author(s): G. Liu

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK-rearranged NSCLC.

      Methods:
      We identified all patients with ALK-rearranged NSCLC, diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in two tertiary centers in Israel.

      Results:
      Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be Caucasian (p=0.006). The occurrence of VTE was associated with a trend towards worse prognosis (overall survival HR=2.88, p=0.059). Within the validation cohort (N=43), VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (N=98) the VTE rate was 36%. Patients with VTE were younger (age 52 vs 58, p=0.04) and had a worse ECOG performance status (p=0.04). VTE was associated with shorter OS (HR=5.71, p=0.01)Figure 1.



      Conclusion:
      We found the rate of VTE in our ALK-rearranged cohort is 3-5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.

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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-036 - An EGFR Tyrosine Kinase Inhibitor Sensitive Patient-Derived Lung Cancer Xenograft Model without Classical Sensitizing Mutations (ID 5398)

      14:30 - 14:30  |  Author(s): G. Liu

      • Abstract

      Background:
      Mutations in the tyrosine kinase (TK) domain of EGFR are oncogenic driver in 10-20% of lung adenocarcinoma (AdC) patients in Western countries. Approximately 90% of EGFR-TK inhibitor (TKI) sensitizing mutations occur as small in-frame deletions in exon 19 or L858R point mutations in exon 21. Recently, novel driver mutations in EGFR with oncogenic and TKI sensitizing activity have been reported. We present here an AdC patient-derived xenograft (PDX) model (PDX12) that is highly sensitive to EGFR-TKI, yet failed to demonstrate classical TKI sensitizing mechanisms.

      Methods:
      Comprehensive genomics profiling was used to characterize the genotype of PDX12, which was established from a resected stage IIIA AdC patient grafted in NGS mouse. The primary human lung cancer cell line (PHLC12) was extracted from its PDX model (PDX12). Aberrant EGFR cell lines used were H3255 (L858R), H2935 (exon 19 deletion), H1975 (L858R and T790M), and H1944 (wild type). Cell viability was assessed after erlotinib treatment at 1nM - 2μM for 72 hours using MTS assay. Levels of EGFR activation in both pre- and post-treatment by Western blot analysis.

      Results:
      PDX12 model had no known oncogenic mutations (EGFR wild type) on exons 18-21 by next-generation sequencing, RT-qPCR, and SISH, but was highly sensitive to EGFR-TKI. The IC50 to erlotinib treatment at 72 hr was 67.13 ± 7.63 nM for PHLC12, compared to 9.70 ± 2.64 nM for H3255, 64.88 ± 8.49 nM for HCC2935, > 2 μM for H1975, and > 2 μM for H1944 EGFR mutant or wild type cells, respectively. Western blot analysis demonstrated a relatively higher molecular weight band for EGFR protein with high expression level in PHLC12 when compared to other lung cancer cell lines. Using RT-qPCR, relative expression level of each EGFR domain (extracellular, tyrosine kinase, and c-terminal domain) in PHLC12 showed no difference compared to EGFR wild type. Phosphorylation status of EGFR in PHLC12 was similar in activity as compared to erlotinib sensitive cell lines.

      Conclusion:
      PHLC12 represents an enigmatic EGFR TKI sensitive lung PDX model without classical TKI sensitizing aberrations. Additional potential mechanisms of EGFR dependency including exon duplication, or post-translational modification of EGFR protein are being investigated.

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    P1.03 - Poster Session with Presenters Present (ID 455)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      P1.03-041 - Do Several Rounds of Negative Screening Low Dose CT Scans Influence the Risk to Develop Lung Cancer? (ID 5373)

      14:30 - 14:30  |  Author(s): G. Liu

      • Abstract

      Background:
      The purpose of this study was to assess whether several years of negative screening low-dose computed tomography (LDCT) scans predict a subsequent lower risk of developing lung cancer. This would have implications for recommended intervals and duration of LDCT lung cancer screening.

