Biomarkers in Colon Cancer: What Does High Microsatellite Instability Mean?

“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. “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.”

Dr. Heather Yeo explains how biomarkers are used in colon cancer. 

There are different types of biomarkers and they include DNA, proteins, and genetic mutations found in blood, in the tumor tissue, or other body fluids. The biomarkers most commonly used in colon cancer management are:

• Genetic mutations within the tumor, such as MMR/MSI, KRAS, BRAF, and HER2
• Bloodstream carcinoembryonic antigen (CEA)

CEA is a protein that is produced by most tumor cells (but not all) and can be picked up in the bloodstream. High CEA levels do not establish a colon cancer diagnosis. However, higher CEA levels correlate with a worse prognosis and potential metastasis. Carcinoembryonic antigen is also very important for post-treatment follow-up to make sure that the cancer hasn't returned. Be sure to check with your doctor before treatment starts to ensure a CEA blood sample has been obtained.

Microsatellite Instability in Colon Cancer

Sometimes in cancer cells, the ability to correct DNA replication errors is disrupted by the mutation of mismatch repair (MMR) genes. When the MMR system is defective, it silences specific proteins (MLH1, MSH6, PMS2, MSH2), whose job it is to correct occasional replication errors. Thus, a mismatch repair deficiency (dMMR) allows errors to accumulate due to the lack of repairs and the accumulation of errors 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)

Should I Have MSI-High Testing?

Yes. According to the 2021 National Comprehensive Cancer Network Guidelines (NCCN), every patient diagnosed with colorectal cancer should be tested for the MSI-H and/or dMMR biomarker since patients with MSI-H or dMMR make up about 15% of patients with colorectal cancer. In early stages, high microsatellite unstable tumors have a better prognosis than microsatellite stable colorectal cancer.

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).

On the other hand, later stage colon cancer patients with dMMR/MSI-H appear to be uniquely susceptible to immune checkpoint inhibitors, such as nivolumab or pembrolizumab. If your cancer have spread or cannot be removed by surgery, it's important that you know your microsatellite stability status. If you have MSI-H, you might be eligible to receive immunotherapy.

What Is Immunotherapy?

Immunotherapy is a type of biological therapy that ushers the power of a person's immune system to recognize and conquer cancer cells. This includes recruiting internal mechanisms like the body's proteins, white blood cells, tissues, and organs or through external mechanisms by synthesizing molecules in the lab. Each type of immunotherapy works differently depending on many factors, while some will work to kill or destroy cancer cells, others will only stop them from growing and spreading to other organs.

Keytruda (generic name embrolizumab) is PD-1/PD-L1 inhibitor. It targets PD-1 protein which is found on T-cells (immune system cells). This drug has been fully approved by the Food & Drug Administration to treat adult and child patients with unresectable (unable to be surgically removed) or metastatic MSI-H or dMMR solid tumors that progressed after previous treatment or who have no other treatment options. That includes patients with colorectal cancer.

"This approval reinforces the important role of Keytruda in certain patients with MSI-H or dMMR solid tumors facing a variety of cancers," Luis A. Diaz, Jr., MD, head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, said in a press release. "These data also further underscore the need for biomarker testing to identify patients who may be eligible for this therapy."

In a previous conversation with SurvivorNet, Dr. Allyson Ocean, a medical oncologist at Weill Cornell, explained the way tumors that are MSI high behave differently from others. “Tumors that are MSI high have a lot of mutations on their surface. A lot of mutations are needed for the immune system to recognize the cancer. For the majority of solid tumors, the immune system doesn’t really care that you have cancer. But in tumors that are MSI-High, they have a lot of proteins on their surface that are kind of like signs for the immune system to say ‘Hey, I’m here! Come fight me!’ And then the immune system sees those mutations, kicks in, and sends T cells.”

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 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 is characterized by an increased risk of 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.

Questions to Ask Your Doctor

• Should I have MSI-High Testing?
• Can my tumor be monitored via CEA-testing?
• If I am determined to be MSI-High, will it change the course of my treatment?
• If I am MSI-High, does it mean I have Lynch Syndrome?
• What is Lynch Syndrome and how will that affect my future regarding cancer?

Dr. Ophira Ginsburg explains Lynch syndrome, an inherited genetic disorder. 

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