What is BRAF?

BRAF is a gene that encodes the B-raf protein. BRAF plays an important role in the way that cell growth, cell proliferation, and cell differentiation are controlled. Cell growth is an increase in cell size, cell proliferation is an increase in the number of cells, and cell differentiation is the process in which immature (unspecialized) cells become mature (specialized) cells. If the BRAF gene has a mutation, the control system (signaling pathway) for these processes may not function properly. This can allow cells to grow abnormally and become cancer. Genes, like BRAF, that can cause normal cells to become tumor (tumour) cells are called oncogenes. The BRAF mutations found in colorectal (bowel) cancer are somatic, which means they occur in non-reproductive cells and are not hereditary.

The BRAF oncogene plays a role in several different cancers. BRAF mutations are present in approximately 10%-15% of colorectal cancers, 35% of melanomas, and more than 50% of thyroid papillary carcinomas. The majority of BRAF mutations are V600E mutations. Other mutations in BRAF do occur but they are rare. The incidence of BRAF mutation is higher in right-sided (proximal) colon cancers compared to left-sided (distal) colon cancers and rectal cancers.

BRAF is both a prognostic factor and a predictive biomarker. BRAF mutation status gives information about the usual course of disease (prognosis) and it predicts which treatments may be more or less effective against a particular colorectal (bowel) cancer, such as conventional chemotherapy drugs or targeted therapy with EGFR (epidermal growth factor receptor) inhibitors.

How is BRAF mutation status tested?

The recommended method of testing for BRAF mutation status is with a biopsy sample of cancer cells, either from the primary colorectal tumor or from tumor metastases in another part of the body (lymph node, liver, peritoneum). The cancer cells are treated in a laboratory to isolate the tumor DNA to be studied.

BRAF may also be tested in a blood sample by examining circulating tumor DNA (ctDNA) for BRAF mutations. This is called a liquid biopsy. BRAF may be tested individually, or as part of a multi-gene panel using next-generation sequencing (NGS). BRAF mutation testing is sometimes also called BRAF mutation analysis or BRAF gene sequencing.

What do my BRAF mutation testing results mean?

If your result is reported as “BRAF wild-type” or “BRAF WT”, this means there is no BRAF mutation in your colorectal cancer (CRC). Wild-type is the normal state of the gene.

If your colon cancer or rectal cancer has a BRAF gene mutation, it will be reported as “BRAF mutant” or as the specific mutation, for example “BRAF V600E mutation”.

How do my BRAF biomarker testing results impact my treatment?

If your BRAF is wild-type (no mutation)

• Colorectal cancer patients with BRAF wild-type tumors are typically treated with EGFR inhibitors.
• Cetuximab (Erbitux) and panitumumab (Vectibix) are EGFR inhibitors used in colorectal cancer. They are sometimes called anti-EGFR therapies or anti-EGFR monoclonal antibodies.
• Treatment options for BRAF wild-type colorectal cancer may also be influenced by the results of other biomarker testing, such as immunotherapy for tumors with microsatellite instability (MSI).
• EGFR inhibitors may be combined with conventional fluorouracil-based chemotherapy regimens, like FOLFOX (containing oxaliplatin) or FOLFIRI (containing irinotecan) for an increased response rate.  

If your colorectal cancer has a BRAF gene mutation

• The BRAF V600E mutation is associated with poor prognosis.
• Colorectal cancer with the BRAF V600E mutation can be treated with targeted therapy, like combined BRAF inhibitors and MEK inhibitors.
• BRAF inhibition, combined with MEK inhibition, can restore control of cell growth processes in tumor cells.
• The BRAF inhibitors used in advanced colorectal cancer treatment are encorafenib (Braftovi), and vemurafenib (Zelboraf).
• The MEK inhibitors used in metastatic CRC treatment are binimetinib (Mektovi) and trametinib (Mekinist).
• Bevacizumab (Avastin) may be added to these targeted therapies. Bevacizumab is also a targeted therapy. It prevents the formation of new blood vessels to supply the tumor with nutrients.
• EGFR inhibitors are not effective when used alone in BRAF mutant colorectal cancer therapy.
• EGFR inhibitors may be added to BRAF inhibitors in BRAF mutant colorectal cancer treatment. These combinations may increase overall survival.
• Traditional chemotherapy drugs are also used to treat the subtype of colorectal cancer with BRAF mutation.
• BRAF mutation and microsatellite instability / deficient mismatch repair coexist in many colorectal cancers, so immunotherapy drugs, like nivolumab (Opdivo), pembrolizumab (Keytruda), and ipilimumab (Yervoy), may be used in combination with other targeted therapies to improve response.

There are ongoing clinical trials for treatments that specifically target BRAF wild-type and BRAF mutant metastatic colorectal cancer, including drugs already approved for use in the treatment of other BRAF mutant cancers. Talk to your oncology team about whether you could benefit from participation in a clinical trial.

Who should have BRAF biomarker testing?

If you have stage IV / metastatic colorectal cancer (mCRC), you should be tested for the BRAF biomarker.