Experts have long appreciated that the clinical entity we call colorectal cancer is a phenotype made up of numerous different genotypes, accounting for the wide variation in clinical course and responses to therapies experienced by different individuals. Observations reported by Khambata-Ford et al1 and subsequently confirmed by Amado et al2 have made the practicing community aware that activating mutations in exon 2 of the gene encoding for KRAS, a key signal transduction protein, result in primary resistance to anti–epidermal growth factor receptor (EGFR) agents by leading to EGFR-independent activation of mitogen-activated protein kinase (MAPK) signaling.
BRAF is a signal transduction protein that is downstream of KRAS in the MAPK pathway. Approximately 5% to 10% of colorectal cancers harbor mutations in BRAF; the most common is the V600E mutation. The occurrence of these mutations in colorectal cancers raises 2 important questions: what are the clinical characteristics of a colorectal cancer with a V600E BRAF mutation, and can that mutation be targeted for therapeutic advantage?
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. De Roock W Claes B Bernasconi D Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010; 11: 753– 762.
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