Expert Highlights Genetic Testing, Immunotherapy in Endometrial Cancer

Martee L. Hensley, MD

Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) testing may improve classifications of endometrial cancer and lead to personalized treatment options, according to Martee L. Hensley, MD.

If patients’ tumors test positive for MSI-H and/or dMMR, immunotherapy is likely to be part of their treatment course, Hensley adds. This specifically includes pembrolizumab (Keytruda), which is the first agent to be FDA approved based on histology alone.

The FDA granted an accelerated approval in May 2017 to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options.

OncLive: What is the role of MSI-H testing in endometrial cancer?

In an interview with OncLive, Hensley, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSK), discussed the role of MSI-H and dMMR testing in the management of endometrial cancer.Hensley: Previously, we classified endometrial cancers as either type 1 endometrial tumors or type 2 serous cancers—a distinction that we made mostly by histology. I argue that we can use dMMR testing and MSI-high testing to better classify our cancers, and that has treatment implications. One of the reasons that I argue that we should do that type of testing is to help us increase the number of patients we identify as potential carriers of germline mutations and mismatch-repair enzymes. [This is] a group of patients who we call [having] Lynch syndrome.

At MSK, we routinely test all endometrial cancers for defective mismatch repair proteins using immunohistochemistry (IHC). We use that information to show us whether that patient might have an underlying germline mutation that would put her in the Lynch syndrome classification. This would have implications for her management, as well as for the management of her blood relatives.

Another question is whether dMMR testing or MSI-H testing influences endometrial prognosis. There are data showing that dMMR tumors have an increased propensity for having lymphovascular invasion and higher tumor grade—which are adverse prognostic factors. Yet the outcomes for patients with dMMR endometrioid cancers were not different, suggesting that the dMMR overcomes those adverse prognostic factors in some way. That may have something to do with immune surveillance.

What is the prevalence of patients who have MSI-H endometrial cancer?

Do you have a preferred diagnostic testing method that you use for your patients?

Finally, the therapeutic implications of dMMR and MSI-H testing comes from recent data with pembrolizumab, which was recently approved by the FDA for use in advanced cancers that have defective MMR proteins or are MSI-H, and that includes endometrial cancers. That is another reason to test for these in our patients with advanced disease; it opens up that door to immunotherapy. We know [that answer] from a paper published in Science looking at over 12,000 solid tumors. About 17% of patients with endometrial cancer can have tumors that are MSI-H, and only a small proportion of those would be explained by underlying germline mutations—such as Lynch—and the rest of them would be because of somatic or epigenetic changes that lead to dMMR. We use IHC because it is readily available and can be done on formal and fixed paraffin-embedded tissue; you don't need fresh tissue to do it. Also, it is pretty inexpensive. Therefore, we use that to test for the presence of the MMR proteins in the tumor tissue itself.

Should a patient test positive for MSI-H, what are their treatment options? How about for those who are microsatellite stable?

An alternative is to do MSI-high testing, which also can be done on paraffin-embedded tissue but required matched normal tissue. This is done by pathologic complete response, so we do that less often. Full somatic profiling, like genomic profiling of the tumor, is more expensive although there is much more information that can be gathered. That may be appropriate for certain patients, particularly patients with advanced disease where you are probably looking not just for the information about MSI, but perhaps for the identification for other tumor targets. If a patient is found to have a MSI-H tumor…[then] more standard or proven therapies are no longer useful. That is in alignment with the FDA label for pembrolizumab, which is indicated for patients with advanced disease who have dMMR or MSI-H tumors. Therefore, pembrolizumab could be a treatment option.

Will additional checkpoint inhibitors be approved for MSI-H tumors?

What are the therapy options for these patients with MSI-H endometrial cancer after relapse on pembrolizumab?

Patients who are microsatellite stable are not currently candidates for immunotherapy. That is probably not worth [wringing hands] over because perhaps immunotherapies don't work so well in those patients. They should seek other treatment options. If they've had somatic profiling, there may be a clinical trial for a targeted agent that might be directed at one of the pathways that is mutated in their tumor, even if it isn't MSI-H.It’s hard to know. We know that nivolumab (Opdivo) was approved in colorectal cancers shortly after pembrolizumab was approved, so one can envision that other immunotherapy agents may expand into the endometrial cancer or MSI-H space. There are a number in development, so it is something to keep an eye on.It depends if there are established cytotoxic agents that they could go back to if it has been a long interval of time from a prior platinum agent or prior taxane, for example. Also, by this time, many of these patients might have had genomic profiling of their tumor and we may have identified particular pathways that may be mutated in that patient. There may be basket trials [or other studies] that have drugs directed at that pathway. That might be an option.