Exploring the Endometrial Cancer Landscape: An Expert's Roadmap to Expanding Indications, Emerging Challenges, and Equity Considerations.

 

Endometrial Cancer: Overview

 

All right. What do we know about endometrial cancer? We know that it is the most common gynecologic malignancy in the United States, as well as in all developed nations. Most patients with endometrial cancer are going to present at stage I or stage II, which is considered an early stage of diagnosis. However, some patients also present with more advanced stage. Specifically, non-Hispanic Black women have a 2 higher-fold likelihood to die and also to present with more advanced stage endometrial cancer.

 

We know that endometrial cancer can be classified as sort of the more early typical histology that we see, like endometrioid or of some of the more aggressive non-endometrioid types, and we know that it can be treated well early with surgery. Normally in late stages, we also have to think about chemotherapy and remission.

 

[00:22:45]

 

Growing Incidence of Early-Onset Endometrial Cancer

 

What I really want to make clear is that there has been an increasing growing incidence of endometrial cancer across all races. What has been a little concerning is that we have seen since 1995 to now, as recent as 2025, that the rates are increasing across all ages, but also in women who are young. Women who are less than 50, a lot of people think about that being as an uncommon age.

 

However, when we think about a lot of the comorbidities we have in our country, we are starting to see this in a much younger age group, and so we really need to be aware of how the incidence is, not just across the years, but also across racial ethnic groups. As you can see, that patients of non-Hispanic black have the highest racial incidence in terms of increasing over the years compared to any other group.

 

[00:23:41]

 

Long-standing Disparities in EC incidence and Mortality

 

Not only do they have a higher incidence, the concerning thing, as you can see, that it really results in a much higher incidence and mortality. It is one thing to have a rising rate of a cancer, but also to have a more 6-fold incidence, but twice as likely rate if you are an African American to die from the same endometrial cancer than white women. As we see this alarming trend, we want to start to think about what are some of the causes and reasons and what can we do to better identify the patients that are most at risk.

 

[00:24:16]

 

Rising Rates of Advanced Stage High-Risk Uterine Cancer

 

When we think about some of the reasons this can happen, we think about early stage vs advanced stage. Most patients, if they have a postmenopausal bleeding and you biopsy them, you will identify 80% of the time of them being early stage. The problem is when we think about racial ethnic groups, there are definitely differences in the histology that we see in terms of how aggressive these cancers are.

 

When we think about patients who have what we call high-risk uterine cancer, as you can see from the graphs, what we would consider high-risk histology would be serous or clear cell or carcinal sarcomas, which you see on the bottom part of the graphs. What we would think is a high-grade 3 endometrioid histology type, which is in contrast to sort of the low-grade, grade 1 endometrial cancers, which tend to be found early stage and are not as aggressive. Then, if you think about these poor histological subtypes and you look at racial ethnic groups, once again, you sort of see the same concerning trend of being non-Hispanic black, having more advanced stage uterine cancer, as well as having the more advanced stage histological subgroups that we are concerned about.

 

[00:25:31]

 

Impact of Delayed Diagnosis: Disproportionate Mortality Rate Ratio in Among Black Patients

  

When we think about these high-risk histology being more prevalent in both black and also in some of the Hispanic populations, that also can lead to some reasons why they may have disproportionate mortality rates that we see specifically among non-Hispanic black women compared to white women and also amongst all other races. However, as we think about the increase in incidence across all races, we definitely need to think about the impact of the delayed diagnosis, particularly for patients who may present with a worse, more aggressive histological subtype, we should really be the goal is to find those patients as early as possible.

 

[00:26:14]

 

PUMBA Study: Timely Endometrial Sampling Following TVU

 

With that in mind, this was a recent study that was presented at the Society of Gene Oncology this year, 2025 annual meeting. What it sought to do was to think about the importance of timely endometrial sampling. In this particular study, it was a retrospective study with the thought that most patients, if you have an episode of postmenopausal bleeding, that was sort of what the people that they considered in their subgroup, some of the patients would specifically go straight to transvaginal ultrasound.

 

If you look at some of the guidelines, most of the guidelines say you can do either or for the first episode of postmenopausal bleeding, the consideration of a biopsy vs transvaginal ultrasound. What they looked at as an abnormal transvaginal ultrasound, it would be if the lining was greater than 4 mm thick, would be considered thick. Anything that was less than 4 mm would be considered thin.

 

Then, is what they call the inadequate ultrasound, which many of us will get where you see fibroids or something distorting where they say the lining appears to be normal, but not completely seen, cannot actually quantify a number of thickness for whatever reason. That would be sort of considered inadequate. What they sought to learn was that if you looked at a diverse group of patient populations who had ultrasounds in the setting of postmenopausal bleeding, what was the rate of guideline-concordant care based on race and ethnicity?

 

What they considered guideline-concordant care is that they had a thin stripe or if they received a biopsy within 3 months of their abnormal ultrasound.

 

[00:27:52]

 

PUMBA Study: Results by Race and Ethnicity

 

In the study, as you can see, the cohort was a pretty reasonable group of diverse population. What they found, if you look at the rates of ultrasound findings, were pretty consistent for most patients having found equally thin or thick endometrium. However, you will see that there were more inadequate ultrasounds found amongst patients who were African American.

 

[00:28:17]

 

PUMBA Study: Results by Race and Ethnicity – Not Receiving Timely Biopsy and Guideline-Concordant Care

 

You also will see, this was a study that looks specifically at what were the actual ultrasound results that were considered abnormal. If those patients who had an abnormal finding, which in this study was considered a thick endometrium or an inadequate ultrasound, how many of those patients were more likely to receive guideline-concordant vs nonconcordant care?

 

If you look, again, this showed that even in the setting of both white and black patients, both having equally close to having the same rates of thick or inadequate ultrasound, somehow, however, African-Americans were less likely to receive the guideline-concordant care, which would be considered a timely biopsy in the setting of an abnormal finding compared to the white population.

 

[00:29:05]

 

PUMBA: Non-concordant Care by Race/Ethnicity

 

When they further looked again, looking at the people who had sort of non-concordant care, you sort of look to kind of make a little bit more granular. If you see amongst the black population who did not have concordant care, they were more likely to have had inadequate transvaginal ultrasound compared to white women. The reason for it being inadequate was most likely due to fibroids. We do know fibroids are very common but are more likely common in African and Hispanic communities.

 

Understanding that this is the population that an ultrasound may not be the best way to know what is going on, I think the key facts that we should take away from this that, number 1, that non-Hispanic black patients have higher rates of getting inadequate ultrasounds due to fibroids. That can then lead to more workup delays, which could result in non-concordant care because maybe some providers feel reassured by the inadequate ultrasound, and that could cause the delay.

 

Number 1, the best thing I wanted you to get out of this is that universal biopsy should be standard across all racial groups because at the end of the day, you cannot depend on ultrasound to feel reassured in these patients who are continuing to have bleeding. In fact, although they looked at thin ultrasounds, feeling reassuring, we know for a lot of the more aggressive histologies, specifically serous carcinoma and clear cell carcinoma, many patients will have thin ultrasounds, thin stripes, such as endometrial stripes. I definitely would like to make it clear that universal biopsy, that is timely, should be the standard for all racial groups to help with these disparities.

