BRAF Biomarker

The BRAF biomarker is a prognostic and predictive biomarker. The BRAF gene is a proto-oncogene responsible for the production of the BRAF protein. Proto-oncogenes typically play a role in regulating normal cellular processes and when mutated (now called an oncogene), have the potential to cause cancer.  BRAF works with other proteins within the EGFR/RAS/MAPK pathway.  

A wild-type BRAF (or normal) protein has both an “on” and an “off” state and is involved in controlling cell growth, proliferation (division), and survival. Mutated BRAF protein acts only in an “on” state, often referred to as being constitutively active, resulting in uncontrollable cell growth and division, which can lead to cancer.  

The most common mutation in BRAF is V600E. While other mutations in BRAF can occur, they are extremely rare. BRAF mutations are more common in right-sided colon cancer than in left-sided colon cancer or rectal cancer.  

These mutations are named to represent the location and types of amino acid being mutated within the protein. The letters represent the amino acids, building blocks of protein, that are mutated. The number refers to the location of the mutation on the chromosome. The location can be thought of as the codon or the amino acid location – as codons are three nucleotide sequences in messenger RNA (mRNA) transcripts that “call” for a specific amino acid. 

Using V600E as an example, V and E represent the amino acids and 600 refers to the amino acid location in the protein. In this case, valine (V) got replaced by glutamic acid (E) at the 600^th codon in a mRNA transcript or amino acid in the protein sequence.  

All patients with stage IV metastatic colorectal cancer should have BRAF biomarker testing.  

The most common method for testing BRAF is using a tumor biopsy sample from the primary or metastatic tumor. Alternatively, a blood sample using circulating tumor DNA (ctDNA), also called a liquid biopsy may be used. BRAF may be tested individually or as part of a multi-gene panel. 

The best way to ensure you have been tested for BRAF mutations is to ask your medical care provider.   

A report for your tumor’s BRAF biomarker may be reported as “BRAF wild-type” or “BRAF WT” if there is no BRAF mutation present. If there is a BRAF mutation present, it may be listed as “BRAF mutant” or with the specific mutation, such as “BRAF V600E mutation.”  

BRAF mutations are found in approximately 10-15% of colorectal cancers. This means approximately 85-90% of colorectal cancers have wild-type (WT) BRAF. BRAF mutations involved in colorectal cancer are not hereditary. 

If your tumor has wild-type BRAF, it  does not have a mutation within its BRAF gene. 

• Patients with wild-type BRAF tumors often benefit from targeted treatment with EGFR inhibitors (or anti-EGFR therapies). EGFR inhibitors may be combined with conventional chemotherapies, like FOLFOX or FOLFIRI.  
• Patients with wild-type BRAF tumors typically have a more favorable prognosis than those with BRAF mutations. 

If you have a tumor with mutant BRAF, it does have a mutation within its BRAF gene. In the majority of cases, a BRAF mutation will be V600E.  

• Patients with mutant BRAF tumors may not respond to targeted EGFR inhibitors and they are often not recommended. However, EGFR may be added in combination to BRAF inhibitors in some cases. 
• Treatment options for patients with mutant BRAF tumors often include traditional chemotherapy combinations.  If indicated by other biomarker testing, other targeted treatments may be recommended for use in patients with BRAF mutant CRC. 
• The presence of a BRAF V600E mutation in a person’s tumor is often suggestive of an aggressive tumor and it is associated with poor prognosis.  
• Patients with tumors that have a BRAF V600E mutation may benefit from combination treatment with targeted therapies, such as BRAF inhibitors and MEK inhibitors. BRAF inhibitors target mutated BRAF to turn off its activity. MEK inhibitors target MEK, a downstream protein in the same signaling pathway as BRAF, to turn off its activity. However, this combination treatment is most often given as a second- or third-line treatment, after cancer progresses following chemotherapy. 

A BRAF-mutant colorectal cancer is often treated with traditional chemotherapy (FOLFOX, FOLFIRI, CAPOX) with or without bevacizumab.  

A BRAF inhibitor, coupled with a MEK inhibitor, may be given as a second- or third-line treatment for metastatic colorectal cancer. BRAF inhibitors often used in colorectal cancer treatment are encorafenib and vemurafenib. MEK inhibitors often used in CRC treatment are binimetinib and trametinib.  

If indicated by other biomarker testing, other targeted treatments may be recommended for use in patients with BRAF mutant CRC.  

The most effective treatment varies by individual. It is best to speak with your medical team to learn more about the best treatment options for you. 

EGFR inhibitors, such as cetuximab or panitumumab, may be used as a stand-alone treatment or in combination with other traditional therapies (FOLFOX or FOLFIRI).  

The most effective treatment varies by individual. It is best to speak with your medical team to learn more about the best treatment options for you. 

There are current clinical trials for treatments that specifically target wild-type or mutant BRAF metastatic colorectal cancers. Many of these treatments are already approved for use in other cancers with BRAF mutations. 

Talk to your medical team to determine if you may benefit from a clinical trial. 

Check out Fight CRC’s Clinical Trial Finder to search for trials for BRAF patients, and read our Clinical Trials Conversations blog for insights on trials to consider.