By Robert Levy
For the past decade, new cases of endometrial (uterine) cancer have been on the rise in the United States. The past few years, however, have brought a more promising rise: A new generation of drugs and drug combinations that are improving the outlook for patients with the disease.
The increase in incidence has been gradual but steady: Rates have gone up about 1% a year for white women and 2% to 3% for women in all other ethnic groups. Mortality — the percentage of women with the disease who die of it — has risen at a similar pace and shows the same racial and ethnic imbalances.
These increases have occurred primarily in a subset of endometrial cancers known as "non-endometrioid." These include endometrial serous cancer, clear cell carcinoma, and uterine carcinosarcoma, all of which have a wide array of genetic abnormalities and are often aggressive.
The reasons for the rise in diagnoses, and for the shift toward non-endometrioid cancers, are unclear, although obesity is a prime suspect. The racial and ethnic disparities associated with endometrial cancer probably have multiple causes. Studies have shown that Black women often are diagnosed with later stages of the disease, when it is harder to treat, and their care is less likely to follow standard care guidelines, which may affect their outcomes.
A further challenge for those working to better understand and treat the disease is financial: National Cancer Institute (NCI) funding for endometrial cancer research declined from $17.5 million in 2017 to an estimated $15 million in 2022 (the most recent year for which figures are available), making it one of very few cancer types to experience a drop in federal research funding.
Ursula Matulonis, MD
"An estimated 68,000 new cases of endometrial cancer are diagnosed in the United States this year; it is now the leading cause of death among gynecologic cancers," says Ursula Matulonis, MD, chief of Gynecologic Oncology at Dana-Farber's Susan F. Smith Center for Women's Cancers. "Many patients, particularly those with early stages of the disease can be cured with standard therapy, but for those with later stages, we need novel treatments. The rise in incidence and mortality makes this even more critical."
The urgency of the situation is reflected in the intensity of endometrial cancer research. At Dana-Farber, scientists are tackling the disease from multiple angles: laboratory research to better understand how the disease develops, which may shed light on why it is becoming more common; and clinical research to test the safety and effectiveness of new therapies.
Endometrial cancer research at the Institute covers four main areas: hormonal therapy, immunotherapy, antibody-drug conjugates, and replication stress, a phenomenon that interferes with cancer cells' ability to copy their DNA. Here is a closer look at recent advances in each of these areas.
Hormonal Therapy Developments
The findings of a Dana-Farber-led trial has prompted the National Comprehensive Cancer Network (NCCN), which sets guidelines for cancer drug use, to state that hormonal therapy, combined with the drug abemaciclib, can be useful for some patients. Hormonal therapy — which might properly be called anti-hormonal therapy because it seeks to deprive cancer of growth-stimulating hormones — is a mainstay of treatment for certain breast and ovarian cancers, but evidence of its effectiveness in endometrial cancer was limited.
A trial led by Panos Konstantinopoulos, MD, PhD, director of clinical research in Gynecologic Oncology and the Velma Eisenson Chair for Clinical and Translational Research at Dana-Farber, tested a novel strategy to increase the activity of hormonal therapy. In the trial, 30 patients with recurrent estrogen receptor-positive endometrial cancer — a subtype fueled by the hormone estrogen — were treated with letrozole, a drug that lowers estrogen production in the body, plus abemaciclib, which blocks cancer cell division. Thirty percent of the patients responded to the regimen, meaning their cancer was halted or reduced, and their cancer did not progress for an average of nine months — an impressive result for a group of patients that included many who had received multiple previous treatments.
Among the participants who benefited from abemaciclib and letrozole were those with a molecular subtype of endometrial cancer dubbed NSMP, which accounts for about half of all cases of the disease and often doesn't respond well to immunotherapy. The results prompted Dr. Konstantinopoulos and his colleagues to launch a follow-up trial to determine if the combination is effective after first-line therapy in patients with this subtype.
Participants in the trial, named ALPINE, receive either the standard maintenance therapy of pembrolizumab, an immunotherapy drug, or the letrozole and abemaciclib. If the results favor the combination therapy, "it could establish a new standard of care for maintenance therapy in this group of patients," Dr. Konstantinopoulos remarks.
Immunotherapy Breakthroughs
A milestone in the use of immunotherapy for endometrial cancer came earlier this year when the U.S. Food and Drug Administration approved the drug pembrolizumab in combination with two chemotherapy agents for patients with advanced or recurrent forms of the disease. Pembrolizumab, which is based on research by Dana-Farber's Gordon Freeman, PhD, and others, is an immune checkpoint inhibitor that exposes cancer cells to a potent immune system attack. Its approval was followed a few months later by approval of the checkpoint inhibitor dostarlimab for the same group of patients.
"As a result of these FDA decisions, all patients with advanced endometrial cancer now can potentially receive an immunotherapy drug along with chemotherapy, followed by the immunotherapy alone to slow or stop the recurrence of the disease," Dr. Matulonis says.
