Improved Molecular Classification Drives Tailored Treatment Approaches in Endometrial Cancer

Abdulrahman Sinno, MD

Approaches in the management of endometrial cancer are shifting towards precision medicine, with the goal of leveraging molecular subtypes to more accurately predict responses, according to Abdulrahman Sinno, MD.

"As our understanding of molecular classification increases, we are able to move forward with our precision medicine approach in endometrial cancer and truly have tailored treatment rather than [that] just being a [buzzword],” Sinno said in an interview with OncLive® regarding a recent OncLive State of the Science Summit™ on gynecologic oncology, which he chaired. “We need to have tailored approaches not just for the patient, but also for their molecular subcategory.”

Sinno added that ongoing and future trials exploring targeted therapies and immunotherapies, such as the phase 3 KEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987) and DOMENICA (NCT05201547) trials of first-line pembrolizumab (Keytruda) and dostarlimab-gxly (Jemperli), respectively, aim to tailor treatment approaches to patients’ molecular profiles and potentially de-escalate chemotherapy in specific subgroups.

In the interview, Sinno discussed the paradigm shift from a histology-based to molecular-based understanding of endometrial cancer and its impact on treatment outcomes. He also underscored the pivotal role of precision medicine in shaping the future of endometrial cancer care. Sinno is an associate professor of Clinical Obstetrics Gynecology and Reproductive Sciences at the University of Miami Miller School of Medicine, as well as the director of Surgical Research and Education at Sylvester Comprehensive Cancer Center in Miami, Florida.

OncLive: What changes have occurred in the classification of endometrial cancer molecular subtypes and how is this impacting patient outcomes?

Sinno: One of the biggest changes in our understanding of endometrial cancer is that histology is not the whole story. In fact, histology is one of the smaller parts of the story and doesn’t always reflect biology. We’ve known for a bit that we have patients who are supposed to have highly aggressive histologies, but they thankfully never recur. Then we have patients with excellent histology and clinical staging [as well as] low-risk factors, and they experience recurrence 6 months later.

We’ve been slowly shifting gears to [focus on] the molecular profile of these tumors. [In doing so, we are] able to predict with greater accuracy the behavior of the cancer, which gives us more information about what cancers we think will respond to specific therapies. We are revisiting a lot of studies of therapies that [did not produce positive] results, and [asking whether] evaluating them [using] these molecular subclassifications changes outcomes with the treatment. Are we more likely to have success with this treatment in one of these categories vs the others [as opposed to] lumping them all together, which is what we practically do when we solely talk about histology?

There are 4 main molecular classifications of endometrial cancer based on the data of The Cancer Genome Atlas. We have POLE [ultra]mutated, microsatellite instability hypermutated, copy number-low, and copy number-high groups. Even within these copy number groups, there are further estrogen receptor–positive and –negative subclassifications. Each of these categories has completely different survival curves.

How might this evolving understanding of molecular subcategories in endometrial cancer guide and improve treatment selection in specific subgroups?

[During the meeting], we also shared some data about how certain categories may benefit more from having chemotherapy rather than radiation therapy, and [how other] categories of patients would benefit from the de-escalation of treatment. [For example,] patients with POLE mutations are much less likely to have recurrences, so are we going to treat these patients with 6 cycles of chemotherapy and radiation or is there a way where we can de-escalate treatment?

A lot of these data are hypothesis-generating and in the next few years, we’re going to be much more precise with which categories we’re selecting for [certain treatment approaches]. One trial [evaluated] the use of the nuclear [export] inhibitor selinexor [Xpovio] as maintenance therapy [and found it] specifically works in 1 of these subgroups. If you lump all these cases together, it doesn’t make a lot of sense because [selinexor] works on the TP53 protein. Having wild-type vs p53-mutated [disease is the] difference between having a successful trial vs an unsuccessful trial.

What future research avenues exist for the continued development of precision medicine approaches in endometrial cancer?

The future of the space is straightforward in the sense that we know what we need to look for now—we need to find what specific targets should be explored for which specific molecular subcategories. This is the big question here. We need more research on carcinosarcomas in our studies, and the question of how early we should start with these treatments is very interesting.

There are also 3 trials in this space [focused on] patients with mismatch repair–deficient [dMMR] disease, given that we know how much patients in the dMMR group respond to immunotherapy. We have the KEYNOTE-C93 trial looking at pembrolizumab vs [platinum doublet] chemotherapy in the upfront setting. When I was a fellow, we were talking about giving everything to the patient. Now, if we know they have dMMR disease, we’re talking about [whether] we can forego chemotherapy altogether in advanced stage IV or recurrent endometrial cancer and go with pembrolizumab. The DOMENICA trial is looking at [first-line] dostarlimab using the same study design [as well].

For the dMMR and MMR proficient [groups of patients], the phase 3 ENGOT-en9/LEAP-001 study (NCT03884101) is looking at pembrolizumab and lenvatinib [Lenvima] vs chemotherapy. With these checkpoint inhibitors, we’re looking to change what patients receive in the upfront setting into something more targeted. Chemotherapy is not going anywhere, but if we can avoid it and get bigger wins in these patients early on, we might need to do less later.

What is your take-home message for colleagues regarding the future of endometrial cancer?

The future is targeted, the future is bright, and women with endometrial cancer are going to live longer and better than ever before. Touching upon some of the social determinants of health data and research that we are doing in endometrial cancer, a lot of these trials are available to us at the University of Miami through our industry partners and foundation. More importantly, as a National Cancer Institute-designated cancer center, we have a plethora of targeted therapies [under evaluation] through the ComboMATCH trials, phase 2 TAPUR trial [NCT02693535], and phase 1 studies.

Whichever stage of cancer patients have, our goal is to cure them and have them live longer. When traditional approaches fail or when we have better options through clinical trials, our priority is always to enroll these patients in clinical trials. Without enrolling patients in clinical trials, we will never have the answers that we’re looking for. Very few patients are not good candidates and there’s always a clinical trial looking at something. It might not be a therapeutic trial—it might be a clinical trial looking at loneliness in endometrial cancer and the dramatic impact that has on Black women and how loneliness might worsen someone’s overall survival. It could also be a study looking at the vaginal microbiome and its ability to predict endometrial cancer. It might be a study looking at how PARP inhibitors impact underserved minority patients. We don’t know these answers, [but] there is always a clinical trial.

Our job at the university is to not just have industry-specific trials. These are very important, and they form the cornerstone of a portfolio, but there are so many other trials that we are very interested in understanding and exploring. We want to understand every aspect of disease because we want to impact every aspect of the disease.