Biomarkers in Colon Cancer: Understanding KRAS, BRAF, and HER2

MMR/MSI testing is recommended for anyone diagnosed with colon cancer, according to the National Comprehensive Cancer Network guidelines.

MMR genes are responsible for helping to correct a certain type of error in which the DNA might be accidentally "mismatched" when cells replicate. When the MMR system is defective, it causes specific proteins (MLH1, MSH6, PMS2, MSH2) to be unable to perform this job. Thus, a mismatch repair deficiency (dMMR) allows errors to accumulate due to the lack of repairs. The accumulation of errors affects areas of the cell's genes responsible for keeping the cell from dividing out of control (a hallmark of cancer), and is known as High Microsatellite Instability (MSI-H).

There are two kinds of laboratory tests for this biomarker, both involve a tissue sample (biopsy) of the tumor. Depending on the method used, an abnormal result is called either microsatellite instability high or mismatch repair deficient (dMMR)

Patients with MSI-H or dMMR make up about 15% of patients with colorectal cancer.

If the cancer has spread (metastasized) to other organs, such as the liver or the lungs (stage four cancer), the NCCN recommends testing for biomarkers such as HER2, KRAS and BRAF. In many cases, these markers will drive treatment choices.

KRAS and NRAS mutations

Approximately 40-45% of colorectal cancer patients have KRAS mutation in their tumors. This mutation is not hereditary and will not be passed from one generation to another — it's completely random. NRAS mutations are much less common, though both KRAS and NRAS are part of the RAS oncogene family.

It's important to know if your tumor is KRAS-mutated because positive KRAS-cancers have poor response to EGFR-inhibitor medications (such as cetuximab or panitumumab), and therefore, shouldn't be treated with those drugs, but rather with conventional chemotherapy lines such as FOLFOX or FOLFIRI, with or without the addition of bevacizumab.

BRAF Mutation

Like KRAS mutation, BRAF gene mutation happens randomly and it's not hereditary. But unlike KRAS, it's not that frequent. Studies have shown that the BRAF gene mutation is found in about 10% of colorectal cancer patients. Knowing about a BRAF gene mutation indicates the need for aggressive treatment, since the mortality risk for patients with a BRAF mutation is more than two times higher than for those with a normal BRAF gene.

“People with a BRAF mutation have a higher risk of the cancer coming back,” Dr. Paul Oberstein, a medical oncologist at NYU Langone’s Perlmutter Cancer Center told SurvivorNet in a previous conversation. “And it may inform how we watch that patient going forward and what we do if it does come back….So it's a piece of information to have that's necessary if the patient has cancer that returns or if they need treatment for their cancer.”

Dr. Paul Oberstein explains treatment options for stage four colon cancer. 

HER2 Testing

The human epidermal growth factor receptor 2 (HER2) is a receptor on the surface of almost all the cells in our body, and it is responsible for the communication between the cells to promote their growth, division, repair, and survival. Approximately 3% of colorectal cancers have amplification of the HER2 oncogene. This mutation is also not hereditary and will not pass from one generation to another.

According to NCCN Guidelines, patients whose tumors are positive for KRAS or BRAF mutation do not need to undergo HER2 testing. Doctors may be able to recommend a more effective therapy combination if a HER2 amplification is detected.

“HER 2 is a mutation that is a common breast cancer mutation, actually, but in about 15% of colorectal cancers, the tumor is HER 2 activated, and we have a drug against HER 2,” Dr. Allyson Ocean, a medical oncologist at Weill Cornell told SurvivorNet in a previous conversation. “It’s called HERceptin, and we can use that in combination with chemotherapy to treat HER 2-activated colon cancers. If we had never done the sequencing for that patient, we would have never known that that tumor carries the HER 2 mutation, so therefore we have to sequence the tumors so we can find out the genetic code is for them, so we can match therapies to it.”

Understanding How Biomarkers Work

In a previous conversation with SurvivorNet, Dr. Heather Yeo, a colorectal cancer surgeon at Weill Cornell, spoke about the role biomarkers have in treating colon cancer, noting that doctors are tailoring certain treatments to individuals, particularly for patients in need of a second therapy after no responding to initial treatment.

"In colon cancer, we're starting to look more and more at people's biomarkers, so we're starting to actually take the cancers, sequence them, understand where the different mutations are to figure out whether or not someone has a normal gene here or an abnormal gene," Dr. Yeo explained.

Dr. Heather Yeo explains how biomarkers are used to determine colon cancer treatment. 

"And those are the areas that people want to be able to target a little bit more. We're getting close to more what we would call precision medicine, meaning we can start looking at people's genetic mutations and think about how they might respond to different drugs."

What to Ask Your Doctor

• Which biomarkers are relevant in the treatment of my colon cancer?
• How do you monitor these biomarkers?
• How will the results help guide my treatment?
• How will I know if the treatment is working?

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