      Methods:
      The cohort was an at-risk population who had previous negative screening LDCTs and had not been screened for at least 5 years. Between 2003 and 2009, 4782 individuals had been enrolled in a lung cancer screening study based on age and smoking alone. At this time, their risk was re-calculated using a multifactorial assessment model, and they were contacted in decreasing order of their re-calculated risk. An initial phone interview assessed interim history, general health, interim diagnosis of lung cancer or interim chest CT. Those participants without lung cancer or recent CT were invited for a single LDCT (40mA, 135kV, 1mm axial reconstructions). Subsequent investigation was recommended depending on the LDCT findings: negative, no new or growing nodules (no further recommendation), positive, low suspicion for malignancy (follow up CT in 3-6 months) or positive, high suspicion for malignancy (referral to the local lung cancer rapid diagnostic assessment program).

      Results:
      To date, 361 individuals or family members have been contacted. Fifty-five individuals had passed away (20 from lung cancer), 24 were alive with lung cancer. 129 did not qualify for a LDCT scan (declined participation, or recent CT). A total of 153 have attended for LDCT, on average 7 years after their last LDCT. Ninety-one (59%) studies were reported as negative. Fourty-five (29%) LDCTs were positive with low suspicion and a follow up scan was recommended; in 13 cases nodules had resolved on follow up imaging, the remaining 32 are awaiting surveillance LDCTs. Seventeen (11%) LDCTs were reported as positive with high suspicion; 11 of those have a subsequently biopsy proven lung cancer and 6 are currently undergoing further investigations or LDCT surveillance. All lung cancers diagnosed were either stage I or II. Of the 11 individuals with biopsy proven cancers, 7 had normal previous CTs, 4 had a pre-existing groundglass nodules in the tumor location on the most recent exam. The overall prevalence of lung cancer in this cohort is 15.2% (55/361) and it may increase. The detection rate of LDCT to date is 7.2% (11/153).

      Conclusion:
      Lung cancer risk remains high despite several negative annual screening LDCT scans. Continued screening beyond three years is recommended in high risk individuals.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P1.05-006 - Identification of miRNAs and mRNAs Associated with Metastasis in Early-Stage Non-Small Cell Lung Cancer (NSCLC) (ID 5829)

      14:30 - 14:30  |  Author(s): G. Liu

      • Abstract

      Background:
      Early-stage NSCLC patients whose tumours can form primary xenografts (XG) in immune deficient mice have significantly shorter disease-free survival and are at a greater risk of early metastasis compared with patients whose tumours do not form xenografts (non-XG). Genomic and proteomic characterization of XG and non-XG-forming primary patient tumours may reveal clinically relevant genetic aberrations that are associated with early metastasis.

      Methods:
      miRNA-seq and RNA-seq data of 100 early-stage NSCLC patients with known engraftment status were acquired. The cohort includes 62% adenocarcinoma (ADC) and 38% squamous cell carcinoma (SQCC). Least absolute shrinkage and selection operator (LASSO) was applied to identify features associated with XG status using integrated miRNA and mRNA abundance profiles. Gene Ontology (GO) annotation was subsequently performed to elucidate biological processes that may be altered between the two patient groups.

      Results:
      Using miRNA and mRNA data alone, ADC patients were classified as XG and non-XG with 88.7% and 95.2% accuracy. The integration of these two data types classified the patients with 100% accuracy using 20 features (7 miRNAs and 13 mRNAs). While less is known regarding the roles of the identified miRNAs in lung ADC, several of the genes have been suggested to affect the metastatic ability of lung cancer cells; these include PITX1, GPNMB and KRT14. In SQCC, both the miRNA and mRNA data alone and the integrated profiles were able to classify patients into XG and non-XG-forming groups with 100% accuracy. However, the roles of the selected features (1 miRNA and 11 mRNAs) in the metastasis of SQCC are not well defined. GO annotation of the identified mRNAs in ADC revealed enrichment of biological processes related to B cell differentiation, wound healing and regulation of the immune response and signalling pathway, while catabolic and metabolic processes were enriched in SQ.

