Correspondence

BRAF Mutation in Metastatic Colorectal Cancer

N Engl J Med 2009; 361:98-99July 2, 2009

Article

To the Editor:

We recently found that progression-free survival was shorter among patients with metastatic colorectal cancer treated with chemotherapy, bevacizumab, and cetuximab (CBC regimen) than among patients who received chemotherapy and bevacizumab alone (CB regimen) (Feb. 5 issue).1 Other investigators have found that the efficacy of cetuximab is limited to patients with wild-type–KRAS tumors.2 In a subgroup of 520 patients with available tumor samples, we observed a shorter median progression-free survival among patients with a mutated-KRAS oncogene in the CBC group than among patients with mutated-KRAS tumors who received the CB regimen and among patients with wild-type–KRAS tumors who received the CBC regimen. An activating mutation in the B-type Raf kinase (BRAF) oncogene encoding the BRAF protein, localized directly downstream of RAS, leads to stimulation of the mitogen-activated protein kinase pathway.3 In a recent study, the efficacy of antibody therapy against the epidermal growth factor receptor for wild-type–KRAS tumors appeared to be restricted to wild-type–BRAF tumors.4 We performed a retrospective analysis of the BRAF V600E mutation status in 519 tumors that were tested in our study to determine KRAS status. A BRAF mutation was detected in 45 tumors (8.7%) (Table 1Table 1Association of the Mutation Status of the BRAF Oncogene with Progression-free Survival, Overall Survival, and Response Rate.). BRAF and KRAS mutations were mutually exclusive. Patients with BRAF-mutated tumors had a significantly shorter median progression-free and median overall survival than patients with wild-type–BRAF tumors, both in the CB group and in the CBC group (Table 1). No difference in response rate was observed. We conclude that a BRAF mutation is a negative prognostic marker in patients with metastatic colorectal cancer and that this effect, in contrast to KRAS mutations, is not restricted to the outcome of cetuximab treatment.

Jolien Tol, M.D.
Iris D. Nagtegaal, M.D., Ph.D.
Cornelis J.A. Punt, M.D., Ph.D.
Radboud University Nijmegen Medical Center, 6500HB Nijmegen, the Netherlands
c.punt@onco.umcn.nl

The DCCG received unrestricted scientific grants from Roche, Merck Serono, and Sanofi-Aventis. Dr. Punt reports receiving grant support from Roche and consulting fees from Roche and Merck Serono. No other potential conflict of interest relevant to this letter was reported.

This letter (10.1056/NEJMc0904160) was updated on August 31, 2011, at NEJM.org.

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