Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer

Julien Taieb, Karine Le Malicot, Qian Shi, Frédérique Penault Lorca, Olivier Bouché, Josep Tabernero, Enrico Mini, Richard M. Goldberg, Gunnar Folprecht, Jean Luc Van Laethem, Daniel J. Sargent, Steven R. Alberts, Jean Francois Emile, Pierre Laurent Puig, Frank A. Sinicrope

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Abstract

© 2016 The Author. Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials. Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors. Results: Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P <. 001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P <. 001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02, 95% CI = 2.32 to 3.93, P <. 001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P <. 001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P <. 001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients. Conclusions: In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.
Original languageEnglish
Article numberdjw272
JournalJournal of the National Cancer Institute
Volume109
Issue number5
DOIs
Publication statusPublished - 1 May 2017

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