 

[00:30:45]

 

Black Women's Perspectives on a Biopsy-First Approach to Improve Early Diagnosis of EC

 

Some people may say, in that particular study, why did patients not get the biopsies, period? There has been some thought to think about what are some qualitative reasons why there may be? Is there mistrust? How do we know why the patient did not receive a biopsy? Could it be because of the provider or could it be because the patient refused? In that particular study, they did not really look or investigate the reasons for why people may or may not have had a biopsy. I think as we make these assumptions around why people choose or not choose to do what we recommend, this was a good study that was also presented at SGO this year. That was a qualitative study looking at perspectives from Black women on a biopsy-first approach, with the idea that if you biopsy first, ultrasound and image second, then that also would potentially help to eliminate some of these disparities.

 

This was a very small study, as a lot of qualitative studies are. This was about 25 patients. This was from patients in the Southeast and Midwest region. A lot of them were from different socioeconomic statuses. What some of the key things they found were things like anxiety and fear that just often experienced by receiving chronological care, some apprehensiveness of trying to do to a biopsy first. Some of the feedback some patients reported is that they felt like they were not really involved in the decision-making. They really did not feel trust. They just said, "This is what you need to do", and did not really understand why it was so important to have this as the first step.

 

[00:32:20]

 

Black Women's Perspectives on a Biopsy-First Components for Successful Discussion About Biopsy

 

What they came out of the study was sort of these 3 main themes that evolved around trust building, information delivery approach, as well as kind of creating detailed culturally relevant education. The goal of this, I would say, is not really just a Black woman's perspective. This is most women's perspective. I treat a lot of women from multiple different racial ethnic groups. I think it is very clear that if you talk to people about, a) why it is important, I think 1 thing that is important with women of color, if you talk to them about the risk, about how that they are more likely to have these advanced stages, there are more likely to have imaging that is not going to be appropriate. A lot of them are understanding, "Yeah, I do not want to be the person who has a higher rate of mortality and death. If I need to do a biopsy to rule this out, I will do it."

 

Also, you have to acknowledge if people have questions. Do you have pain? What are the experiences they might have had with previous providers doing something that maybe they felt was either inappropriate or was painful to them?

 

Again, I think this is a cross-cultural conversation that I have with many women where they said, "I know this is going to hurt." Or "My other doctor told me this would not be a problem, and it really was not." Really setting expectations and allowing time for people to answer. What they found is that people were much happier when they were given the time and listened to about their past negative experiences, and it led them to be okay with proceeding with the biopsy first.

 

[00:33:53]

 

BWHS and Sister Study: Overview and Summary

 

Some other topics I wanted to bring up is that this is something that has been a little controversial, sort of thinking about how Black women, are there specific risks that are related to women of color that may lead to having endometrial cancer? These were 2 major studies that were a lot in the press. One is called the Sister Study, and the other study is looking at the Black Women's Health Study that they had. The Sister Study was a long-term research project that followed a group of women who had a sister diagnosed with breast cancer.

 

The researchers analyzed data from over 33,000 participants to identify specific risk factors for various health conditions, and one of which was uterine cancer. The second study, the Women's Health Study, looked at nearly 45,000 women in the Women's Health Study who had no prior history of cancer and an intact uterus, and they asked them about their past use of chemical hair relaxers. This was across both studies.

 

These were patients that were followed for many years, and they followed them with sort of self-report on follow-up questionnaires. What they looked at was the incidence of uterine cancer in these patients, and you see for both studies, they were around 378 for one, 347 for the other. Most of them were looking at just endometrial cancer without specific details per se.

 

In the Women's Health Study, there were some sarcomas. What they really were trying to determine is if exposure to chemical hair products increased their rates of having endometrial cancer.

 

[00:35:46]

 

I bring up these 2 studies because there are patients who will come in and say, "Did you hear about this study about chemical relaxers or straightening products? Is this the reason why I have endometrial cancer?"

 

These are the 2 largest studies that have reported a potential association, I will say, that having had use of more frequency use of straighteners may have a higher incidence of having uterine cancer. In the Sister Study, what they showed is that frequent use, which they defined as using some sort of chemical straightener products greater than 4 times in the past 12 months, as compared to people who never used, had a higher hazard ratio risk for developing uterine cancer. In the Women's Health Study, they show that their definition for heavy users vs never or light users, which they compare had a higher hazard ratio, specifically in postmenopausal women's risk for developing uterine cancer compared to those who were considered light users.

 

[00:36:53]

 

Expert's Take on BWHS and Sister Study

 

I bring this up, these 2 particular studies, because they both were somewhat problematic. I just want to say sort of the experts' takes on this that there may be some association, but there really needs to be more studies to determine if that association really is the main cause. Some of the reasons why there was some pushback is that for both of those studies, they were collected data at only 1 time point in over a 15-year window.

 

They asked people these questions at 1 time point, and then looked later on and said, "Did you develop uterine cancer?" If you look specifically at the Sister Study, the majority of the patients in that study, which was really focused around people who had sisters with breast cancer, only 7% of the patients in that study were black women. Also, they had no information on whether the hair products contain dyes or coloring or anything like that.

 

In the other Women's Health Study, they had a higher proportion of many of those women who develop uterine cancer had well-established risk factors. For instance, high rates of obesity, not lower use of OCPs, diabetes, which are kind of well-established risk factors. They really could not account for that in the studies. It is unclear to know what exactly the association truly is. However, I would say it is something to think about because these were 2 major observational studies that showed similar findings. What would have been great is if we had more information beyond the so-called chemical hair straightener, whether it contained lye vs no lye.

 

However, 1 thing that the Sister Study did is they did ask about if people not only use chemical straighteners, but if they use coloring and dye. They looked at the hair products that did have just coloring or dye, and that study did not seem to be associated with an increased risk. However, I do feel like what it left us with was more questions than answers.

 

However, I would say that if patients are asking you about things like this, there may be some association, but it is not clear exactly how much, what type, and what are the things that really can cause this association.

 

Strategies for Overcoming Challenges to Receipt of Optimal Care for Underserved Patients With EC  

[00:39:13]

 

What are some of the strategies for overcoming challenges to receipt of care for underserved patients?

 

[00:39:20]

 

Inclusive Clinical Resources

 

One of the things that we really want to think about is having inclusive clinical resources. In the beginning, I talked about a woman who did not speak very good English. Some of the things we need to think about is not only health literacy considerations, but also cultural sensitivity and language. What you also need to do is think about how we can connect patients with resources and advocacy. There is a lot of groups that do have things in different languages, whether they are for Mandarin Chinese, for Latina women. Also, just some of these advocacy groups that are specifically for patients who have their cancer from their specific group.

 

[00:39:58]

 

Navigating the Healthcare Ecosystem: Addressing Potential Healthcare Disparities

 

We also want to kind of think about just all navigating the health care system, which is hard for anybody. We know that a lot of these result in health care disparities. We talked a little about communication, but it comes from both the patient and the provider side, acknowledging that there may be some bias. To do this, we should increase representation of providers of color that may help.

 

Also thinking about costs, having healthcare is very important. As we think about where things are going with Medicaid and Medicare and Affordable Care Act, this is going to lead to more problems and widen in disparities. These are things that we need to think about. If we can get patients through telehealth, if they cannot come, that is still important. These are all things that we need to think about as far as the cancer treatment continuum.

 

[00:40:53]

 

Factors Affecting Willingness to Participate in Clinical Trials

 

Then, also thinking about clinical trials, there has been a lot of data to show that once a patient does have something like endometrial cancer, that if you were to get patients in trials, that it actually help to lower the risk of mortality and close some of the divide that you see in disparities. When we think about can there be bias from providers? Is there any element of racism? Are there other things that may make patients not receive the exact care? The good thing about clinical trials is that they are standardized care and standardized things that need to be done. Some of the things that people felt was that a lot of minorities did not want to be in clinical trials. That has been debunked time over time with many initiatives where all you have to do is just ask. A lot of people are willing to participate once they have better information. Also, if it is recommended by their provider that they trust, that also lets much more people being involved in clinical trials.

