Immunotherapy drugs use your own immune system to fight disease. These drugs have improved treatment for many types of cancer.
Still, immunotherapy does not work for everyone. Whether these drugs work well depends on a tumor’s genes. We can predict how well immunotherapy will work by testing tumors for 3 genetic traits:
- Mismatch repair deficient (MMRd)
- High microsatellite instability (MSI-H)
- High tumor mutational burden (TMB-H)
Memorial Sloan Kettering Cancer Center (MSK) is leading the way in developing immunotherapy treatments for cancers with MMRd, MSI-H, or TMB-H.
This information explains MMRd, MSI-H, and TMB-H and how we test tumors for these traits. We also explain how these tests can predict whether immunotherapy is likely to help someone.
What is DNA mismatch repair deficiency (MMRd)?
When a cancer or normal cell divides it must make a copy of its DNA. This lets each “daughter cell” have a full set of genes. But mistakes can happen during that copying process.
Our cells have ways of fixing these copying errors. One way is called DNA mismatch repair.
When the mismatch repair does not work, these cells are mismatch repair deficient (MMRd). If a cell cannot fix the mistakes it can become cancer.
What is high microsatellite instability (MSI-H)?
High microsatellite instability (MY-kroh-SA-teh-lite in-stuh-BIH-lih-tee), or MSI-H, is a type of mismatch repair deficiency. MMRd and MSI-H are often used to describe the same thing.
Microsatellites are short, repeated pieces of DNA. The number of microsatellites in a cell can become unstable when a cell cannot fix mistakes. This instability can cause cancer.
What does it mean when a tumor has a high mutational burden (TMB-H)?
All cancer cells have changes (mutations or variants) in their genes. These mutations let cells divide out of control and grow tumors.
Many tumors are caused by a few specific mutations. But some tumor cells have dozens of mutations.
These cells keep making more errors as they divide. When that happens, the tumors have a high mutational burden (TMB-H).
TMB-H may be caused by MMRd or MSI-H. It also may be caused by exposure to carcinogens. These are substances that cause cancer, such as tobacco and the sun’s ultraviolet (UV) light rays.
Why are tumors with MMRd, MSI-H, and TMB-H more likely to respond to immunotherapy?
Immunotherapy drugs called checkpoint inhibitors work by helping the immune system find and attack cancer cells. They work best when the cells are easier for the immune system to find.
Cancer cells that are MMRd, MSI-H, or TMB-H look more foreign to the immune system. That makes them easier for immune cells to find. The checkpoint inhibitor drugs are more likely to work.
We often think of cancer mutations as bad. But tumors with MMRd and MSI-H can be easier to treat because they respond better to immunotherapy.
Your doctor may recommend a checkpoint inhibitor drug if tests show the cancer is MMRd or MSI-H, depending on the cancer’s stage.
One checkpoint inhibitor drug is pembrolizumab (Keytruda®). In March 2023, this drug was fully approved by the U.S. Food and Drug Administration for any advanced cancer located anywhere in the body if the cancer is MMRd or MSI-H.
Often, immunotherapy drugs are also used to treat cancers that are caused by exposure to carcinogens. These cancers include melanoma, lung cancer, and bladder cancer.
How do doctors test for MMRd, MSI-H, and TMB-H?
MSK analyzes many tumors with a molecular sequencing test called MSK-IMPACT®. This test can find many kinds of genetic errors, including whether a tumor has a lot of mutations overall (TMB-H). It also can tell if there’s a mutation in a gene linked to DNA repair.
MSK-IMPACT is not like most other tumor molecular tests. It can also study a sample of normal DNA to compare with your tumor sample.
If you give your permission for this other analysis, our experts can tell whether it’s an inherited mutation. Inherited means the genes you were born with, passed on to you from a parent.
If it’s an inherited mutation, family members related to you by blood also may want to get tested. This inherited mutation means you may be at risk for getting other cancers.
Lynch syndrome is the best-known inherited condition that causes MSI-H or MMRd tumors. It’s linked to a higher risk of some types of cancer. They include colon cancer, rectal cancer, uterine (endometrial) cancer, and some cancers of the urinary tract.
Lynch syndrome is caused by a mutation in any of 5 genes that prevent DNA errors. These genes are MLH1, MSH2, MSH6, PMS2, and EPCAM.
Some MSI-H or MMRd tumors are caused by Lynch syndrome. MSK recommends genetic testing for Lynch syndrome if the cancer is MSI-H or MMRd.
Lynch syndrome is passed on from parents to their children, so it’s important for family members to get tested. MSK’s Clinical Genetics Service can do genetic testing for both people with cancer and those at risk for cancer.
