Can GLP-1 Receptor Agonists Improve Outcomes in Patients at Risk for Endometrial Cancer?

In this Q&A with Pharmacy Times, Jennifer MacDonald, PharmD, BCOP, MUSC Oncology PGY2 Residency Program Director, Clinical Oncology Pharmacy Specialist at Hollings Cancer Center, discusses the growing role of GLP-1 receptor agonists in gynecologic oncology and endometrial cancer risk reduction. MacDonald explains how obesity, metabolic disease, and hormonal factors contribute to endometrial cancer development and highlights how pharmacists can help integrate emerging evidence into patient care. She also explores the expanding role of molecular profiling in uterine cancer, including how biomarkers and molecular classifications may guide prognosis and treatment selection.

Pharmacy Times: What implications do the findings on GLP-1 receptor agonists reducing endometrial cancer risk have for pharmacists managing patients with obesity or metabolic disease?

Jennifer MacDonald, PharmD, BCOP: I think this is a great question. This kind of lends itself to preventive maintenance. When we talk about helping patients primarily prevent cancer, we do a lot of epidemiologic studies to look at risk factors for the development of various cancers and identify risk-reduction strategies that may help prevent them.

What we know about endometrial cancer is that rates are actually on the rise, and we are also seeing an increased risk of poorer prognosis types of endometrial cancer with a higher risk of death. This disproportionately affects African American women, making it a huge area of research and something that needs continued attention to improve outcomes, particularly for African American women.

When we look at uterine cancer, we know there is a link between obesity and the development of endometrial cancer, likely driven primarily by estrogen. Women who have more fat available to convert cholesterol into estrogen may be at a higher risk for the development of endometrial cancer.

So, yes, I think agents such as GLP-1 receptor agonists, which can help manage obesity, diabetes, and other comorbid conditions that may contribute to an increased risk of endometrial cancer, should be considered more frequently. I think there has been some hesitation to use them because of safety concerns and the need for robust data demonstrating that these agents are safe for patients with metabolic syndrome, obesity, diabetes, or prediabetes.

However, I think these findings should be of particular interest to pharmacists managing obesity and metabolic disease because they provide another positive reason to consider these therapies for patients, especially those who have tried other avenues for weight loss or management of metabolic disease that have not been successful to date.

Pharmacy Times: How can pharmacists incorporate emerging evidence around GLP-1 therapies and progestins into counseling or preventive care strategies for at-risk patients?

MacDonald: I think this is another great question and something pharmacists do a great job with: keeping up with emerging data and making sure providers are aware of it.

I work in gynecologic oncology, so we see many of these at-risk patients, including patients with endometriosis or polycystic ovarian syndrome (PCOS) who may require surgery because their pain is severe, they have recurrent large fibroids, or they have dysplasia that is identified early, before the development of endometrial cancer. We can see atypical hyperplasia occurring within the endometrium, which represents an early stage before progression to endometrial cancer.

For these patients, we use progestins to help luteinize the cells and reduce the risk of further dysplasia progressing into full-blown cancer. We know that this progestin strategy can be effective for these patients. We also have patients with potentially early-stage endometrial cancer who still desire fertility preservation. They want to maintain their uterus and avoid hysterectomy so they can have children. In those cases, we may use progestin therapy and encourage them to pursue pregnancy as quickly as possible before addressing the cancer risk more definitively.

Progestins can certainly be helpful, but adding something such as a GLP-1 receptor agonist, given the emerging evidence in these high-risk patients, is something the gynecologic oncology world is just beginning to consider more seriously. I think it is our job as pharmacists to educate and ask important questions, such as when it may be appropriate not only to prescribe progesterone for an at-risk patient but also to consider adding a GLP-1 receptor agonist.

At the same time, when discussing fertility and a woman’s ability to have children after struggling with infertility, we know obesity can be a significant risk factor for infertility. Potentially, this combination approach could also help women who have struggled with infertility conceive and have children, depending on their level of risk and whether they already have atypical hyperplasia versus being someone with a long history of endometriosis, PCOS, or other concerning risk factors.

Pharmacy Times: With novel tools like the ACR-368 OncoSignature assay receiving FDA breakthrough designation, how do you see biomarker-driven treatment selection evolving, and what role will pharmacists play in interpreting and applying these results?

MacDonald: I think molecular testing profiles in cancer are something we have already been using, and we are continuing to see them expand as the research improves, access to these assays increases, and they become more integrated into clinical practice. Pharmacists are particularly well equipped to review these assays, understand the results, and apply them therapeutically for patients. The key question becomes, how can we use this information to guide patient management?