 

We also have done things like getting testimonials from patients who are like them who have participated in trials and also helping with just logistical barriers such as transportation.

 

[00:42:07]

 

Risk Factors Potentially Leading to Suboptimal Care

 

Finally, I am going to wrap this up about women who may have risk for worse outcomes. I hope that we sort of thought about not only racial ethnic concerns, but also patient related factors, financial constraints, low income, lack of insurance, just obesity, comorbidities, age, functional status, then also health care systems. Obviously, we can be a part of the delayed diagnosis, but sometimes it is not the provider or the patient, it is the healthcare system where their next appointment is not for several months. People are not getting referred right away. Also, people are having gaps in their own ability and access to insurance, which could lead to variable treatment, and also, they are presenting at a later stage in their cancer care.

 

Then, also just thinking about the health care professional, thinking about our own unconscious bias, thinking about whether or not we truly are adherent to the guidelines. Then, also, if you have the expertise and whether or not you should early on be referring people to those who may have the expertise that you do not have.

 

[00:43:16]

 

We Invite Your Patients to join the Smart Patients Gynecologic Cancer community

 

Finally, I just want you to know, there are a lot of different things out there in the community that can be helpful. This is 1 thing called SmartPatients.com, if you are interested in, that can help people have their own direct peer-to-peer support to have people guide them. There is no advertisements or solicitations. They are throughout communities nationwide because understanding that people are in different environments and in rural areas, and sometimes they are not able to get their answers completely taken care of with the limited time that we have as providers to take care of patients.

 

If someone seems like they are not ready to follow up, maybe they just need to have another source and opportunity to talk to people that will help them lead them down the path that you would like them to and get proper care.

 

[00:44:09]

 

Posttest 1: Based on recent demographic evidence, which of the following groups have the highest incidence and mortality from endometrial cancer?

 

We will go end it back at the posttest. Based on our recent demographic evidence, which of the following groups have the highest incidence and mortality from endometrial cancer?

 

1. Non-Hispanic White;
2. Hispanic/Latina;
3. Non-Hispanic Black;
4. Asian/Pacific Islander.

 

[00:44:42]

 

Yes, 95%. I love it. Obviously, from what we just discussed, from the latest statistic, non-Hispanic black woman, I hope we have seen, has the highest incidence and mortality and from all the higher-risk endometrial cancer compared to any other racial ethnic group.

 

Finally, I am about to pass this over. I hope from the very beginning poll, the answer to that was really timely endometrial sampling. I hope I really made it clear that it is very important to realize that biopsy overall can really help. I know there is a lot of other socioeconomic factors, but it has been shown that once people know they have an actual diagnosis of cancer, most people want to do something about it.

 

Getting to the diagnosis is the priority over a lot of the other things that also all do contribute to delays in care. However, the biggest delay is the delay to the diagnosis itself. I think as all those other things were factors, I just want to highlight that the important factor is to make the diagnosis through biopsy. Thank you so much for your time.

 

Recent Advances on Biomarkers and Molecular Classification in Endometrial Cancer

 

[00:45:48]

 

Dr Secord: Thank you. Thank you, Dr Chapman-Davis. That was fantastic. I wish we had more time for a panel discussion. I will try to summarize our recent advances on biomarkers and molecular classification in endometrial cancer. And I just wanted to give a warm welcome to everybody who is joining us today.

 

This is one of my favorite topics. If we could advance to the next slide. As we are trying to identify the biomarkers to direct therapy for our patients.

 

[00:46:20]

 

Patient Case 2: Young Black Woman Presents With Newly Diagnosed Endometrial Cancer

 

All right. We will start with a case. This is a patient who is only 39 years old, who identifies as black, and presents with a newly diagnosed endometrial cancer. Biopsy demonstrated a grade 3 serious endometrial adenocarcinoma. She underwent robotic-assisted total laparoscopic hysterectomy with removal of tubes and ovaries and bilateral pelvic sentinel lymphadenectomy. Her pathology demonstrated an invasive endometrial adenocarcinoma that was FIGO grade 3 and serious histologic subtype. The tumor was deeply invasive, 8 out of 11 mm of myometrial thickness for 73%.

 

There was extensive lymph vascular space invasion, and there was 1 positive lymph node.

 

[00:46:58]

 

Pretest 2: What molecular testing can help you best direct first-line therapy for this patient?

 

What we wanted to query today was what molecular testing do you obtain to best direct first-line therapy for this type of patient? Is it:

 

1. MMR IHC with reflux MLH methylation;
2. P53 status by immunohistochemistry;
3. HER2 by immunohistochemistry with reflux to ISH; or
4. In situ hybridization, MMR and p53 status by immunohistochemistry with HER2 IHC and ISH;
5. NGS panel to include a POLE testing; or
6. You do not obtain molecular testing at this time.

 

Let us see what the votes are. This is a very controversial topic, I think, in terms of how many biomarkers individuals obtain as well as the route. It has important implications for directing of therapy but also cost efficiency.

 

It looks like most people are doing MMR p53 and HER2 IHC, and then HER2 ISH for reflux testing. We really wanted to ask this question more from an exploratory point of view. I do not think there is necessarily wrong or right answer, but I think that is a very good answer. I think it is more cost effective than doing NGS testing.

 

All right. Let us move forward.

 

[00:48:16]

 

Poll 3: Are you performing POLE testing for endometrial cancer at the time of diagnosis?

 

What about POLE testing? Are you doing POLE testing? No. Or if you are, yes. Are you using NGS for POLE or are you using single gene POLE testing?

 

Again, POLE mutation is really interesting. I will show you some data. I am sure you are already aware of it, that patients who have a POLE mutation have or appear to have a much better prognosis, and it may be an opportunity to deescalate therapy.

 

However, the percentage of POLE testing is still uncertain, and it appears to be differences within different demographic groups.

 

All right. Pretty evenly split there. Almost 50-50 in terms of people are ordering it vs not ordering it. For those who order it, they are utilizing an NGS approach for the most part.

 

All right. Let us launch into the data. Oh, 1 more. All right.

 

[00:49:07]

 

Pretest 3: How would you rate your level of confidence for counseling patients about predictive biomarkers and the underlying biology and rationale to help them with treatment selection for newly diagnosed advanced endometrial cancer and to evaluate family cancer risk?

 

How would you rate your level of confidence for counseling patients about predictive biomarkers and the underlying biology and rationale to help them with treatment selection for newly diagnosed advanced endometrial cancer and to evaluate family cancer risk? I think that last point there about evaluating family cancer risk is incredibly important. One of the things that I think has really changed since most of us are doing universal mismatch repair testing, evaluating for the possibility of Lynch syndrome.

 

All right. Really quite a range here. What we would like to do is get everybody to that confident and very confident level, which I am sure we will be able to do. I am confident we will be able to achieve.

 

All right. Let us slide into those predictive and prognostic biomarkers.

 

Predictive and Prognostic Biomarkers in Endometrial Cancer

 

[00:49:58]

 

Genetic Determinants of Poor Outcomes in Underserved Women With Endometrial Cancer

 

I am going to focus on genetic and genomic determinants of poor outcomes in patients with endometrial cancer. In terms of the genetic predisposition, actually there are a few different inherited syndromes. I think the most common ones are associated with BRCA1, which is mostly known to be associated with increased risk of breast and ovarian cancer, as well as many other types of cancers. Endometrial cancer is one of those as well.

