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M. Pintilie



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    MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI05.13 - Treatment of EGFR/ALK-Driven Non-Small Cell Lung Cancer (NSCLC) Brain Metastases: Impact of First-Line Whole Brain Radiotherapy on Outcome (ID 1251)

      16:45 - 18:15  |  Author(s): M. Pintilie

      • Abstract
      • Presentation
      • Slides

      Background:
      Brain metastases (mets) in EGFR/ALK-driven NSCLC are common, and frequently pose treatment dilemmas. Effective systemic therapy with tyrosine kinase inhibitors (TKIs) controls extracranial disease in up to 70% of patients, but often radiotherapy is required for intracranial control. As whole brain radiation (WBRT) may be associated with neurocognitive toxicity, we aimed to evaluate the impact of molecularly targeted therapy and stereotactic radiotherapy (SRS) for EGFR/ALK-driven NSCLC on intracranial disease control with and without WBRT.

      Methods:
      This retrospective analysis included patients treated with EGFR/ALK-positive NSCLC at Princess Margaret Cancer Centre from 1998-2015, with brain mets at lung cancer diagnosis or during treatment/follow-up. Demographic data were collected from electronic patient records. Time to intracranial progression (TTIP) and overall survival (OS) were calculated from date of diagnosis of brain mets, using the cumulative incidence function and Kaplan-Meier methods respectively; differences between groups were tested with Gray’s or log-rank test.

      Results:
      From 1998-2015, 162 patients with brain mets from EGFR/ALK-driven NSCLC were identified: 138 in the EGFR cohort, 23 in the ALK cohort and one included in both cohorts for analysis, whose tumour carries both an EGFR mutation and ALK rearrangement. Table 1 contains clinical characteristics and treatment details. In the EGFR cohort, initial brain mets treatment consisted of systemic therapy alone in 19 patients (17 TKI, 2 chemotherapy), SRS +/- surgery in 27 patients and WBRT +/- SRS/surgery in 88 patients. 1-year intracranial progression rates were 26%, 32% and 12%, respectively, and median TTIP was 18, 16 and 40 months [p=0.12]. Median OS was 26, 27 and 34 months respectively [p=0.49]. In the ALK cohort, initial brain mets treatment consisted of systemic therapy alone in 4 patients (1 TKI, 3 chemotherapy), SRS/surgery alone for 4 patients and WBRT +/- SRS/surgery for 15 patients. 1-year intracranial progression rates were 50%, 50% and 13%, respectively, and median TTIP was 18, 14 and 69 months [p=0.028]. Median OS was 35 months, not reached and 51 months, respectively [p=0.75]. Multivariable analysis for the whole group showed that age [p=0.021], number of brain mets [p=0.012] and extracranial control [p=0.008] were significantly associated with OS, but not WBRT [p=0.61].

      Conclusion:
      In this cohort of patients with brain mets from EGFR/ALK-driven NSCLC, patients treated with WBRT trended to longer TTIP. Although not statistically significant, our data also show a trend towards longer survival in patients who received WBRT. These observations require further validation in this patient population.

      EGFR (N=139) ALK (N=24)
      Median Age (Range) 59(29-86) 53(31-77)
      Female Sex 93(67%) 15(62%)
      Ethnicity Asian Caucasian Other 58(42%) 63(45%) 18(13%) 7(29%) 13(54%) 4(17%)
      Smoking Never Smoker Former/Current Smoker Unknown 108(77%) 30(22%) 1(1%) 19(79%) 5(21%) 0
      ECOG PS (Diagnosis) 0 1 2-4 66(48%) 67(48%) 6(4%) 7(29%) 14(58%) 3(13%)
      Brain Mets at Stage IV diagnosis 93(67%) 13(52%)
      Number of Brain Mets 1 2-4 5+ N/A 32(23%) 39(28%) 62(45%) 6(4%) 9(38%) 6(24%) 9(38%) 0
      Symptomatic Brain Mets No Yes 78(56%) 61(44%) 16(67%) 8(33%)
      Initial Brain Mets treatment WBRT WBRT+SRS/Surgery SRS+/-Surgery Systemic Therapy None 71(51%) 17(12%) 27(19%) 19(14%) 5(4%) 13(54%) 3(12%) 4(17%) 4(17%) 0


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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI14.12 - Genomic Profiling of Patient-Derived Xenografts Identify Passenger Aberrations Associated with Better Prognosis in Non-Small Cell Lung Cancer (ID 1735)

      10:45 - 12:15  |  Author(s): M. Pintilie

      • Abstract
      • Slides

      Background:
      Patient-derived tumor xenografts (PDXs) increasingly are being used as preclinical models to study human cancers, test novel therapeutics, and identify potential biomarkers, as they more accurately model human cancers than established tumor cell line cultures. However, uncertainty remains as to how well the genomic characteristics of patient non-small cell lung cancer (NSCLC) are recapitulated in these PDX models.

