PROGNOSTIC ROLE OF BRAF IN COLORECTAL CANCER

Clin Cancer Res. 2011 Dec 6. [Epub ahead of print]

Predictive and Prognostic Roles of BRAF Mutation in Stage III Colon Cancer: Results from Intergroup Trial CALGB 89803.

Ogino S, Shima K, Meyerhardt J, McCleary N, Ng K, Hollis D, Saltz LB, Mayer RJ, Schaefer P, Whittom R, Hantel A, Benson AB, Spiegelman D, Goldberg RM, Bertagnolli MM, Fuchs CS.

Source

Dept. of Pathology, BWH, Dana-Farber Cancer Institute.

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 to 431 BRAF-wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank p=0.015; multivariate hazard ratio (HR)=1.66; 95% confidence interval (CI), 1.05-2.63]. By assessing combined status of BRAF and MSI, it appeared that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, while 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 non-significant trend toward improved OS was observed for IFL vs. 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.