 

Then the other big one we have already talked about was Lynch syndrome, which is characterized by loss and mismatch repair proteins. Then there are also some genomic determinants. Those are where the patient has a somatic mutation in the tumor, but it is not necessarily inherited by a familial predisposition.

 

Now, p53 can also be associated with what is called Li-Fraumeni syndrome, which is a genetic inherited syndrome, but that is very rare. Most of the p53 mutations are going to be somatic. There are some differences in mutations in patients who are more likely to have a poor outcome. What we do find is that individuals who identify as black are more likely to have these aggressive cancers characterized by these genes that may portend a more dismal prognosis. However, I want to be very careful. I do not think it is because someone is black that they have these mutations, I think it is because of something in their environment that may predispose them to be at risk for these mutations, and thus these higher risk cancers. That is an area of interest for me from a research perspective. P53 is a well-known one.

 

Another gene, and some of these genes you may not be familiar with, is PPP21A and FBXW7. In terms of PIK3R1 mutations being more common, that is a little bit more controversial with studies going different ways. I think some of that is based on the composition of the patients in the study and whether they have these high-grade cancers or not.

 

HER2 protein expression and amplification appears to be higher in individuals who identify as black compared to other racial groups. In terms of low-grade cancers, they are more likely to have alterations in the P10 pathway and higher expression of estrogen and progesterone. A study that was recently conducted by our group and confirmed previous reports from a different subset was that BCL-2 and FGF, or fibroblast growth factor receptor mutations, may be more common in black compared to white patients. We will share some of that data today.

 

[00:52:28]

 

Molecular Subtyping of EC: PORTEC-3 Trial

 

However, first, I want to go over some of the molecular subtyping from 2 pivotal trials evaluating treatment options for patients with endometrial cancer. Where we first identified these different classifications for endometrial cancer was from the TCGA study, that instead of looking at endometrial cancers that simplified type 1 and type 2, but rather into these 4 different classifications based on POLE mutations, it was MSI, or microsatellite instability, and then copy number high and copy number low.

 

However, it is very difficult to do those techniques in the lab. The PROMIS algorithm was developed by some of our investigators in Canada and just did a fabulous job of evaluating different ways that were easier and could be facilitated in a practice setting for a relatively less expensive cost point. They evaluated POLE mutation, and then p53 status based on protein expression, and instead of MSI, evaluating mismatch repair protein expression. What they found when they evaluated these molecular subtypes in the PORTEC-3 trial is that patients who had cancers with p53 abnormal expression did much worse. You can see that in the blue graph, how their outcomes were worse regardless of whether they were treated with radiation alone or they received chemotherapy.

 

The other interesting aspect here was, is there a predictive value of these biomarkers in terms of which therapy they responded to best? What they found is that individuals that were treated, who had the p53 abnormal cancers, did much better if they received chemotherapy in addition to their radiation. However, there was not that much difference in the POLE group, probably because it is such a low number of patients. Or in the dMMR group, you can see that those completely overlap.

 

Numerically, there appeared to be some or slight improvement if those patients with copy number low or p53 normal cancers received chemotherapy with the radiation, but it did not meet statistical significance with that confidence interval crossing 1. This study really led to a more support for treating patients who have p53 abnormal cancers with chemotherapy. There are some nuances, and I wish I could go into that more time, but we do not have a lot of time today. However, feel free to call me and we can discuss.

 

Now, GOG-258, our group did this work, kind of trying to reevaluate these modified PROMIS algorithm in these patients based on p53 and mismatch repair protein staining. What we found is that, again, they are prognostic for outcomes. Patients with p53 abnormal tumors did the worst. Interestingly, the patients who had p53 wild-type cancers, demonstrated in red, seemed to have a benefit from adding radiation therapy to chemotherapy. The control arm here was chemo, but that was not seen in the other groups. In the deficient MMR group, it actually was flipped where, from a hypothesis point of view, it may be that radiation therapy may not benefit those patients. They may actually do worse, but again, very exploratory and hypothetical.

 

[00:55:43]

 

Current Guidelines on Biomarker Testing Recommendations for EC

 

Now, in terms of the different groups we talked about already, I just wanted to share with you the NCCN recommendations, which are for POLE sequencing first, and then followed by MMR and p53. I think this is somewhat debatable, in my opinion. This is just my opinion regarding the value of doing POLE sequencing first. I think it is pretty rare. We will have to wait and see if a modified PROMIS algorithm or maybe a select POLE testing may be an option.

 

[00:56:11]

 

HER2/neu Testing in Serous/Carcinosarcoma EC

 

What about HER2 testing in serous cancers and carcinosarcomas? Yes, absolutely test these patients. However, I think we may need to do further evaluation of other subtypes as well. We know that HER2 overexpression and gene amplification can be variable, ranging anywhere from 25-30% in serous cancer cases. There are drugs that we can use to target this, like trastuzumab or trastuzumab deruxtecan. Trastuzumab deruxtecan is FDA-approved for the treatment of tumor agnostic approval for patients who have 3+ expression. The NCCN guidelines have also incorporated 2+ protein expression in that group. Very important to test for HER2.

 

[00:56:51]

 

Clinical Implications of Key Biomarkers

 

Then, this is just a table summarizing all of the biomarkers, whether there is an FDA-approved companion biomarker, whether it is predictive, prognostic, or exploratory. In the interest of time, we will leave this for you to evaluate on your own as you will get these data sets.

 

[00:57:08]

 

ECMT2: Molecular Profiles of Endometrial Cancers Between White and Black Women

 

What about expanding more information on molecular profiles of endometrial cancers between white and black women? I think this is really important because, often, patients of color or these underserved populations are not included in these trials, and we may come up with data that is not as really helpful because it is not relevant to all the diverse patients that we see. We established the Endometrial Cancer Molecular Targeted Therapy Consortium in 2019. We now have 23 sites and moving in on 25 sites. This was an earlier study that was conducted with 16 sites. There are a lot of sub-studies within the consortium, and this study was led by UNC.

 

[00:57:46]

 

ECMT2: Methods

 

Basically, the idea was to further evaluate broadly what the genomic alterations were between these different patients. The typical data was abstracted, including demographics, the tumor type, and the profiling and genomic alterations.

 

[00:58:05]

 

ECMT2: Baseline Characteristics

 

What Dr Boyles recently presented at the winter meeting, as reported similarly in other studies, is that there are differences in these characteristics. We had 191 patients who identified in black in the study, which is really wonderful. That is larger than a lot of the other studies that have been published. Patients who identify as black were more likely to have a slightly higher BMI, are much more likely to have a non-endometrioid cancer, and high-grade cancers, and more advanced disease.

 

[00:58:36]

 

ECMT2: Prominent Biomarkers in Black vs White Patients

 

What we also found, which is similar to other studies, is higher likelihood of having abnormal p53 expression, high HER2 expression, and unfortunately, less likely to have MMR deficiency. The reason I say unfortunately is because we have immunotherapy that can really help treat those patients. We need better therapies for all of our patients with endometrial cancer.

 

[00:58:56]

 

ECMT2: Select Genomic Alterations by Race for Endometrioid Tumors

 

What they found here is that patients who identify as black were more likely to have FGFR and BCL-2 mutations. Now, there are some drugs that target BCL-2, but look at how many patients you need to evaluate to come up with this very small number. These are the patients with endometrioid cancers, which is really important to distinguish between the endometrioid tumors and now the non-endometrioid cancers, where we can see there are some differences in tumor biology between these patients.