      Conclusion:
      The use of single-dimensional data to classify patients into different prognostic groups may not be sufficient in the presence of heterogeneous patient populations. Integrative analysis of multi-omic data can provide greater insights into clinically relevant genetic aberrations, which can be used to improve the molecular classification of NSCLC.

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    P1.06 - Poster Session with Presenters Present (ID 458)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.06-039 - Retrospective Study of the Incidence and Outcomes from Lung Cancer That Developed Following a Solid Organ Transplant (ID 5136)

      14:30 - 14:30  |  Author(s): G. Liu

      • Abstract
      • Slides

      Background:
      Organ transplant recipients (OTR) have an increased risk of developing post-transplant malignancies with lung cancer being one of the most common. We investigated incidence and outcomes of lung cancer in OTR managed at the University Health Network.

      Methods:
      The study population, patient characteristics, treatments and outcomes were summarized from solid OTR databases, our cancer registry and patient charts from January 1, 1980 to December 31, 2015. Univariate Kaplan-Meyer curves estimated overall survival (OS) by histology, stage and chemotherapy.

      Results:
      Amongst 7994 OTR (heart [N=765], lung [n=1668], liver [n=238], kidney [n=3273]), 123 developed lung cancer (1.54%) of which (55) 44.7% occurred in lung OTR; 108 (1.35%) patients had sufficient data for subsequent analyses. Median age: 62 years (29 - 85); male: 66%; smoking status at time of transplant - former/current/never/unknown: 62%/10%/15%/8%. Histologies included non-small cell lung cancer (NSCLC): 81%; small cell lung cancer (SCLC): 10%; neuro-endocrine tumours: 9%. NSCLC: Adjuvant chemotherapy, after it became standard of care (SOC), was given to 16% of eligible NSCLC patients. At recurrence, 28% received chemotherapy while 28% received a TKI. In patients initially presenting with stage IV NSCLC, 18% received chemotherapy and 3% received a TKI. SCLC: For limited and extensive stage SCLC patients, 83% and 60% received SOC chemotherapy, respectively. All: Where chemotherapy dosing was known (n=23), 42% of patients received initial dose reductions. For early stage patients, 22% required dose reduction and 11% had chemotherapy discontinuation due to toxicity. For stage IV patients, 42% required dose reductions and 50% required discontinuations.

      Median OS by Subgroup
      Patients by Histology, Stage at Diagnosis & Systemic Treatment n median OS (months) 95% C.I.
      NSCLC: Stage I/II Systemic Treatment No treatment 48 11 37 24.9 25.7 24.9 (17.3-36.6) (14-51.6) (16.2-72.9)
      NSCLC: Stage III Systemic Treatment No treatment 7 1 6 24.6 84.0 24.6 (4.5-NA) NA (4.5-NA)
      NSCLC: Stage IV Systemic Treatment No treatment 33 7 26 3.2 8.7 2.3 (2-4) (4.7-52.4) (1.5-3.5)
      SCLC: Limited Stage Systemic Treatment No treatment 6 5 1 9.6 14.3 2.0 (2-NA) (8.4-NA) NA
      SCLC: Extensive Stage Systemic Treatment No treatment 5 3 2 1.7 5.5 0.2 (0.2-NA) (1.7-NA) (0.2-NA)


      Conclusion:
      Survival was poor in our OTR population compared to historical norms in non-transplant patients. A minority of NSCLC patients received adjuvant or palliative chemotherapy, while most SCLC patients were treated. Both often had sub-standard dosing. Chemotherapy appeared better tolerated in early stage disease.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P2.03b-008 - The Impact of Brain Metastases and Their Treatment on Health Utility Scores in Molecular Subsets of Lung Cancer Patients (ID 4348)

      14:30 - 14:30  |  Author(s): G. Liu

      • Abstract

      Background:
      New therapies, particularly in advanced patients with EGFR-mutated and ALK-rearranged tumors, result in prolonged survival. Brain metastases and/or their treatment, may have a negative impact on health-related quality of life. Technological assessment of the cost-effectiveness of various treatments for brain metastases will benefit from measurements of health-related qualify of life and health utility scores (HUS). This study evaluated the impact of brain metastases on HUS across multiple health states defined on the basis on disease stability, brain-specific therapies, and molecularly-defined subsets of NSCLC.

