Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer Journal Article

Authors: Arbour, K. C.; Jordan, E.; Kim, H. R.; Dienstag, J.; Yu, H. A.; Sanchez-Vega, F.; Lito, P.; Berger, M.; Solit, D. B.; Hellmann, M.; Kris, M. G.; Rudin, C. M.; Ni, A.; Arcila, M.; Ladanyi, M.; Riely, G. J.
Article Title: Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer
Abstract: 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: Among330 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. © 2017 AACR.
Keywords: adult; cancer chemotherapy; cancer survival; controlled study; treatment outcome; treatment response; aged; survival rate; gene mutation; major clinical study; overall survival; disease course; treatment duration; disease association; cancer immunotherapy; cohort analysis; genotype; protein p53; lung adenocarcinoma; platinum derivative; oncogene k ras; pemetrexed; non small cell lung cancer; protein kinase lkb1; tp53 gene; kelch like ech associated protein 1; keap1 gene; nfe2l2 gene; human; male; female; priority journal; article; stk11 gene
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 2
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-01-15
Start Page: 334
End Page: 340
Language: English
DOI: 10.1158/1078-0432.ccr-17-1841
PROVIDER: scopus
PMCID: PMC5771996
PUBMED: 29089357
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
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MSK Authors
  1. David Solit
    420 Solit
  2. Helena Alexandra Yu
    86 Yu
  3. Piro Lito
    15 Lito
  4. Marc Ladanyi
    848 Ladanyi
  5. Gregory J Riely
    334 Riely
  6. Michael Forman Berger
    373 Berger
  7. Maria Eugenia Arcila
    328 Arcila
  8. Mark Kris
    581 Kris
  9. Matthew David Hellmann
    147 Hellmann
  10. Charles Rudin
    154 Rudin
  11. Emmet John Jordan
    27 Jordan
  12. Ai   Ni
    45 Ni
  13. Kathryn Cecilia Arbour
    13 Arbour
  14. Hyunjae Ryan Kim
    5 Kim