 

[00:59:27]

 

ECMT2: Select Genomic Alterations by Race for Nonendometrioid Tumors

 

This is a table that evaluates the genomic alterations based on nonendometrioid cancers.

 

I think what is interesting here is we see again that the patients who identified as black are less likely to have these PI3K and P10 and ARID1A mutations. There are drugs to target the P10/PI3K pathway, and so we need to identify drugs that can target all these different pathways. Also, the other issue here is that only 1 patient who identifies as black had a POLE mutation.

 

Again, these mutations are very rare. While we see a higher frequency of patients who have the p53 abnormal cancers, when we disaggregate this data based on the tumor histology, we did not quite have enough power to show a difference here, but there was a trend, which is not a surprise.

 

[01:00:13]

 

Molecular Classification of Early-Stage EC in GOG-249

 

What about molecular classification in patients who have high-intermediate risk endometrial cancer? This was just presented at SGO. This was the GOG-249 study that showed no difference in outcomes whether patients were treated with external beam radiation therapy or vaginal cuff chemotherapy.

 

[01:00:30]

 

GOG-249 by Molecular Subgroup: BL Patient/Tumor Characteristics by Modified PROMIS Algorithm

 

I just want to share some of this data with you because we went through molecular classification in this dataset. We found that within this group, patients with serous cancers were more likely to have the p53 alterations, no surprise here. Then, patients who were identified as black had a much higher frequency of p53 abnormal tumors that did not quite obtain statistical significance. However, this is a Phase III clinical trial that had a very small number of black patients in it, and chose to go back to the point that was made so well earlier is that we need to just ask our patients about all these trials so that we can have fair representation.

 

I am going to move to these next 2 slides here for importance.

 

[01:01:14]

 

GOG-249 by Molecular Subgroups: RFS and OS per Modified ProMiSe Algorithm

 

They just show that the protein expression is also prognostic for patients in terms of recurrence-free survival and overall survival. Now, we have 3 different studies in the frontline setting evaluating patients from high-intermediate risk to advanced stage disease where you can use this information to counsel your patients. Not all these patients have the same survival outcomes. Patients who have the p53 abnormal tumors have a 4-fold risk of disease progression or relapse as shown by this red line. Patients with p53 abnormal tumors have a 9-fold increased risk of death as shown by this overall survival curve on the right. Patients who have a p53 wild-type tumor have a much better prognosis. This can really help those patients understand more the risk of disease. Patients with deficient MMR are right in the middle.

 

[01:02:05]

 

GOG-249 by Molecular Subgroups: 5-Yr RFS Comparing VCB/C vs Pelvic RT

 

What about is it predictive of outcome to therapy? Unfortunately, we did not see that. However, I want to go over this because there are some nuances. You can see that these survival curves are right on top of each other in terms of deficient MMR and for p53 wild-type. Giving these patients vaginal cuff branchy and chemotherapy rather than radiation therapy alone does not make a lot of sense.

 

What about the p53 abnormal group, where I think a lot of us utilize chemotherapy and vaginal brachy rather than external beam without chemo? While there is a numerical difference of 65.1% at 5-year RFS compared to 52%, it did not achieve statistical significance. However, what I will tell you is we only had 30% power in this group to show a difference. We need desperately to be evaluating these patients separately and making sure that we have a power to show a difference in whatever treatment we choose to compare to the control. It also tells us that chemotherapy is not enough. We need to be smarter about how we direct treatment and directing it at the biology.

 

[01:03:12]

 

GOG-249 by Molecular Subgroups: Primary Site of Recurrence by ProMiSe Algorithm

 

What we wanted to illustrate in this table is that patients with these cancers, we have to be careful, because look at this high risk of distant metastasis in this red line here. There is not a lot of patients. However, you can see in this p53 abnormal group that the distant met rates, if they were treated with radiation alone, was 83%. Again, just have to be cautious with some of this data. The distant recurrence rate overall was very low, was 18%. However, that is where we really need to try to prevent recurrence.

 

[01:03:48]

 

Durva + CP Followed by Durva Maintenance ± Ola as 1L in Newly Diagnosed Advanced EC (DUO-E)

 

DUO-E is a biomarker festival that we are going to share with you right now. This was data that was just reported by Dr Moore at SGO. The DUO-E study evaluated durvalumab. There were 3 different arms, a control arm, durva only, and then durva and olaparib.

 

[01:04:05]

 

DUO-E Biomarker-Known Subpopulation

 

There were so many biomarkers evaluated here in terms of PD-L1, POLE, p53, homologous recombination repair mutations, and BRCA mutations.

 

[01:04:16]

 

DUO-E Biomarker-Known Subpopulation: Prevalence of Biomarkers

 

They also evaluated ctDNA. Really what is astounding here is the number of patients that had at least 1 biomarker positive was 84%. However, also look at all this tremendous overlap that is here. You have a lot of overlap between the serous and the p53 mutation group. Not a surprise. However, look, there is a lot of patients that have p53 mutations that do not have serous cancers. We need to be evaluating p53 mutations across the board for patients who have endometrial cancer. Then, you can also see the overlap between BRCA mutations, TP53 alterations, and serous cancers. Then, another big overlap here is PD-L1 expression. Very hypothesis-generating study.

 

[01:04:57]

 

DUO-E: ctDNA Detection Rate in Evaluable Population

 

How do we determine which patients are going to benefit from durvalumab or any immunotherapy? I think it is really easy based on their deficient MMR. However, what about those patients that need more in that pMMR group? What about the role of olaparib? How can we utilize this biomarker data to help us understand who will benefit from adding olaparib to durva in the maintenance setting after they have been treated with IO therapy and chemotherapy?

 

I think a lot more to come here. We have not quite figured it out. However, we have done a lot of great work trying to get there. Let us go to our post-test question.

 

Posttest 2: What molecular testing can help you best direct first-line therapy for a patient with grade 3 serous endometrial invasive adenocarcinoma?

 

What molecular testing can help you best direct first-line therapy for this patient?

 

1. MMR IHC with reflex MLH;
2. P53 status by IHC only;
3. HER2 with IHC/ISH;
4. MMR, p53 by IHC and HER2 IHC/ISH;
5. NGS panel to include POLE;
6. Molecular testing is not needed at this time.

 

Let us see. I know I went through that very quickly. I wish we had more time. I think you could probably spend several hours on just the biomarker story alone in endometrial cancer and testing. There we go, 85%. Yes, I think that this is a very relevant testing option to determine how you are going to treat your patient and also counsel them in that front-line setting.

 

Posttest 3: Now, how would you rate your level of confidence for counseling patients about predictive biomarkers and the underlying biology and rationale to help them with treatment selection for newly diagnosed advanced endometrial cancer and to evaluate family cancer risk?

 

How would you rate your level of confidence for counseling patients with predictive biomarkers and prognosis for their disease? I am hoping we will see this move toward more confident and confident. I will ask Eloise and Whitney, how confident are you all?

 

Dr Chapman-Davis: Moderately confident.

 

Dr Secord: I love it. I think we got a little higher here on confident. That is awesome. We always want to be available. I love talking to people as we try to sort out. We are hearing so many new interesting studies coming forward and abstracts that are just late-breaking and how we synthesize all this information to care for our patients.

 

Dr Chapman-Davis: I think that is why it is the moderately confident, because we are confident now, but then I think it will change again in another year.

