Microsatellite Instability and Endometrial Cancer: A Doctor Explains
If you’re an endometrial cancer patient, you’ve probably been hearing a lot about something called microsatellite instability (MSI). If you’re not quite sure what that is or what you need to know about it, read on.
HealthCentral talked to a gynecologic oncologist Mian Shahzad, M.D., to get the scoop on how MSI impacts diagnosis and treatment of endometrial cancer. As the medical director of the department of gynecological oncology at Moffitt Cancer Center, he sees first-hand how new treatments can improve outcomes.
But first, some definitions you need to know: Microsatellites are copies of DNA sequences. DNA Mismatch Repair (dMMR) steps in to make sure the copies are correct. When dMMR isn’t working, the mistakes that result lead to microsatellite instability.
HealthCentral (HC): What’s the connection between Lynch syndrome, microsatellite instability, and endometrial cancer?
Dr. Shahzad: Lynch syndrome is a type of inherited cancer syndrome that makes one more likely to develop certain different cancer types. It is caused by an alteration of certain genes that is carried from parents. Depending on which type of gene is altered, patients with Lynch syndrome can have a 25-70 percent risk of endometrial cancer.
People with Lynch syndrome have a higher risk of many other cancers as well, including colon and ovarian. If there’s a family history of multiple family members who have had one of these cancers — including colon, ovary, urinary tract, gastric and genitourinary cancers — or if you’ve had a personal history of endometrial cancer, you should be checked for Lynch syndrome. You can ask your doctor to do molecular testing where they stain the tissue from a surgery or biopsy and check for changes in the DNA in the tumor tissue. At Moffitt Cancer Center, every patient who has surgery for endometrial cancer now gets checked for changes in these genes.
Tumors that are caused by Lynch syndrome (transmitted by parents) have mutations in mismatch repair genes (MMR) or defective repair of DNA, while others who acquire these changes later in life have microsatellite instability resulting in similar defective repair of damaged DNA.
HC: How do you get MSI?
Dr. Shahzad: If the mutations in MMR aren’t caused by Lynch syndrome, you could have sporadic MSI. That’s when you have a tumor that silences expression. The genes are chemically modified in a way that they’re no longer able to make the proteins they’re supposed to. About 20 percent of endometrial cancer is from MSI. After surgery, we check for MSI and look for changes in those genes.
The majority of endometrial cancers are in the upper end called the fundus, but these are lower, near the cervix, so they can be misdiagnosed as cervical cancer.
HC: So, MSI causes cancer?
Dr. Shahzad: Yes, because it leads to the shutdown of critical genes. If that [MMR] repair is done, there’s less of a chance of forming cancer. If it’s not done, then abnormal cells continue to grow.
HC: What are the types of MSI?
Dr. Shahzad: MSI is graded as MSI-high and MSI low. MSI-high patients may benefit from the addition of immunotherapy to their treatment, whereas MSI low — not so much.
HC: How does it help to know if your cancer is caused by MSI?
Dr. Shahzad: Knowing the status of MSI opens windows for use of other therapeutic agents or enrollment into clinical trial. MSI-H seen in endometrioid-type of uterine cancers has been shown to be associated with more aggressive tumors (higher grade, deep invasion, and higher stage). Evidence in early-phase trials is now starting to show improved clinical outcomes if patients with MSI-H are treated with immune checkpoint inhibitors. For patients, it is essential that their doctor checks endometrial tumor samples for MSI, and if found to have MSI-H, they may consider enrolling into a study with agents like pembrolizumab or starting on a PD-1 inhibitor off-trial in palliative setting in selected patients.