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Randomized Controlled Trial
. 2012 Feb 1;18(3):890-900.
doi: 10.1158/1078-0432.CCR-11-2246. Epub 2011 Dec 6.

Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803

Shuji Ogino  1 , Kaori Shima, Jeffrey A Meyerhardt, Nadine J McCleary, Kimmie Ng, Donna Hollis, Leonard B Saltz, Robert J Mayer, Paul Schaefer, Renaud Whittom, Alexander Hantel, Al B Benson 3rd, Donna Spiegelman, Richard M Goldberg, Monica M Bertagnolli, Charles S Fuchs
Affiliations
Randomized Controlled Trial

Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803

Shuji Ogino et al. Clin Cancer Res. .

Abstract

Purpose: Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer.

Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status.

Results: Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46).

Conclusions: BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

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Figures

Figure 1
Figure 1
BRAF mutation and clinical outcome in colon cancer. A-C. Kaplan-Meier curves according to BRAF mutation in 506 stage III colon cancers for recurrence-free survival (RFS) (A), disease-free survival (DFS) (B), and overall survival (OS) (C). The y axis indicates the survival probability. D-F. Kaplan-Meier curves for RFS (D), DFS (E) and OS (F) according to treatment arm and BRAF mutation status. G. Proposed strategy for prognostication of colon cancer by MSI and BRAF tests. DFS, disease-free survival; FU/LV, 5-fluorouracil and leucovorin; IFL, irinotecan, 5-fluorouracil and leucovorin; MSI, microsatellite instability; MSS, microsatellite stable; Mut, mutant; OS, overall survival; RFS, recurrence-free survival; WT, wild-type.
Figure 1
Figure 1
BRAF mutation and clinical outcome in colon cancer. A-C. Kaplan-Meier curves according to BRAF mutation in 506 stage III colon cancers for recurrence-free survival (RFS) (A), disease-free survival (DFS) (B), and overall survival (OS) (C). The y axis indicates the survival probability. D-F. Kaplan-Meier curves for RFS (D), DFS (E) and OS (F) according to treatment arm and BRAF mutation status. G. Proposed strategy for prognostication of colon cancer by MSI and BRAF tests. DFS, disease-free survival; FU/LV, 5-fluorouracil and leucovorin; IFL, irinotecan, 5-fluorouracil and leucovorin; MSI, microsatellite instability; MSS, microsatellite stable; Mut, mutant; OS, overall survival; RFS, recurrence-free survival; WT, wild-type.
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