 

Dr Secord: It will change in June. Dr Graybill, I am handing this over to you.

 

Recent Advances in the Treatment Landscape for Endometrial Cancer

 

 

[01:07:45]

 

Dr Whitney Graybill (MUSC Hollings Cancer Center): Thank you. That was a wonderful presentation. I am also going to be moving pretty quickly through this, just in the interest of time. Let me go here.

 

[01:08:00]

 

Patient Case 3: 56-Yr-Old White Woman Presents With Newly Diagnosed EC

 

This is a Patient Case 3: 56-year-old white woman referred to a gene oncologist with newly diagnosed endometrial cancer. She is obese with a good performance status. Endometrial biopsy shows grade 3 serous endometrial adenocarcinoma. CT scans demonstrate lung metastasis, which are confirmed by biopsy. CA-125 is elevated. Biomarker testing demonstrates the tumor is pMMR, or proficient, HER2 negative. The patient is young. Her primary goal is prolonging survival.

 

[01:08:37]

 

Pretest 4: Considering FDA approvals, clinical guidelines, and most recent clinical trial data, what would be your recommended primary treatment for this patient with newly diagnosed EC and pMMR/MSS, HER2-negative status?

 

Considering FDA approvals, clinical guidelines, what would be your recommended primary treatment for this patient?

 

1. Chemotherapy;
2. Chemotherapy with immunotherapy, either dostarlimab or pembrolizumab with immunotherapy maintenance;
3. Chemotherapy with durvalimab, followed by durvalimab ± PARP inhibitor maintenance;
4. Chemo with selinexor maintenance, if she is p53 wild-type;
5. Pembro/lenvatinib.

 

Majority, chemotherapy plus immunotherapy with immunotherapy maintenance. We will talk through this a little bit more as we go.

 

[01:09:50]

 

Management Recommendations for Newly Diagnosed or Relapsed EC

 

For the interest of time, this is a great resource to have. You will have access to these slides. I think I am just going to point out that, for the purposes of our talk, looking at advanced stage disease in newly diagnosed patients, you can see the different options here in regimens, chemotherapy and immunotherapy with immunotherapy maintenance being listed. Then over here with systemic recurrence, again, depending on what the patient had initially gotten where she had been treated previously, immunotherapy with chemo. Then a host of other options down here that include combined immunotherapies, chemotherapy, and more targeted options.

 

I do not go into detail about lenvatinib and pembrolizumab. It is approved in patients that have pMMR tumors, so proficient tumors. However, it is approved following, or in patients that have already received chemotherapy.

 

[01:11:00]

 

Phase III Trials of Immunotherapy + Chemotherapy for Advanced Stage III/IV or Recurrent Endometrial Cancer

 

This is also another great slide just to have for reference. This includes 4 big trials that are looking at immunotherapy with chemotherapy. I am not going to go into all of the details. We will talk about a few more of these in detail in a minute. GY018 was pembrolizumab with chemo, followed by pembrolizumab maintenance vs placebo. Again, the patient population for most of these, there are some nuances and small differences. However, primarily, for advanced stage III and IV disease and/or recurrent endometrial cancer. The thing to point out here is that there was an improvement in median progression-free survival, as well as overall survival. The other thing to point out is this is the only trial out of these here that pre-specified to look at the pMMR cohort from a statistical standpoint.

 

If we look here at the RUBY trial, that was looking at dostarlimab with chemo and dostarlimab maintenance vs chemo and placebo. This shows the 2-year progression-free and overall survival, and then the median overall survival. Things to point out here, again, there was a statistically significant improvement in progression-free survival. The median overall survival, down here looking at both groups, 44.6 months vs 28.2 months. There was a 16-month increase in overall survival, which was really impressive. Both of these trials were responsible for both pembrolizumab and dostarlimab being approved in patients with dMMR or pMMR tumors.

 

The AtTEnd trial was looking at atezolizumab with chemotherapy, similar to the others. Median progression-free survival is listed here. There was a significant improvement in progression-free survival in the dMMR and the overall population. Then there was a trend towards improvement in survival.

 

Then you just heard a little bit about the DUO-E study and the different arms in that trial. There was a statistically significant improvement in progression-free and overall survival for this trial as well. Of note, the FDA approval was only for the dMMR subgroup. It was for durva with chemo, followed by durva maintenance.

 

[01:13:52]

 

Common AEs of Immunotherapy + Chemotherapy for Advanced Stage III/IV or Recurrent Endometrial Cancer

 

Common AEs of immunotherapy and chemotherapy. Across chemotherapy and immunotherapy trials, the most common grade 3 AEs were alopecia, fatigue, anemia, nausea, neuropathy, thrombocytopenia, constipation, and diarrhea. A lot of the things that we would expect. The bolded numbers here show any-grade AEs, followed by the grade 3 or greater below. As expected, the grade 3 or greater AEs were a little bit higher in the group that received the chemo plus immunotherapy.

 

[01:14:31]

 

Carboplatin + Paclitaxel ± Pembrolizumab as Frontline Treatment for Patients with EC (NRG GY018)

 

As I just told you that for GY018, there was an improvement that was seen in progression-free and overall survival. Again, this was looking at pembrolizumab with chemo, followed by pembrolizumab maintenance compared to placebo.

 

[01:14:50]

 

NRG GY018: PROs With CT + Pembrolizumab in Patients with Advanced/Recurrent EC and pMMR Status

 

At SGO, this was some updated information that was provided. This was looking at patient-related outcomes with chemo plus pembrolizumab in patients with advanced or recurrent endometrial cancer. Analysis assessed whether adding pembro to the chemotherapy affected quality of life vs receiving the chemotherapy alone. They looked at FACT-Endometrial Trial Outcome Index, PROMIS-Fatigue and Physical Function Short Form. The assessments were made prior to starting treatment, then at week 6, 18, 30, and 54. Here on the right, you can see some of the things that were evaluated.

 

[01:15:39]

 

NRG GY018 PROs: FACT-En and PROMIS-Fatigue

 

I think this is really interesting. It is really important for just patient education. This is the patient-reported FACT Trial Outcome Index. Again, the fatigue subscale. There are statistically significant but small negative effects with the addition of pembrolizumab during combination phase of the study. You can see that here, the blue line. Then, here as well.

 

There was no difference in patient-related outcomes between treatment arms after week 18. I think that is really important. Basically, once patients moved into that maintenance phase, you did not see any difference. We know there is an overall clinical benefit with the addition of pembrolizumab to chemotherapy.

 

[01:16:34]

 

Dostarlimab + CT in Primary Advanced or Recurrent EC (ENGOT-EN6/GOG-3031/RUBY)

 

Then this is looking a little closer at the RUBY trial and the design. This was the dostarlimab plus chemo followed by dostarlimab maintenance, or placebo plus chemo and placebo maintenance. Primary outcomes were progression-free survival and overall survival. Secondary outcomes are seen as listed here.

 

[01:17:01]

 

GOG-3031/RUBY: Updated Duration of Response With CP + Dostarlimab vs CP + Placebo in Adv/Recurrent EC

 

What was presented at SGO was really an updated duration of response with chemotherapy plus dostarlimab vs chemotherapy plus placebo. What was found is in the overall population, 61% and 57% of patients in the dostarlimab and placebo arms achieved a response. The median duration of response was increased by 4.4 months with the addition of dostarlimab to chemotherapy. Improvement in duration of response was also observed across all populations.

