Author of

• 16751

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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
  • Moderators:
  • Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 16768

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    P1.05-017 - The Prognostic Impact of EGFR, KRAS and TP53 Somatic Mutations in Curatively Resected Early-Stage Lung Adenocarcinomas (ID 4527)

    14:30 - 14:30  |  Author(s): R. Das
    • Abstract

    Background:
    As the 5-year survival among individuals undergoing curative-intent resection for early-stage lung cancer approaches 50%, identification of prognostic biomarkers useful for risk stratification is a priority. While somatic mutation profiling drives treatment choice in advanced disease, its usefulness among early-stage patients is not well-established.
    
    Methods:
    From May 2011 through December 2014, The Yale Lung Cancer Biorepository enrolled 192 individuals who underwent curative-intent complete resection for Stage IA-IIIA adenocarcinoma. Demographics and lifestyle choices were ascertained by interview using validated questionnaires. Pathologic characterization of index tumors, including CLIA Laboratory-assayed EGFR/KRAS status, was extracted from the medical record. A custom targeted resequencing panel covering all coding exons from 93 lung adenocarcinoma-related genes was designed. Buffy coat-derived germline DNA and tumor DNA, extracted from the FFPE surgical specimen, were sequenced on the Ion Torrent platform with >90% of the assayed amplicons achieving >30x coverage in both tumor and germline from each case. Somatic nonsynonymous tumor variants were identified using the Torrent Variant Caller. Bivariate associations were evaluated by Chi-square or ANOVA. Survival analyses were conducted using Cox modeling.
    
    Results:
    181/192 (94.3%) participants underwent EGFR/KRAS somatic mutation profiling with 43 EGFR mutations and 71 KRAS mutations detected. EGFR mutations were more common among well- and moderately-differentiated lesions (p=0.06) and among never or former light smokers (p=0.0007). Seventy-two percent of EGFR and 81.7% of KRAS mutations were found among female patients (p=0.0008). The joint distribution between smoking and gender favored EGFR mutations among female never/former smokers, KRAS mutations among female ever-smokers and EGFR/KRAS wild-type status among male ever-smokers (p=0.0002). After adjustment for AJCC 7[th] edition Tstage, Nstage and presence of lymphovascular invasion, KRAS mutations (HR=2.14; 95% CI:1.04-4.43; p=0.04) but not EGFR mutations (p=0.63) were prognostic for poorer disease-free survival. Targeted resequencing data is available on 148 cases. The nonsynonymous mutation burden ranged from 0-7 with 84% of cases having ≤3. In addition to KRAS and EGFR, frequent mutations were noted in p53 (n=40; 27.0%), STK11 (n=10; 6.8%) and PIK3CA (n=7; 4.7%) with 4 genes mutated in 6 cases. TP53 mutations were associated with high nonsynonymous mutation burden (p<0.0001) and the joint distribution with EGFR/KRAS status revealed the highest burden among KRAS[mut]/TP53[mut] (3.94±1.57) followed by EGFR[mut]/TP53[mut] (3.07±1.61) and EGFR_KRAS[wt]/TP53[mut] (2.20±1.40; p<0.0001).
    
    Conclusion:
    KRAS[mut], like EGFR[mut], is associated with female gender but only KRAS[mut] is prognostic following curative-intent resection. Elevated mutation burden observed among KRAS[mut]/TP53[mut] may offer novel therapeutic options following recurrence.