Biomarkers Improve Targeting and Risk Assessment in Endometrial Cancer

Casey M. Cosgrove, MD

Biomarkers such as mismatch repair deficiency (dMMR), microsatellite instability (MSI), p53 positivity, and POLE mutations can inform treatment and care options in patients with endometrial cancer, but the role of biomarkers in the endometrial cancer setting is still being investigated. Consequently, patients can be divided into subgroups for risk assessment and treatment needs in addition to traditional staging and histology-based methods.

Care can be tailored to individual patients with shared molecular features determined by testing. The National Comprehensive Cancer Network (NCCN) has begun to use molecular biomarkers to recommend treatment options including chemotherapy and immunotherapy. However, more research is in progress to assess the efficacy of treatments such as the RAINBO umbrella program of trials of biomarker-targeted treatments in 4 molecular subtypes: p53 abnormal, dMMR, POLE-mutated, and no specific molecular profile.

In an interview with Targeted Oncology™, Casey M. Cosgrove, MD, an assistant professor in the Department of Gynecologic Oncology at The Ohio State University College of Medicine in Columbus, discussed the current state of biomarkers for patients with endometrial cancer and how they can be used for prognostic purposes.

Targeted Oncology^TM: Please explain the interest in biomarkers for endometrial cancers.

COSGROVE: With many different types of cancers, we’re starting to look at a more specialized approach as to how we can better take care of our patients. Endometrial cancer certainly has many opportunities where we can identify molecular markers or things that we can’t see under the microscope to help guide the best way to treat these patients.

We can use biomarkers to treat patients, to guide which trial metric to use, [or] which type of treatment we want to use. But we can also use biomarkers to tell us which patients should be treated or maybe even…should not be treated. It’s an incredibly exciting area of research for endometrial cancer because it allows us to home in on their individual types of cancers and treat them with the most individualized approach.

What is the current landscape of endometrial cancer?

Endometrial cancer is…one of the few cancers that is getting worse. We have more patients dying of endometrial cancer now than we did last year, and that’s a travesty. Endometrial cancer is aligning itself to overtake ovarian cancer [as] the deadliest gynecologic cancer in the United States….We need our researchers and clinicians to be aligned with what patients…having poor outcomes are seeing.

What biomarkers are most relevant to endometrial cancer and what role do they play?

With biomarkers in endometrial cancer, there are 2 fundamental questions. The first question is, “Who should we be treating?”…Several studies…have looked at the best ways that we can predict whether patients’ cancers will come back.

[Traditionally], we’ve been guided by [cancer] stages or the histology, as well as several other features. But now we are starting to appreciate that we can use molecular signatures to tell us whether these cancers are at higher or lower risk for recurrence.

Reports from our group, as well as others…have looked at different markers that have predicted higher-risk cancers. These can be things like p53 or genomic alterations and several other mutations we’ve noted. If we identify patients that have some of those higher-risk features, they may benefit from having extra treatment. There’s also a marker called POLE, which is needed to help the DNA repair itself. This allows for your body’s immune system, without any additional treatment, to fight those cancer cells better. We see that those patients [with POLE] tend to not [have their cancer] recur.

A question we’ve been asking has been, “Can we not treat these patients, even if they traditionally would have had higher-risk features?” The other major question that we’ve been trying to address with biomarkers is, “Can we work smarter, not necessarily harder? Can we target therapies that are based off molecular signatures?”

Perhaps the one that we have the most research and…knowledge about and most experience with is deficiencies in MMR proteins or MSI within endometrial cancers. These markers predict response for immunotherapies. When we look at an endometrial cancer that has 1 of these markers, perhaps we should jump right to immunotherapy as opposed to going through our [traditional] chemotherapy algorithms. We also know that the MMR and MSI status can be an important prognostic biomarker because these patients seem to also have poor outcomes.

So taken together, a patient [with] a dMMR tumor or MSI-high tumor may benefit from having more aggressive treatment and a smarter treatment with immunotherapy as opposed to traditional chemotherapy.

What are the most significant findings you’re presenting at the SGO Winter Meeting?

The most significant findings we’re presenting are the potential areas for improvement for patient care…on the horizon. There are several ongoing clinical trials…that are trying to refine the way we take care of a patient with endometrial cancer. What I hope we can see through all these clinical trials is that we have some easily applied clinical markers that are going to directly impact our decision-making. The ProMisE [Proactive Molecular Risk Classifier for Endometrial Cancer system] from the University of British Columbia, which establishes endometrial cancer into 4…molecular groups, has the most traction right now throughout the gynecologic oncology community.¹ This is testing for dMMR, POLE [mutations], as well as p53 [positivity], and grouping endometrial cancers into 1 of 4 groups.

