Why a Tailored Approach to Colon Cancer Treatment Matters

Biomarkers are becoming more commonly used in cancer diagnosis, prognosis, and management. They are useful at various times during the illness to figure out how the disease is getting worse, if it’s coming back, and to show how well the treatment is working just for you.

“It can help us understand the genetic makeup of the cancer. We can use those testing results to gain insights into the cancer genetics, which can help us make some important treatment decisions and also help us in prognostication,” Dr. Aman Opneja, Medical Oncologist at Duke Cancer Center Gastrointestinal Clinic and Duke Cancer Center Raleigh, told SurvivorNet.

Colon Cancer Driver Mutations

These are specific mistakes in the DNA that fuel tumor growth. These are the most common mutations that drive colon cancer:

• MMR/MSI
• KRAS
• BRAF
• NRAS
• APC
• TP53
• HER2

Dr. Opneja points out that MSI testing and KRAS testing are some of the most common tests used.

MMR/MSI testing

“Microsatellites are like regions of repeated DNA that help in the repair of cancer DNA,” explains Dr Opneja. “If you have early stage colon cancer, one of the most common testing that’s done is MSI testing, which can help us identify if your cancer has some changes, which makes it more prone to immunotherapy. It can also help us prognostic and see what the cancer outcomes are.”

Mismatch repair (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 (MSI-H) or mismatch repair deficient (dMMR)

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

How do the results help?

Dr Opneja explains that when patients have MSI high results, their cancer is more prone to immunotherapy.

Determining if a patient has this mutation could affect what treatment they are ultimately given. For instance, if you have stage II disease and have MSI-H, you don’t need to receive chemotherapy after surgery. While stage II patients who are microsatellite-stable, might receive FOLFOX (a specific chemotherapy regimen for treatment of colorectal cancer).

“It can also help us identify if you may have a genetic syndrome that made you prone to having such kind of cancer in early stage colon cancer.”

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

Lynch Syndrome and MSI-H

If the tumor is dMMR/MSI-H, additional tests are required to determine if the MSI-H is caused by Lynch syndrome, also known as Hereditary (Non-Polyposis) Colon Cancer.

“Lynch syndrome is one of the hereditary syndromes which make you prone to having colon cancer,” explains Dr Opneja.

Lynch syndrome is an inherited disease that significantly increases a person’s risk of developing colon cancer. And if you do develop colon cancer with Lynch syndrome, treatment will need to be tailored to prevent additional cancers from developing.

Lynch syndrome increases a person’s risk for various cancers, including:

• Colon
• Endometrial
• Ovarian
• Stomach
• Small Bowel
• Pancreas
• Gallbladder
• Genitourinary

It’s important for patients to know if they have Lynch syndrome, so that they can seek specialized care to screen and prevent additional types of cancer.

Besides that, it’s really important for you to know if you have Lynch syndrome, so your family members can be tested as well.

“If you are tested positive for lynch syndrome, then your other family members [your siblings, your kids] might also be more prone to having colon cancer,” adds Dr Opneja.

“If you test positive, it is also important to have your family members tested. In case they also are found to have Lynch syndrome, then they need to start their colon cancer screening early.”

If you want to know more about Lynch syndrome, make sure to check this article that SurvivorNet has put together explaining the basics.

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 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.”

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 (called an oncogene). 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.

“HER2 is a mutation that is a common breast cancer mutation, actually, but in about 15% of colorectal cancers, the tumor is HER2 activated, and we have a drug against HER2,” 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 HER2-activated colon cancers. If we had never done the sequencing for that patient, we would have never known that that tumor carries the HER2 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.”

Types of NGS Testing On The Market

There are a number of tests you may encounter, depending on where you are getting treatment and what you are getting treatment for. Here are some of the common ones currently on the market:

• FoundationOne®CDx looks at 324 genes in solid tumors and says it can takes up to 12 days for results. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB) to help inform immunotherapy decisions.
• OmniSeq Insight provides comprehensive genomic and immune profiling for all solid tumors. It looks for 523 different genes. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB), as well as PD-L1 by immunohistochemistry (IHC).
• Cobas EGFR Mutation Test v2 identifies 42 mutations in exons 18, 19, 20 and 21 of the epidermal growth factor receptor (EGFR) gene. It is designed to test both tissue and plasma specimens with a single kit, and allows labs to run tissue and plasma on the same plate simultaneously.

You should ask your healthcare team if the brand of molecular testing they are doing is optimal for your cancer type.

Questions to Ask Your Doctor

• Should I have next-generation sequencing testing?
• Do you need both the tissue sample and blood samples for NGS testing?
• Do I have any genetic mutation that would change the course of my treatment?
• Am I eligible to receive targeted therapy? Am I more, or less, likely to respond to this treatment?
• Is there a clinical trial that would be relevant for me?

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