What Does MSI-H Mean on a Report?

This page is for people who see "MSI-H" or "MSI-high" on a tumor test report. It explains what the result means, why it can open up immunotherapy, and how it relates to Lynch syndrome.

Microsatellites are short repeated stretches of DNA. MSI-H means high microsatellite instability. MSI-H tumors are linked to defects in four mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. NCI says the MSI-H pattern is the main one seen in tumors from people with Lynch syndrome.

A report may say MSI-H, or it may say dMMR (mismatch repair deficient). NCI describes both routes. Molecular genetic tests look for microsatellite instability in tumor tissue, usually by PCR. Immunohistochemistry stains the tissue for mismatch repair proteins and looks for their loss. Ask your team which test was used, and what follow-on tests were done.

Pembrolizumab and dostarlimab are immunotherapy drugs that the FDA has approved for MSI-H or dMMR tumors in certain settings. The sections below give the approval wording and trial numbers from FDA and NCI.

The clearest evidence comes from colorectal cancer. FDA's approval summary describes KEYNOTE-177, an open-label randomized trial (everyone knew which treatment they got) of 307 patients with previously untreated, unresectable (cannot be removed with surgery) or metastatic MSI-H or dMMR colorectal cancer.

Patients were assigned to pembrolizumab intravenously every 3 weeks, or to the investigator's choice of mFOLFOX6 or FOLFIRI, with or without bevacizumab or cetuximab, every 2 weeks. Anyone assigned to chemotherapy was offered pembrolizumab when the disease progressed.

Median progression-free survival was 16.5 months with pembrolizumab and 8.2 months with chemotherapy, with a hazard ratio of 0.60. That means the risk of the cancer growing over time was lower with pembrolizumab. FDA notes that the overall survival data were not mature at the time of the progression-free survival analysis.

Tumor status in that trial was determined locally, by PCR for MSI or by immunohistochemistry for mismatch repair. That detail matters, because it is the same pair of tests likely to appear on a report.

Pembrolizumab also carries an approval that ignores where the cancer started. NCI states the indication: adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors whose disease progressed after prior treatment, and who have no satisfactory alternative.

That approval rested on five uncontrolled single-arm trials covering 149 patients. The pooled objective response rate was 39.6%. Eleven patients (7.4%) had a complete response and 48 (32.2%) had a partial response. Response was 36% in colorectal cancer and 46% in the other cancers.

Dostarlimab holds a related indication for adults with dMMR recurrent or advanced solid tumors after prior treatment. In the GARNET trial, the efficacy population was 209 patients, and the objective response rate was 41.6%, with 9.1% complete responses.

NCI names the VENTANA MMR RxDx Panel as the companion diagnostic used to select patients with dMMR solid tumors for dostarlimab. In KEYNOTE-177 the testing was done in local labs.

A response rate near 40% means most people in these trials did not have a response. It is an option, not a certainty. It is also worth asking whether the approval being discussed is the tissue-agnostic one, which requires prior treatment and no good alternative, or a cancer-specific one such as the colorectal first-line indication.

MSI-H is the main tumor pattern seen in Lynch syndrome, also called hereditary nonpolyposis colorectal cancer. The germline defects behind it sit in the same four genes: MLH1, MSH2, MSH6 and PMS2.

But NCI is careful here. NCI says a tumor can also have the MSI-H pattern because one of those genes was silenced by DNA methylation.

So the tumor result raises the question. It does not answer it. Ask your team whether germline testing (testing for inherited gene changes) and genetic counseling are needed.

It is not a guarantee. In the pooled trials NCI describes, the objective response rate was 39.6%. Whether immunotherapy is right for you is a question for your care team. It turns on:

• The cancer type.
• Where you are in treatment.
• The exact current approval wording for the drug proposed.
• Your own health.

For how this fits with other molecular results, see biomarker testing and precision medicine. For how checkpoint drugs work more generally, see immunotherapy. For what a tumor test can and cannot say about inheritance, see tumor testing vs inherited genetic testing.

• FDA — Pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer (KEYNOTE-177).
• NCI PDQ — Agnostic Cancer Therapies (Health Professional Version).