 

[01:17:40]

 

GOG-3031/RUBY: irAEs Over Time in Overall, dMMR/MSI-H and pMMR/MSS Populations

 

I think this is really interesting. You could probably spend a little time looking over this in more detail. This looked at immune-related AEs over time in the overall population, which is here at the top, and then the dMMR and the pMMR subgroups. The dostarlimab is in blue and the placebo in red. It just gives you an idea of when you see some of these immune-related AEs over time. I think 1 of the things that stood out to me is the arthralgia. If you look in the overall population and the dMMR, that is something that you tend to see further out, Year 3 to 4, more so than Years 1 to 2. I thought that was very interesting.

 

[01:18:30]

 

Differences in AEs Between Chemotherapy and ICI

 

Differences in AEs from chemotherapy and immunotherapy. AEs with immunotherapy are pretty consistent between different agents. They are immune-related or mediated events. AEs with chemotherapy and targeted agents tend to vary by class of the drug, and then by the individual agents. Again, chemotherapy, almost all patients have some kind of AE. The safety profile is well described. A few organs are affected. We have a pretty good idea of the time course, of when these are going to occur. It is much more predictable. Immunotherapy is very different. It is a much more variable safety profile. It really can affect any organ, as can be seen over here. The time course is variable. It is a lot more unpredictable.

 

[01:19:24]

 

General Recommendations for Managing AEs with Chemoimmunotherapy

 

This is just general recommendations. It does not go into specific recommendations for managing a specific AE with immunotherapy. However, compared to chemotherapy, you can see, obviously, if you have a significant AE, you are going to hold the dose. With chemotherapy, we tend to hold and then reduce the dose, or we can switch to a less toxic agent. That is not something we typically do with immunotherapy. We do not typically give steroids for AEs with chemotherapy. However, we do with immunotherapy. Obviously, if anything is severe, you would permanently discontinue regardless.

 

[01:20:10]

 

Durva + CP Followed by Durva Maintenance ± Ola as 1L in Newly Diagnosed Advanced EC (DUO-E)

 

This is the same slide looking at the DUO-E study. I am not going to spend really any time here because you just saw this a few minutes ago. Dr Secord presented it.

 

[01:20:25]

 

DUO-E: PFS by MMR Status

 

We are going to look at progression-free survival by MMR status. I think the important thing, this is the dMMR subpopulation and the pMMR subpopulation on the right. There is a clinically meaningful benefit in durvalumab vs control and durvalumab plus olaparib vs control. However, you see these lines overlap here. There really was not much of a difference between the 2 in the dMMR subpopulation. Over here, what is interesting is you do see a separation in these lines. The addition of olaparib to durvalumab increases progression-free survival benefit of durva alone.

 

[01:21:17]

 

DUO-E: PFS by Biomarker Subgroup

 

Now, we just heard a lot about biomarker subgroups and the importance of biomarkers. Not to go into detail, but what I think is important here is obviously enhanced progression-free survival was observed in the pMMR subpopulation that received olaparib across a range of biomarker and histologic subtypes. Here, you can look at PD-L1 expression. Where that really stands out, POLE and p53, serous histology, and then detection of ctDNA.

 

Recent Advances in the Adjuvant Setting  

[01:21:58]

 

Recent advances in the adjuvant setting.

 

[01:22:04]

 

KEYNOTE-B21/GOG-3053: Adjuvant CT With or Without Radiotherapy ± Pembrolizumab

 

I am just briefly going to comment on this. This is KEYNOTE-B21 or GOG-3053. It was looking at adjuvant chemotherapy with or without radiation plus or minus pembrolizumab. It can be a little bit hard to read this, so I will walk you through it for a minute. These were patients that had newly diagnosed endometrial cancer or carcinosarcoma. Curative surgery with no residual disease. This is a very different study. They were at high risk for recurrence. They had stage I/II non-endometrioid with uterine wall invasion, or stage III/IV of any histology. They were randomized to chemotherapy plus pembro with pembrolizumab maintenance, plus or minus radiation, plus or minus cisplatin. Or chemotherapy with placebo and placebo maintenance, plus or minus radiation, plus or minus cisplatin. Coprimary endpoints were disease-free survival and overall survival.

 

[01:23:14]

 

KEYNOTE-B21: DFS in ITT Population (Primary Endpoint)

 

Interesting, you see here disease-free survival in the intention-to-treat population. You really do not see any difference in these 2 curves. The HR value was 1.02 and P value of .57.

 

[01:23:34]

 

KEYNOTE-B21: DFS in pMMR and dMMR Subgroups

 

Here, we are looking at disease-free status in the pMMR and dMMR subgroups. In the pMMR subgroup, the hazard ratio for DFS did not differ. This is 1.02 here. If we look over here in the dMMR subgroup, the median disease-free survival was not reached in either treatment group. The hazard ratio for disease-free survival favored the pembrolizumab group. That was a pre-planned subgroup analysis. Of note, there is an ongoing Phase III trial that is looking at patients with early-stage intermediate-to-high-risk uterine cancer, dMMR, and looking at the role of single-agent pembrolizumab in the treatment of that group.

 

Recent ADC Approvals in EC  

[01:24:34]

 

Recent ADC approvals in endometrial cancer.

 

[01:24:39]

 

HER2-Targeted ADC: Trastuzumab Deruxtecan

 

Trastuzumab deruxtecan, humanized anti-HER2 monoclonal antibody attached to a topoisomerase I inhibitor. That is the payload. it is high drug-to-antibody ratio, which is what you always want to see. A very stable linker-payload, high potency, and has a bystander killing effect. All good things.

 

[01:25:04]

 

Phase II DESTINY-PanTumor02: Trastuzumab Deruxtecan in HER2-Positive Solid Tumors (EC Cohort)

 

This was the Phase II DESTINY-PanTumor trial that was evaluating this drug in HER2-positive solid tumors. This was in patients that were IHC 2-plus or 3-plus and had progressed on prior treatment. The endometrial cancer cohort had 40 patients that received treatment. Primary endpoint was response rate. Secondary endpoint, PFS and OS. In general, the FDA approved this drug based on this data for patients with inoperable or metastatic solid tumors that express HER2, and who have received prior systemic treatment and have no satisfactory alternatives.

 

[01:25:49]

 

DESTINY-PanTumor02: Response and Safety Outcomes

 

When we look at the data specifically for endometrial cancer and the overall response rate, here we have 8 CRs, 15 partial responses, and 12 with stable disease. The median duration of response was not reached. If you look over here, response rate was a lot higher in patients that had IHC 3-plus vs 2-plus. The overall response rate, like I said, was 57%. If we look at drug-related AEs, this was in greater than or equal to 10% of patients with GYN cancers, so included things other than uterine cancer. However, a lot of patients did have drug-related AE, with about 45% having grade 3 or greater event. Most common here, neutropenia and anemia. There were 13 patients, or 10%, that had ILD or pneumonitis.

 

[01:26:55]

 

Posttest 4: Considering FDA approvals, clinical guidelines, and most recent clinical trial data, what would be your recommended primary treatment for a patient with newly diagnosed EC and pMMMR/MSS, HER2-negative status?

 

We are coming back to this question. However, I will be talking about selinexor here in just a minute. This is the question we were talking about, the patient with newly diagnosed endometrial cancer that is pMMR and HER2-negative and has not had any prior treatment.

