Author of

• 16549

  +

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

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 16600

    +

    P1.02-051 - Concomitant Driver Mutations in Advanced Stage Non-Small-Cell Lung Cancer of Adenocarcinoma Subtype with Activating EGFR-Mutation (ID 5957)

    14:30 - 14:30  |  Author(s): J.N. Jakobsen
    • Abstract

    Background:
    Patients having non-small-cell lung cancer (NSCLC) with activating EGFR-mutations benefit from EGFR-Tyrosine Kinase Inhibitor (TKI) treatment. However, other driver mutations may occur simultaneously and other pathways may be amplified/overexpressed, potentially hampering efficacy of EGFR-TKI treatment. The frequency of such alterations at time of diagnosis was examined.
    
    Methods:
    All patients referred to Rigshospitalet, Copenhagen University Hospital for pulmonary adenocarcinoma (ADC) from July 2013 to August 2015 were routinely tested for EGFR-mutations by EGFR Cobas RT-PCR technique (Roche Diagnostics) on DNA extracted from diagnostic tumor biopsies or cytological samples. If positive for EGFR-mutations these patients were, prior to any treatment, also tested by targeted Next Generation Sequencing (NGS; Ion Torrent Ampliseq Colon-Lung v.2 panel and PGM NGS-sequenator) for other simultaneous cancer-relevant mutations, by fluorescence in-situ hybridization (FISH) for MET-amplification, and by immunohistochemistry (IHC) for expression of MET receptor as well as ALK fusion-protein.
    
    Results:
    Totally 512 ADC patients were tested, among whom 22 out of 282 advanced stage patients (7.8%) had activating EGFR-mutations, distributed as follows: 1 G719C-mutation, 13 exon 19-deletions, 1 T790M-mutation, 1 S768I-mutation and 8 L858R-mutations with 2 of the patients harboring EGFR-double-mutations G719C + S768I and L858R + T790M (i.e., activating and resistance mutation), respectively. Complete concordance between EGFR-mutation-status by EGFR Cobas and NGS was observed for all NGS tested patients. For one of the patients NGS analysis could not be carried out, due to lacking DNA-extract and remaining tumor tissue. NGS-analysis identified several concomitant driver mutations in the 21 analyzed patients, including one 1 with KRAS-mutation (G12V), 12 with TP53-mutations (7 in TP53-exon 5), 1 with FGFR-mutation (S125_E126insS), 2 with CTNNB1-mutations (S33C and S37F), 1 with MET-mutation (T1010I), 1 with SMAD4-mutation (R135stop), and 1 with PIK3CA-mutation (E545K). FISH and IHC for MET were successful in tumor samples from 16 and 19 patients, respectively. Three patients had concomitant MET-amplification (1 with and 1 without corresponding MET-overexpression, 1 with unsuccessful IHC), whereas 2 other patients had increased copy number (ICN; both with corresponding MET-overexpression). Interestingly, 4 of these 5 patients with MET-amplification or -ICN also carried TP53-mutations. Expression of ALK fusion-protein was not detected in any of the 22 patients with activating EGFR mutations.
    
    Conclusion:
    At time of diagnosis, concomitant mutations in other cancer driver genes can be detected in advanced EGFR-mutation-positive NSCLC of ADC subtype. These concomitant mutations may impact the response to first-line EGFR-TKI treatment and represent additional therapeutic targets.