DNA mismatch repair status: What colorectal cancer patients should know

When you’re facing a colorectal cancer diagnosis, your doctor will order a test to determine your mismatch repair (MMR) status. But what does it mean, why does it matter and how does it differ from microsatellite instability?

“Mismatch repair status can provide insights on if a patient’s cancer may be hereditary, but it also has important treatment implications,” says gastrointestinal medical oncologist S. Daniel Haldar, M.D. Here’s what to know.

What is DNA mismatch repair?

As cells replicate, DNA is copied to create a new cell, and errors can occasionally occur. These errors are known as mutations and can increase your risk of cancer.

A natural process called DNA mismatch repair identifies and corrects errors when cells copies their DNA. In some tumors, this repair system does not function normally. Tumors with a working mismatch repair system are called mismatch repair proficient (pMMR). Tumors in which the system isn’t working are called mismatch repair deficient (dMMR).

Although it sounds negative to hear a natural safety mechanism isn’t functioning properly, it can have a meaningful impact on your treatment options.

“Research has shown that mismatch repair deficient colorectal cancers are uniquely responsive to immunotherapy,” Haldar says.

Mismatch repair deficiency linked to Lynch syndrome

Mismatch repair deficiency has been linked to Lynch syndrome, which is an inherited condition passed down from parents to child. Lynch syndrome is caused by genetic mutations in the mismatch repair pathway that can in turn increase a person’s risk of several cancers, including colorectal cancer.

“Patients with Lynch syndrome are more likely to have mismatch repair deficient tumors but not every patient with mismatch repair deficient colorectal cancer has Lynch syndrome,” Haldar says. In most patients, mismatch repair deficiency develops because of changes within the tumor that are not hereditary. Germline testing helps confirm if it has been inherited or occurred sporadically.

Determining DNA mismatch repair status

You may have heard of microsatellite instability (MSI), and Haldar clarifies that mismatch match repair status is similar. “We’re looking at a similar biomarker, but we’re testing it in different ways,” Haldar says.

Mismatch repair status is determined by a test called immunohistochemistry that looks at the presence of key proteins, including MLH1, MSH2, MSH6 and PMS2. The microsatellite instability of a tumor is determined at the DNA level of the cell, using testing called a polymerase chain reaction (PCR) test or next-generation sequencing.

“Immunohistochemistry testing is a quick and cost-effective place to start, but we’ll typically follow up on abnormal results with a second test,” Haldar says. Additional testing and, in some cases, genetic counseling may be recommended to determine if the patient has Lynch syndrome.

Since these tests can help guide treatment decision-making, they should be done at initial workup.

Mismatch repair deficient status improves immunotherapy response

Regardless of which test is used, the goal is to determine whether the tumor’s DNA repair system is working properly. When mismatch repair is deficient, DNA errors collect and can make abnormal proteins that help the immune system recognize the cancer.

“We can think of it this way: having more mutations makes the cancer more visible to the immune system and therefore more likely to respond to immunotherapy,” Haldar says.

Led by researchers at UT MD Anderson, the CheckMate 142 Phase 2 clinical trial established that immune checkpoint inhibitors are effective in patients with mismatch repair deficient colorectal cancer.

Building on these findings, the more recent CheckMate 8HW Phase 3 study showed that patients with stage 4 mismatch repair deficient colorectal cancer respond well to a combination of the immune checkpoint inhibitors ipilimumab and nivolumab.

Research aims to expand benefit of immunotherapy to more patients

Approximately 15% of newly diagnosed colorectal cancers are mismatch repair deficient or microsatellite instability high. However, this biomarker is found in only about 5% of all metastatic colorectal cancers.

“The breakthroughs in immunotherapy for mismatch repair deficient disease have been spectacular, but it’s a common misconception that immunotherapy is an option for every colorectal cancer patient,” Haldar says.

Most colorectal cancers are mismatch repair proficient or microsatellite stable, so they’re less likely to respond to currently approved immune checkpoint inhibitors when those drugs are used by themselves.

Through clinical trials, Haldar and his colleagues are dedicated to addressing the gap through next-generation immunotherapies, cellular therapies and vaccine strategies. These approaches also are trying to leverage the immune system to treat cancer, but they’re doing so with new drugs and new molecules.

For example, studies are underway investigating a bispecific antibody called ivonescimab. As a bispecific antibody, it targets two elements at the same time: one is the traditional immune checkpoint PD-1 and the other is a protein found in the blood vessels of a tumor cell called VEGF.

“The idea is that by targeting both of these proteins simultaneously, we could be more effective in treating the cancer using an immune-based approach,” Haldar says.

For now, Haldar encourages patients to consider clinical trials. “We don't have any FDA-approved immunotherapies for the majority of colorectal cancer patients, but through trials, we’re pushing the field forward and hope to offer patients access to the most cutting-edge approaches here at UT MD Anderson,” Haldar says.

Request an appointment at UT MD Anderson online or call 1-877-632-6789.