Depending on which group [patients] fall into, the next question is, “What’s the best treatment for those individuals?” This has been evaluated through several trials right now. There’s a lot of excitement that hopefully we’ll be getting some answers in the next couple of years. I think the endometrial cancer [setting] has a lot of opportunity for growth in patient care. And [we] as clinicians are going to have to start integrating a lot of this information quickly as it becomes more available. With the improvements in technology, we’re going to be getting more information for each cancer type…than we’ve ever had before. I can see assimilating that information into the clinical setting as a major barrier for patients and clinicians. But hopefully, we’ll have some standardized protocols that allow us to have the right way to take care of each individual patient.

Are there any other studies that are upcoming that you feel are important to biomarkers in the endometrial setting?

The RAINBO [set of trials] is very exciting because not only are they using the molecular classifications to determine the risk for recurrence and the aggressiveness of treatment, but they’re also integrating novel treatment strategies for the different molecular groups. I might identify that a patient is at higher risk, and I know what [treatments are] available, but I can [consider adding] more targeted therapies because of that molecular class, and I can treat them more aggressively and with a smarter therapy.

One of the things…most notable from my presentation is the vast amount of ongoing research that we have in the area right now, which also highlights the…number of unknown questions….One of the potential concerns we may have is that physicians may start integrating little pieces of this information into their clinical practice without having a full tool belt available for what they need to be doing and what are the right tests and…treatments that might be available.

How do the NCCN guidelines align with the new biomarker research you are discussing?

Within the past 1 or 2 years, the NCCN guidelines have started incorporating the algorithms for molecular classification with endometrial cancer.² Traditionally, we’ve broken endometrial cancers into type 1 and type 2, with type 1 being a less aggressive type…and type 2 being the more aggressive….What the Cancer Genome Atlas [TCGA] did in 2013 was to break endometrial cancer into 4 important groups with differing risk of recurrence and…molecular features.³ Recent research has tried to integrate those in the clinical setting because TCGA uses technologies we can’t apply to the bedside. By utilizing newer technologies, we’re able to start integrating some of their findings into clinical care.

The NCCN has started to appreciate that and [uses] the algorithm for breaking endometrial cancers into 1 of 4 molecular groups as opposed to the 2 groups that we had traditionally [used]. There’s also greater emphasis on what we can do with that information in the NCCN guidelines. For instance, one of the most important molecular groups is the MSI or dMMR group. Not only is this an important prognostic biomarker, but it’s also a predictive biomarker for the use of immunotherapy. That has been highlighted in the more recent editions of the NCCN guidelines, where they say if you have a recurrence with an MSI-high disease or dMMR, then immunotherapy is very appropriate.

The other thing that the NCCN guidelines highlight is that even in the absence of having a biomarker, patients [can] get immunotherapy with the combination of lenvatinib [Lenvima] and pembrolizumab [Keytruda]. Sometimes having a negative biomarker can be just as informative for guiding treatment.

What is the most important takeaway that you would like community oncologists to get from your presentation?

We don’t have all the answers quite yet, and we’re still working on it. As we get more information, [we may find other biomarkers] to look for. It’s hard to cherry-pick 1 or 2 things that physicians can utilize [for all their patients]. The question is whether we need to have a whole grouping of testing to make the right decision for our patients.

We’re [in] a situation where there are clearly defined biomarkers that can be utilized in a clinical setting, like dMMR or MSI status and increase in tumor mutational burden, but we still have unclear knowledge whether a patient with a tumor with [for instance] a POLE mutation can safely forego treatment. If you hear that these tumors have no recurrences, [we want to know] why we are treating them with chemotherapy and radiation, which have high toxicities, but at the same time we haven’t clearly proven that withholding treatment is not compromising outcomes.

Right now, physicians must continue to integrate the right biomarkers that we have information for into clinical practice….It’s easy to order a lot of testing, but if we don’t have a clear game plan with what we’re going to do with that testing, then we [could] harm our patients.

Some caution [must] be applied when we’re discussing biomarkers and new technologies with any cancer types. Another thing…highlighted in our presentation is our reliance on our [traditional] pathologic findings, histology, and stage and how we integrate that into our patient care algorithms. Once we start getting more molecular data, how do we integrate the old and new data? What do we do if we have conflicting information? It could cause problems in the future if we don’t adequately study these questions.

_References:

_{1. Kommoss S, McConechy MK, Kommoss F, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol. 2018;29(5):1180-1188. doi:10.1093/annonc/mdy058}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Uterine Neoplasms, version 1.2022. Accessed January 24, 2022. https://bit.ly/3nWzdqd}

_{3. Cancer Genome Atlas Research Network; Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. Published correction appears in Nature. 2013;500(7461):242.}