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G. Iyer

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    PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      PLEN04.05 - Multiregion Whole Exome and Transcriptome Sequencing Defines the Genomic Spectrum of EGFR+ NSCLC and Reveals Novel Mechanisms of TKI Resistance (ID 3118)

      10:45 - 12:15  |  Author(s): G. Iyer

      • Abstract
      • Presentation

      EGFR mutant (M+) NSCLC is an archetypical oncogene-driven solid tumor, typified by high response rates when treated with a tyrosine kinase inhibitor (TKI), and median progression free survival of 10 months, commonly due to emergence of T790M. The genomic architecture and spectra of EGFR M+ tumours may provide insights to mechanisms of treatment failure and has not been well described to date.

      Paired tumor-normal exome/ transcriptome sequencing and SNP array was performed on 30 tbiopsies from 25 patients with TKI resistance (TKI-R) as well as multiple regions (n=46) of 8 treatment naïve (TKI-N), never smoker East Asian EGFR M+ NSCLC (L858R, n=5; exon 19 del, n=2; exon 20 ins, n=1). Genomic alterations were validated with targeted re-sequencing at a mean depth of 2000x. Alterations were identified and annotated using established pipelines.

      Exome sequencing of 46 sectors (4-11 sectors/tumor) from 8 resected NSCLC (Stage IA, n=5; Stage IB, n=3), revealed a median of 52.5 validated mutations (Range: 15-112) per tumor. Primary EGFR mutations (including exon 20 ins) were identified as truncal events in all cases, with the notable absence of T790M even at sequencing depths of 2000x. Private mutations comprised 10-33% of all mutations per tumor, and in some cases harbored potential drivers of subclonal diversity including p53, AKT1 and ATXN1. For the 30 TKI-R tumors (T790M+, n=16; T790M-, n=14), exome sequencing revealed a higher mutation burden (median 80 vs 49 in TKI-N), while SNP array and expression data confirmed ERBB2 and MET as common co-existing resistance mechanisms. We next inferred the relevance of alterations and their hierarchical order (trunk, T; branch, B; private, P). In a TKI-N tumor where 11 sectors were subject to exome-sequencing, 39 of 112 mutations were truncal events – with MAP3K19 and PTEN splice site mutations co-existing with EGFR L858R mutation. Strikingly, when comparing the transcriptomic profiles of TKI-N and TKI-R tumors, all 8 evaluated sectors in this tumor clustered together with the TKI-R signature, suggesting that truncal co-mutations can contribute to primary TKI resistance. Finally, we attempted to curate novel genes in the 46 TKI-N sectors that may be implicated in TKI resistance by identifying genes in common with those altered in TKI-R samples with allele frequency > 0.25. We shortlisted approximately 150 recurrent genes or putative drivers – 85% of which were either trunk or branch mutations including TP53 (T,P), PTEN (B), LRP1B (B), GPRIN3 (B), MAP3K19 (T), ARID3A (P) and MED12 (P).

      Multi-region sequencing of 8 never smoker EGFR M+ NSCLC revealed a low mutation burden, with a significant proportion of alterations occurring as trunk or branch events. The different activating EGFR mutations were ubiquitous truncal events and T790M was not found in ultra-deep sequencing across 46 sectors. Mutation hierarchy provides a basis for patterns of TKI treatment failure: with co-occurring truncal events (e.g. MAP3K19, PTEN) potentially contributing to primary resistance, and the low incidence of private subclonal drivers consistent with the relatively high prevalence of T790M mutation in the setting of secondary resistance.

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