Could Immunotherapy Treat Early-Stage Endometrial Cancer While Preserving Fertility In People with Lynch Syndrome?

by Sue Friedman, DVM, Jennifer Mueller, MD and Paul Johannet, MD

FORCE spoke with gynecologic oncologists Dr. Jennifer Mueller and Dr. Paul Johannet of from Memorial Sloan Kettering about a research study looking at a new approach to treatment for women with Lynch syndrome who have endometrial cancer and want to preserve their fertility.

For younger people diagnosed with early-stage endometrial cancer, standard treatment may create a painful tradeoff: treating the cancer can mean giving up the possibility of carrying a pregnancy. A phase II clinical trial at Memorial Sloan Kettering Cancer Center is studying whether the immunotherapy dostarlimab can treat certain early-stage endometrial cancers while allowing participants who respond to delay or avoid surgery. FORCE spoke with study leads, Dr. Jennifer Mueller and Dr. Paul Johannet, about why the study is needed, what participation involves and who may want to learn more.

Why this study matters

Young women with endometrial cancer must often choose between established cancer treatment and fertility goals. For most people with endometrial cancer, hysterectomy to remove the uterus is a highly effective treatment. But for someone who hopes to become pregnant, this surgery permanently ends the ability to carry a pregnancy. Removing the ovaries also causes surgical menopause, which can lead to many side effects.

What are mismatch repair-deficient (dMMR) tumors?

When someone is diagnosed with endometrial cancer, their tumor is tested for a biomarker known as mismatch repair deficiency (dMMR or MMRd).  These tumors may also be referred to as MSI-high (MSI-H). Testing for this biomarker is important for two reasons:

• The results may affect treatment selection. Cancers that are dMMR tend to respond well to a type of immunotherapy known as PD-1 inhibitors (also called immune checkpoint inhibitors).  
• Some, but not all, mismatch repair deficient tumors are caused by Lynch syndrome, an inherited syndrome that can affect a person’s risk for additional cancers.  Additional testing can help determine whether a person may have Lynch syndrome. Because Lynch syndrome is inherited and can be passed on to children, testing can also help relatives understand their risk for cancer.

Why people with dMMR endometrial cancer need another option

Some patients may be offered medication instead of immediate surgery to preserve their fertility. The usual fertility-preserving approach includes treatment with hormones, such as a progestin-releasing intrauterine device, or an oral progestin, such as megestrol acetate. Research suggests that mismatch repair-deficient endometrial cancers—including many cancers associated with Lynch syndrome—may not respond well to these hormone treatments, even low-grade tumors that have not invaded the uterine muscle. This leaves an important unmet need for people who want to preserve fertility.

What treatment and follow-up involve

Participants typically receive dostarlimab once every three weeks for six months. Those whose cancer completely responds may have the option to continue without surgery. The study will follow participants closely for five years to learn how durable responses are, how often monitoring is needed and whether people with Lynch syndrome who receive PD-1 immunotherapy face a risk of developing another cancer. The answers to these long-term questions are not yet fully understood.

Understanding the risks and tradeoffs

Dostarlimab is a PD-1 inhibitor, a type of immunotherapy used across several cancers. These medicines are often well tolerated, but they can cause the immune system to attack healthy organs and tissues, and some immune-related side effects can be serious. Study participants are monitored closely so the care team can identify and promptly manage side effects.

Progestin-based therapy also has tradeoffs. Although it does not necessarily harm fertility, side effects such as bloating, weight gain, fatigue and muscle or joint pain can substantially affect quality of life. Neither the current approach nor immunotherapy is free of risk. Whether the potential benefits outweigh those risks is a personal decision that each participant makes with the study team.

Who may want to ask about the trial

The study may be relevant for people with early-stage, mismatch repair-deficient endometrial cancer who want to preserve their fertility. Prior progestin treatment does not automatically rule someone out, although it must be stopped before study treatment begins. The research team can review an individual’s diagnosis, imaging, treatment history and other eligibility requirements.

Why tumor testing matters

Everyone diagnosed with endometrial cancer should ask whether their tumor has been tested for mismatch repair deficiency. This testing is recommended as part of the initial evaluation of endometrial cancer and is especially important for younger patients. A mismatch repair-deficient result may be caused by changes that occurred only in the tumor, but it can also be a sign of Lynch syndrome and may lead to genetic counseling and germline genetic testing. Family history alone cannot identify everyone with Lynch syndrome.

How to learn more

For more information about the study, visit the study listing on the FORCE website. People who think the study may be relevant can contact the research team for an initial discussion about whether it could be an option.