4.7 Article

Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer

Journal

CLINICAL CANCER RESEARCH
Volume 24, Issue 2, Pages 334-340

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-1841

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Funding

  1. U.S. Department of Health and Human Services through NCI of the NIH [P30 CA008748]
  2. DallePezze Family Foundation
  3. Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACRDT1715]
  4. American Association for Cancer Research
  5. SU2C

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Purpose: KRAS mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of KRAS mutations, patients with KRAS-mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with KRAS-mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. Experimental Design: We identified patients with advanced KRAS-mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors. Results: Among 330 patients with advanced KRAS-mutant lung cancers, the most frequent co-mutations were found in TP53 (42%), STK11 (29%), and KEAP1/NFE2L2 (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in KEAP1/NFE2L2 [HR, 1.96; 95% confidence interval (CI), 1.33-2.92; P <= 0.001]. STK11 (HR, 1.3; P = 0.22) and TP53 (HR 1.11, P = 0.58) co-mutation statuses were not associated with survival. Co-mutation in KEAP1/NFE2L2 was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04-2.59; P = 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55-8.11; P = 0.003). Conclusions: Among people with KRAS-mutant advanced NSCLC, TP53, STK11, and KEAP1/NFE2L2 are the most commonly co-occurring somatic genomic alterations. Co-mutation of KRAS and KEAP1/NFE2L2 is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy. (C) 2017 AACR.

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