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Purpose Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. Patients and Methods We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. Conclusion BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.

ECENT RETROSPECTIVE CORrelative analyses of metastatic colorectal cancer trials indicate that patients with KRAS-mutated tumors (NCBI Entrez Gene 3845) do not benefit from the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab. 1 These retrospective analyses were performed independently, and for each analysis, KRAS wild-type vs mutant were studied grouping codons 12 and 13 mutations together, without subgroup analysis. Health authorities in the United States and Europe have indicated that patients with KRAS codon 12-or KRAS codon 13-mutated tumors should not receive cetuximab or panitumumab. 2-4 However, indications exist that not all KRAS mutations are equal in their biological characteristics. First, the pattern of KRAS mutations is tumor-type spe-Author Affiliations are listed at the end of this article.