Together, colon and rectal cancer (colorectal cancer, or CRC) comprise the third most common cancer in the United States, with an estimated 50,000 deaths caused by CRC in 2009. The risk of CRC increases with age, with 90% diagnosed when the patient is older than 50 years of age. The 5-year survival rate for the 150,000 individuals diagnosed each year with CRC is 65.2% over all stages, but drops to 11.3% in those with metastatic disease. Single or multiagent chemotherapy regimens may be chosen based on the drugs that are currently approved for treating metastatic CRC, which include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, oxaliplatin, and panitumumab. Cetuximab (Erbitux®; Imclone Systems Inc./Bristol-Myers Squibb) and panitumumab (Vectibix®; Amgen Inc.) are anti–epidermal growth factor receptor (EGFR) monoclonal antibodies
that are generally used for second- or third-line treatment in patients with metastatic disease following failure of first-line chemotherapy. EGFR is a component of the HER/Erb-B (human EGFR) signaling pathway. Clinical evidence suggests that the benefit from the EGFR monoclonal antibody inhibitors cetuximab and panitumumab is limited to a subgroup of only 10% to 30% of CRC patients. Biomarkers are therefore needed to help select the patients who will benefit from treatment with EGFR inhibitors. Recently, the presence of sequence variants in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene has been approved by the Food and Drug Administration (FDA) as a negative prognostic indicator for response to treatment with cetuximab and panitumumab. Another biomarker that is part of the same EGFR signaling pathway as KRAS that has been investigated for predicting response to EGFR monoclonal antibody treatment in CRC is the v-raf murine sarcoma viral oncogene homolog B, known as BRAF. The BRAF gene sequence
variant p.Val600Glu, often called V600E, is the variant that is usually associated with CRC. The frequency of the BRAF p.Val600Glu variant was 5% to 12% in CRC populations, and the presence of this variant has been found to be associated with poor survival in patients with CRC in several studies in which patients were not treated with anti-EGFR monoclonal antibody. As testing for the presence of KRAS sequence variants to predict response to therapy with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now included in the FDA prescribing information, this report focuses on the assessment of genetic testing for BRAF p.Val600Glu following KRAS testing.