Clinical trials led by Dana-Farber investigators are further exploring the potential of immunotherapies for the disease. One, led by Elizabeth Lee, MD, tested a combination of two drugs, avelumab and axitinib, which exploit different vulnerabilities of endometrial cancer cells. Avelumab is an immune checkpoint inhibitor and axitinib blocks blood vessel growth in tumors.
The trial involved 35 patients with recurrent or persistent endometrial cancer that was mismatch repair-proficient (MMRP), meaning the tumor cells were able to detect and correct spelling errors in their DNA. Fourteen of the participants achieved a response — a decrease in the extent of their cancer — including two who had a complete response to the therapy. Responses were seen in patients across all subtypes of endometrial cancer.
Another trial, led by Dr. Konstantinopoulos, paired avelumab with talazoparib, a drug that hampers cancer cells' ability to repair damaged DNA, in patients with MMRP endometrial cancer. Of the 35 participants in the trial, more than 25% benefited from the combination, and 23% were living with no advance of the cancer six months after starting therapy.
Targeted Therapy Innovations
Antibody-drug conjugates, or ADCs, deliver a direct strike on tumor cells by hitching a chemotherapy drug to a cancer-seeking antibody. Approved for the treatment of a variety of cancers, these "smart" chemotherapy agents constitute a new class of targeted therapies. Traditional targeted therapies take aim at specific cancer-related proteins within tumor cells. Antibody-drug conjugates, by contrast, zero in on proteins located on the surface of tumor cells.
Rebecca Porter, MD, PhD
Investigators at Dana-Farber are leading several trials of these agents. They include a phase 1 trial of the antibody-drug conjugate trastuzumab deruxtecan plus the drug olaparib in endometrial and other cancers with high levels of the HER2 protein. Another trial is testing the antibody-drug conjugate disitamab vedotin in patients with endometrial cancer or certain other solid tumors that express HER2 and have metastasized or cannot be surgically removed.
A trial led by Rebecca Porter, MD, PhD, of Gynecologic Oncology focused on serous endometrial cancer, an aggressive subtype that accounts for about 5% of all cases of endometrial cancer but about 40% of deaths from the disease. She and her colleagues reported that a combination of pembrolizumab and an antibody-drug conjugate called mirvetuximab soravtansine reduced tumors in six of the first 16 patients tested.
Replication Stress Opens New Frontier
In early 2024, endometrial cancer researchers at Dana-Farber received a major five-year grant from the NCI funding three projects focusing on a self-inflicted problem of cancer cells known as replication stress. The projects are led by Drs. Konstantinopoulos, Liu, and Matulonis. For all the relentlessness with which cancer cells grow and divide, the fitful pace of that growth can hamper the copying of DNA, a critical part of cell division. The cells cope with this stress in a variety of ways — switching on DNA-repair genes, for example, or altering the sections of DNA that need to be copied.
A stressed cancer cell is a vulnerable cancer cell. Researchers now recognize that if they block the cells' coping mechanisms — the molecular signals and pathways that help get DNA replication back on track — the cancer cells will die.
The three projects covered by the new grant are in the early stages of research. They include:
- Tracking the molecular mechanism by which targeted drugs known as WEE1 inhibitors act in recurrent uterine serous cancer and in endometrial cancers harboring a mutation in the p53 gene.
- Testing the hypothesis that blocking a key protein pathway can increase replication stress in endometrial tumor cells and work in combination with targeted drugs known as ATR inhibitors.
- Exploring the possibility of targeting two types of "checkpoint" proteins in endometrial cancer cells. One acts as a checkpoint on repair of DNA damage while the other acts as a checkpoint on the immune response to cancer.
Joyce Liu, MD, MPH
To conduct this kind of research, Susan F. Smith Center scientists are working with colleagues at Dana-Farber's Robert and Renée Belfer Center for Applied Cancer Science to create laboratory models of endometrial cancer. The models, which are constructed from patients' tumor cells, allow researchers to study replication stress in individual, living cells — something that can't be done with cells mounted on a microscope slide or situated deep in a tumor inside the body. The models also help researchers understand how potential drugs that target replication stress affect tumor cells at a fundamental level.
There are three major types of these models, explains Joyce Liu, MD, MPH, associate chief of Gynecologic Oncology. They include organoids, tiny three-dimensional cultures of tumor cells; xenografts, human tumor tissue cells growing in animal models; and organotypic spheroids, aggregations of tumor and immune system cells.
"These models enable us to explore questions that are critical to understanding endometrial cancer and its treatment within living cells so that we can observe the dynamic effect of drugs on tumor cells and develop a deeper understanding of why some tumor cells might respond to certain therapies and resist others," Dr. Liu remarks. "Finding these answers will lay the foundation for the development of the next generation of therapies."