      Methods:
      A longitudinal cohort study at Princess Margaret Cancer Centre evaluated 1571 EQ5D-3L-derived HUS in 476 Stage IV lung cancer outpatients, from Dec, 2014 through May, 2016: EGFR+ (n=183), ALK+ (n=38), wild-type (WT) non-squamous (n=171), squamous (n=29), and small cell lung cancer (SCLC) (n=30). Patients were stratified according to presence or absence of brain metastases at the time of assessment; mean HUS (± standard error of the mean, SEM) by presence of brain metastases and various health states and disease subtypes were reported. For patients with repeated measures, only the earliest time point was analyzed.

      Results:
      172 patients had brain metastases, median age 62, (range 32-86) years and 304 patients did not have brain metastases, median age 66 (29-96) years. Overall HUS was related to disease subtype but not presence of brain metastases: EGFR/ALK+ patients with (0.78±0.02) or without brain metastases (0.79±0.01) versus WT/SCC/SCLC with (0.74±0.02) and without brain metastases (0.73±0.01) (p=0.01 by subtype; p>0.10 by presence of brain metastases). However, symptomatic CNS disease (0.69±0.04) had lower HUS (versus asymptomatic disease (0.77±0.02)) (p=0.03). Patients achieving intracranial stability or response to treatment had significantly higher HUS (0.81±0.05) than patients with progressive CNS metastases (0.72±0.02) (p=0.03). Extra-cranial control also correlated with higher HUS (0.81±0.02 versus 0.69±0.03, p<0.0001). When local treatment for brain metastases was delivered within 6 months, HUS was lower (0.71±0.02 versus 0.82±0.02, p=0.0005). CNS disease treated only with systemic therapy or on no active therapy had mean HUS of 0.81±0.03, while patients treated only with stereotactic radiosurgery (SRS) had values of 0.80±0.04; there was a trend for lower HUS with whole brain radiation (WBRT) only (0.72±0.03) or WBRT+SRS (0.74±0.03) (p=0.11).

      Conclusion:
      Brain metastasis stability has significant impact on HUS in lung cancer patients. Treatment modalities of brain metastases may also impact HUS. Data collection is ongoing; updated HUS data including longitudinal assessments and multivariable analyses will be presented.

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      P2.03b-077 - EGFR/ALK+ Patient-Derived Xenografts from Advanced NSCLC for TKI Drug Selection & Resistance Development: The REAL-PDX Study (ID 6081)

      14:30 - 14:30  |  Author(s): G. Liu

      • Abstract

      Background:
      Lung cancer patient-derived xenografts (PDX) have shown to be representative models for individual patient tumors. Theoretically, such models could inform the choice of subsequent lines of therapy, since PDX development, TKI resistance induction, and subsequent drug-screening can be completed before TKI resistance develops in the patient. The goal of Resistance modeling in EGFR and ALK Lung cancer (REAL)-PDX is to develop PDX models for real-time treatment selection of subsequent lines of therapy in advanced-stage NSCLC patients.

      Methods:
      Since August 2015, Princess Margaret Cancer Centre patients with EGFR/ALK+, as well as lifetime never-smoking lung cancer patients with unknown mutation status, were consented to have additional tumor sampling for PDX development during routine- or trial-related biopsies. Tumor sufficiency was confirmed prior to implantation into non-obese severe combined immunodeficient (NOD-SCID) mice, with successful engraftment defined as propagation beyond first passage; unsuccessful implantations had no palpable tumor after 6 months.