      Methods:
      PDXs were established by implantation of surgically resected NSCLC patient tumors into the subcutaneous or sub-renal capsule of non-obese diabetic severe combined immune deficient (NOD-SCID mice. Comprehensive genomic profiling including exome, gene copy number, DNA methylation and mRNA expression were conducted on 36 independent PDX models, their matched patient tumors and normal lung tissue. Publicly available cell line and TCGA data were used for comparison. Integrative analysis was performed to identify genomic alterations in PDXs that are associated with significant clinical outcomes in patients.

      Results:
      From 441 resected NSCLC tumors, 127 serially transplantable and stable PDX models were established. Among 264 NSCLC patients with at least 3-years follow-up, patients whose tumor formed stable PDXs (versus those who did not) showed significantly worse disease free (HR=3.12, 95% CI =2.02-4.83, P<0.0001) and overall survival (HR=4.08, 95% CI =2.16-7.73, P<0.0001), after multivariable adjustment for clinical pathological factors. Genomic and transcriptomic profiling of 36 PDXs showed greater similarity in somatic alterations between PDX and primary tumors than with published cell line data. In addition to known mutations, we found at least 16 non-synonymous somatic mutations in known oncogenes and tumor suppressors that have never been reported. All these mutations had higher observed variant allele frequency in PDXs compared to their matched patient tumors, suggesting that these were tumor sub-clones selected or enriched for growth in the PDXs. Tumor models characterized by a higher number of somatic alterations among 865 frequently altered genes were associated with better overall patient survival (HR=0.15, p=0.00015) compared to patients with corresponding PDXs characterized by higher alteration number; this was validated in the TCGA lung cancer dataset patients (HR=0.28, p=0.000022). These 865 genes were enriched for those encoding for proteins involved in cell adhesion and interactions with the extracellular matrix, and a quarter of the genomic alterations would putatively form neo-antigens implicating a potential role of immune response in the observed improved patient survival.

      Conclusion:
      PDXs are close preclinical models of patient tumors. Further investigations of passenger mutations may clarify their clinical impact on interactions between tumor cells, stroma, immune microenvironment and patient prognosis.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-099 - Proteome Signatures with Prognostic Impact Distinguish Non-Small Cell Lung Cancer Histology Subtypes and Metabolic States (ID 1009)

      09:30 - 17:00  |  Author(s): M. Pintilie

      • Abstract

      Background:
      We showed that the ability to establish a primary tumor­derived xenograft (PDX) is an independent predictor of shorter disease-free survival in early stage non-small cell lung carcinoma (NSCLC). Hence, NSCLC engraftment may select for critical, aggressive aspects of the cancer phenotype linked to disease progression. More recently we reported dramatic remodeling of NSCLC proteomes not predicted by genomics analyses, and which distinguish between the major histological subtypes of NSCLC. Herein we report details on NSCLC proteome remodeling as a major determinant of the expression of the metabolism proteome, engraftment, and related to patient outcome.

      Methods:
      Omics platforms were used to comprehensively characterize the genomes and proteomes of non-engrafting, engrafting, and derived PDX tumors associated with NSCLC. To facilitate proteome quantification by mass spectrometry, tumor samples were spiked with stable-isotope-labeled proteomes from a mixture of representative NSCLC cell lines as an internal standard.

      Results:
      Proteome remodeling in NSCLC is extensive and largely unpredicted by gene copy number variation, and not highly correlated with mRNA-based expression. Analysis of the proteomes of cognate engrafting primary and PDX tumor pairs revealed signatures comprising sets of metabolism proteins that distinguished between the major histological subtypes, and which were particularly highly recapitulated in PDX tumors. Interrogation of The Cancer Genome Atlas showed that the genes encoding the highly recapitulated metabolism protein signatures are for the most part not highly mutated in cancers. However, when the signature-encoding genes are considered as a singular polygene, then patients with mutations are recognized as having significantly different overall survival compared to patients without mutations. The proteomes of non-engrafting NSCLC tumors were generally more similar to normal lung than were engrafting tumor proteomes. Hence, proteome remodeling affects metabolic states associated with NSCLC outcome.

      Conclusion:
      NSCLC is characterized by significant proteome remodeling that is invisible to genomics platforms. The proteomes of engrafting and non-engrafting NSCLC primary tumors are different, suggesting the potential to develop proteome signatures as prognostic biomarkers. Moreover, proteome signatures associated with PDX engraftment and poor outcome may be a source of new drivers and targets in NSCLC.