In uterine cancer specifically, there is a newer molecular classification system, and guidelines are beginning to move toward incorporating these molecular classifications into prognosis alongside histology. Not every uterine cancer is created equal. Certain uterine cancers are much higher risk. I mentioned earlier that tumors such as carcinosarcoma, serous endometrial cancers, and clear cell carcinomas are more aggressive. These tumors are not typically associated with estrogen-related risk factors, tend to present at younger ages and more advanced stages, and are associated with worse prognoses. They can also disproportionately affect African American patients.

What we are seeing in the guidelines is an effort to align what we know about these tumors with biomarkers and how those biomarkers correlate with prognosis. It is becoming less about stage alone and more about understanding the patient’s molecular classification and how that affects outcomes. That is where molecular classification becomes so important. Treatment approaches should differ for a patient with a POLE-mutated tumor versus a patient who is mismatch repair (MMR)-deficient or MMR-proficient.

There is still more research emerging regarding p53 status, including how to approach patients with aberrant versus wild-type p53 when no other mutations are identified. There are also questions about whether HER2-positive patients should receive HER2-targeted therapies in the frontline setting instead of immunotherapy. For patients classified as NSMP, meaning no specific molecular subgroup identified, there is ongoing discussion about whether therapies such as PARP inhibitors should play a role compared with other treatment approaches used for patients with p53 wild-type disease.

There is a tremendous amount of research underway, and it can be challenging to keep up with, but it is also incredibly exciting. Pharmacists are at the forefront of these developments and are actively involved in discussions about how patient-specific molecular assays can guide treatment decisions and improve outcomes.

Ultimately, we are seeing increasing incidence and mortality associated with uterine cancer, so advances are urgently needed. Being able to use molecular profiling to guide therapy is one of the most promising ways we can improve treatment, patient care, and overall survival for these patients.

Pharmacy Times: What challenges or considerations should pharmacists keep in mind regarding long-term safety, access, and adherence when GLP-1 receptor agonists are being considered in patients at risk for or diagnosed with endometrial cancer?

MacDonald: I think there is a lot to unpack here. GLP-1 receptor agonists have a well-established safety profile in diabetes, including long-term cardiovascular outcomes data, as well as improvements in A1C and other markers we look for in diabetes. However, these therapies have been more controversial in the weight loss and obesity management space.

Some of that is because every therapy comes with its own set of side effects and safety concerns. I know it is not common, but thyroid cancers are something to consider. It is a very low-incidence risk, but I work in the cancer realm, so it is something patients should be counseled about and monitored for. When GLP-1 receptor agonists first came to the market, there may have been some concern about a potential increase in pancreatic cancer risk as well. I think some of that data has not really panned out as much, and I do not even know that it is really listed anymore, but those are still things I keep in the back of my mind.

When looking at these therapies, we also need to consider infection risk and other potential concerns that can come with treatment. We do not yet know all of the long-term safety data for patients who do not have diabetes or even prediabetes. Most patients with metabolic disease and obesity have those conditions present, so these therapies should be safe to use for them. However, there is this middle class of women, in particular, who are not necessarily obese but want to use these medications because menopause changes the body, metabolism, and ability to lose weight, along with many other effects that come from estrogen loss.

I think we have been cautious about these therapies, and we still need to continue following the long-term safety data. This is especially important because we know that much of what women are losing with these therapies is muscle mass. We do not want to see rapid weight loss. Patients need appropriate nutrition counseling and monitoring so they can lose weight safely and maintain good muscle mass, which helps prevent osteoporosis, fractures, and other important risks for women that are increased during menopause because of estrogen loss.

Another question is how this will affect cardiac safety. That is one of the major things I think about with weight loss drugs in general. If you look over decades, the biggest issue with weight loss drugs has often been cardiovascular risk. The heart is a muscle, and if patients are losing muscle mass, there is concern about whether that could increase the risk of cardiovascular side effects, possible myocardial infarction, heart failure, or other outcomes that need to be monitored long-term.

Hopefully, we are moving into an era where we feel more comfortable using these therapies in high-risk patient populations, particularly when we are concerned about progression to endometrial cancer. These therapies may also have an important role in the management of obesity and metabolic disease. We want people to make lifestyle modifications and live healthy lives, but we also have an obesity crisis in the United States that needs to be managed and is associated with significant morbidity and mortality.

To round out what I am saying: yes, I still think we need more long-term safety data. I think we are starting to see it, and I think these therapies need to be more accessible for women. The stigma around them also needs to come down, while still appropriately monitoring long-term safety data and recognizing that recommendations may need to change over time.

These therapies do come with side effects, including GI adverse effects, and they need to be titrated appropriately. In my opinion, patients should not just be going online to get prescriptions without following up with a provider who can provide appropriate nutrition counseling, monitor weight loss to ensure it is happening at a safe rate and in a safe way, monitor laboratory values, assess GI side effects, and watch for rare adverse effects such as thyroid cancer.

Hopefully, with more appropriate use of these therapies in the right patients, we will also see improvements in some endometrial cancer outcomes.

Watch the full interview here.