      Results:
      72/82 (88%) approached patients consented; 49/72 (68%) had adequate tumor tissue for implantation (71% stage III/IV): 46 adenocarcinomas, 2 squamous cell carcinoma, 1 LCNEC. 36/49 (73%) were lifetime never smokers. Patients received adjuvant chemotherapy (3), TKI therapy (15), both (5), or no treatment (26) prior to sampling. Tumor samples were taken from surgically resected lung (18), metastatic adrenal (1) and brain (2), CT-guided lung biopsies (5), endoscopic ultrasound-guided (EBUS) biopsies (6), and thoracentesis pleural fluid (17) specimens. Twenty-eight implanted tumors were EGFR+ (12 exon19 deletions, 2 exon19 deletion/T790M, 1 exon19 del/exon18 mutation, 12 L858R, and 1 L858R/T790M); 7 had ALK-rearrangements, and 1 had ROS1-rearrangement. Engraftment rates of 31 assessable implanted tumors were as follows: lung resections 12/12 (100%), metastatic resections 2/3 (67%), CT- or EBUS-guided biopsies 1/5 (20%), and pleural fluid 2/11 (18%); Engraftment rate was associated with no prior treatment (14/17 no treatment vs 3/14 any treatment, p=0.001). Of 17 assessable tumors with EGFR activating mutations, 9 engrafted (53%). Of 3 assessable tumors with ALK-rearrangement, 1 was successful (33%).

      Conclusion:
      PDX development of EGFR/ALK+ models for testing with novel therapeutics from various tumor biopsy sites is feasible and will provide valuable real-time information for subsequent treatment decisions in advanced NSCLC patients. Updated engraftment and drug screening data will be presented.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-028 - Characterizing Residual Erlotinib-Tolerant Population Using EGFR-Mutated NSCLC Primary Derived Xenografts: The Last Holdouts (ID 5455)

      14:30 - 14:30  |  Author(s): G. Liu

      • Abstract

      Background:
      Three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have led to multi-fold improvements in progression free survival of advanced stage non-small cell lung cancer (NSCLC) patients carrying EGFR kinase domain mutations. However, cure is not yet achievable with any EGFR TKI monotherapy, as patients will eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of epigenetically modified drug tolerant cells (DTCs) may be one important mechanism for tumor cells surviving the TKI. We hypothesize that characterizing the genomic and epigenomic alterations observed in DTCs in vivo and comparing them to the bulk tumour will delineate a number of mechanisms of tolerance exhibited by DTCs.

      Methods:
      DTCs were induced via chronic erlotinib treatment of a lung adenocarcinoma primary derived xenograft (PDX) harbouring an erlotinib sensitive exon 19 deletion. Molecular profiles of DTCs are compared to untreated controls via immunohistochemistry (IHC) and gene expression array. We are now undertaking exome-sequencing, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), methylated DNA immunoprecipitation and sequencing (MeDIP-seq).

      Results:
      When compared to untreated tumours, DTCs exhibit decreased apoptosis (CC3 IHC) and proliferation (Ki67 IHC). DTCs maintained strong signaling via the EGFR pathway (pERK, pAKT, pS6). DTCs exhibited 2437 significantly differentially expressed genes (DEGs; >1.5-fold change and adjusted p-value <0.05) including multiple cancer stem cell markers (ALDH1A1, ALDH1A3, CD44). DEGs also were involved in vesicle-mediated transport (including lysosomes, exosomes and endosomes), autophagy, stress/unfolded protein response, cytoskeleton organization, chromatin organization, ion pumps and transporters, cell adhesion, WNT, NOTCH, PI3K and MAPK pathways. DTCs remained resistant to three cycles of cisplatin/vinorelbine either alone or when combined with erlotinib. Genomic and epigenomic profiling are on-going and results will be presented.

      Conclusion:
      DTCs may be a major impediment to cure by single-agent EGFR targeted therapies. Understanding the mechanisms and developing strategies to overcome DTCs may give insights on therapeutic strategy to further improve the survival of EGFR-mutated NSCLC patients.