KRAS and BRAF

KRAS and BRAF testing can be used for metastatic colorectal cancer prognosis and therapy evaluation.  The tests can aid in the identification of patients eligible for treatment with cetuximab (Erbitux®) or panitumumab (Vectibix®)

KRAS Mutation Analysis

Mutations in the K-ras oncogene are frequently found in human cancers. They are common in pancreatic cancer, colorectal cancer, lung adenocarcinoma, gall bladder cancer, bile duct cancer, and thryoid cancer.  Metastatic colorectal cancer patients with wild type KRAS and the BRAF V600E mutation do not have a strong response to anti-EGFR therapies such as cetuximab and panitumumab and the National Comprehensive Cancer Network (NCCN) recommends that patients should be tested for KRAS status before receiving these therapies. The NCCN additionally recommends testing for BRAF in colon cancer patients that have wild type KRAS.

BRAF Mutation Analysis

Somatic mutations in the BRAF oncogene are common in melanomas, colorectal cancer, lung cancer, ovarian cancer, and thyroid gland cancer. More than 90% of mutations are the V600E(1799T>A) mutation. Metastatic colorectal cancer patients with this BRAF mutation do not have a strong response to anti-EGFR therapies such as cetuximab and panitumumab.

Support for Use of KRAS and BRAF in Colorectal Cancer:

• The FDA has updated the "indication and usage" section of the labels of  with cetuximab and panitumumab to note that "retrospective analyses of metastatic colorectal cancer trials have not shown a treatment benefit for the EGFR inhibitors in patients whose tumors had KRAS mutations in codon 12 or 13," and that the use of the drugs is not recommended for the treatment of colorectal cancer patients with these mutations.
• The American Society of Clinical Oncology (ASCO) issued a Provisional Clinical Opinion on the use of KRAS gene mutation testing in patients with metastatic colorectal cancer to guide treatment with monoclonal antibodies against the epidermal growth factor receptor (EGFR) protein, such as cetuximab and panitumumab.  The ASCO document recommends that all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy have their tumors tested for KRAS gene mutations.  If a patient has a mutated KRAS gene, ASCO recommends against the use of anti-EGFR antibody therapies.  This recommendation is based on a series of recent studies indicating that anti-EGFR antibody therapies are effective only in patients with a normal (wild-type) version of the KRAS gene.  Studies have shown that 35% to 45% of colon cancer patients have KRAS mutations in their tumor specimens.
• The National Comprehensive Cancer Network (NCCN) also recently modified their treatment guidelines for colon cancer to include testing for KRAS mutations as a part of the clinical workup for patients with stage IV disease who are being considered for cetuximab or panitumumab therapy.  Additionally, the NCCN recommends that patients who test positive for wild-type KRAS should be considered for BRAF testing.