 

[01:28:09]

 

We will come here. This is the correct answer. The reason why that is the case is both paclitaxel/carboplatin and immune checkpoint inhibitor with dostarlimab or pembrolizumab, followed by immunotherapy single-agent maintenance is indicated for a patient with advanced disease, regardless of MMR status. Although, chemotherapy alone would be an option, it would not give this patient the longest possible survival that she is interested in. Then, chemotherapy plus durvalimab, followed by single agent durva maintenance is indicated for primary advanced recurrent endometrial cancer with dMMR status. That is different than this patient. That would not be applicable. Then the other thing of note is, when we were talking about the DUO-E study results, the indication for chemo plus durva does not include the use of a PARP inhibitor currently. That is not currently approved. Then, both chemotherapy and selinexor maintenance, if p53 wild-type or pembro/levantinib is not indicated.

 

[01:29:34]

 

New Directions in Individualized Treatment of Advanced Endometrial Cancer  

[01:29:33]

 

Quickly going to go through new directions in individualized treatment.

 

On the Horizon: Emerging Options  

[01:29:43]

 

ENGOT-EN5/GOG-3055/SIENDO: Selinexor vs Pbo Maintenance in TP53wt Advanced/Recuirrent EC

 

I told you I was going to get to this in just a second. This is what I am mainly going to focus on in this section. This is GOG-3055 or SIENDO. This is looking at selinexor vs placebo maintenance. We are going to be particularly talking about in patients with p53 wild-type advanced recurrent disease. Again, these are patients who were either stage IV at initial diagnosis or had their first relapse and had a PR or CR on chemotherapy. This is purely a maintenance trial. Patients were stratified by stage and response.

 

[01:30:26]

 

Long-term Follow-up from SIENDO: Baseline Characteristics

 

This is just looking at long-term follow-up, the baseline characteristics of these patients who receive selinexor vs placebo. I am sorry, I am going to kind of move quickly here.

 

[01:30:41]

 

Long-term Follow-up from SIENDO: PFS in TP53wt

 

Again, the data that we are looking at is the long-term follow-up. Progression-free survival in these patients that were p53 wild-type, median follow-up was 36.8 months. Long-term median progression-free survival of 28.4 months in patients who receive selinexor was observed in the p53 wild-type group. That is really impressive.

 

[01:31:08]

 

Long-term Follow-up from SIENDO: PFS in MMR Subgroups

 

Then, we are looking at the progression-free survival in the MMR subgroups. Over here, looking at pMMR subgroup, and on the right, the dMMR subgroup. The PFS improvements were observed in the p53 wild-type subgroups regardless of MMR status. I think that is really important. You can see that the curves are significant in both cases and are parallel to one another.

 

[01:31:41]

 

Long-term Follow-up from SIENDO: Median TFST in the TP53wt Subgroup

 

Then here we are looking at median time to first subsequent therapy. Median time to first subsequent therapy was 31.7 months for selinexor, which was statistically significant. 50% of patients discontinued selinexor and initiated subsequent therapy vs 83% of patients receiving placebo.

 

[01:32:08]

 

Long-term Follow-up from SIENDO: PFS2 in the TP53wt Subgroup

 

Then, here, we were looking at time to second disease progression. Again, selinexor increased time to second disease progression compared to placebo.

 

[01:32:20]

 

Long-term Follow-up from SIENDO: TSST in the TP53wt Subgroup

 

Then, selinexor also increased the time to subsequent anti-cancer therapy.

 

[01:32:29]

 

Long-term Follow-up from SIENDO: OS in the TP53wt Subgroup

 

There was a favorable trend for overall survival observed in this group vs placebo treatment arms.

 

Long-term Follow-up from SIENDO: TEAEs

 

Long term follow-up of TEAEs. Treatment emergent AEs were generally low-grade and were very manageable. Of note, there is an ongoing Phase III trial of selinexor as maintenance therapy in patients with advanced or recurrent p53 wild-type endometrial cancer. We will be getting a lot more data.

 

[01:33:03]

 

IOV-END-201: Lifileucel (TILs) in Previously Treated Advanced Endometrial Cancer

 

Quickly, this is the last slide here. This is just talking about tumor-infiltrating lymphocytes in previously treated advanced endometrial cancer. This is an open-label Phase II study. Patients had been previously treated with platinum-based chemotherapy and anti-PD-1 or PD-L1 therapy, so immunotherapy, in the past for recurrent or metastatic disease. The way this was set up was that there would be manufacturing of the TILs. Then there would be 30 patients in each arm, 1 arm being patients with pMMR disease and the other with patients with dMMR disease. On Day -5, patients would undergo chemotherapy conditioning. Then on Day 1, they would receive TILs plus IL-2. The primary endpoint for this trial is overall response rate. Then secondary endpoints are seen below.

 

Panel Discussion 3  

[01:34:10]

 

I thought I just flew through that.

 

[01:34:16]

 

Panel Discussion Topics

 

I am going to bring up the panel discussion topics. I think 1 thing that came up in questions had to do with what do we do if patients get immunotherapy and chemotherapy up front? Then, when they recur, how do we manage that? Some of the topics are looking at: Are there investigational immunotherapies, novel biomarkers? Are there novel immunotherapy and chemotherapy combinations? Can we even de-escalate first-line therapy in patients that are dMMR?

 

Dr Secord: Hey, Whitney, I think those are really great topics. I was very curious to see what you all are doing for patients who have pMMR disease in the advanced or recurrent setting, and if you are offering those patients immunotherapy.

 

Dr Graybill: That is a great question. We are typical, or I am typically, offering those patients immunotherapy in the upfront setting with chemotherapy if they have advanced disease, stage III or IV disease. Very similar to the patient that we discussed previously. I think the question that comes up too, is what do you do if you treat with that up front and then that patient recurs?

 

Dr Secord: Can I build on that?

 

Dr Graybill: Yes.

 

Dr Secord: Stage III does not matter if it is measurable or not measurable, you offer, or …?

 

Dr Graybill: Typically doing it in the measurable setting.

 

Dr Secord: That is what I am doing too. If it is dMMR, it is a no-brainer. If it is pMMR, if it is measurable, advanced or recurrent, I am offering it. Eloise, it looks like you are nodding your head.

 

Dr Chapman-Davis: I do as well.

 

Dr Secord: Because I think the data supports it, and maybe it is the idea of creating the neo-antigens when you are combining it with chemotherapy. However, in the B21 data, which I think you did a wonderful job presenting, those are patients that if it is not measurable stage III, just with a single positive sentinel node, I am not automatically.

 

Dr Chapman-Davis: Neither am I, because I think you do not want to use all of it up front because even in those patients who recur, then you have something to use later. I do think we do not have enough data right now because in the second line with pMMR, most people would turn to lenvatinib and Keytruda. If we are using lenvatinib and pembrosilamab and you use it the first line, is there a concern about giving immunotherapy after immunotherapy? What do you guys do in those situations?

 

Dr Graybill: I just want to say to Angeles, thanks for clarifying that, because that is exactly correct. In the pMMR, I am only doing it in the patients that have measurable disease.

 

Dr Secord: Eloise, you brought up a point. I think this is such an important question. One of the great things I think that we are seeing with patients who have dMMR disease that they are doing so well. I have not had a lot of them recur. It is still early on. I have just had one of my first RUBY patients that I put on come off of her IO therapy. I guess maybe it has been about 9 months or so. Then the patients that I struggle with are those patients who mostly it is the pMMR disease. What can we offer them? There is some intriguing data about adding lenvatinib if they progress on pembrolizumab. There was a single site that was doing that. We are actually trying to study that within our consortium that we have. I have not done it very often. I have 1 patient that I did on. She has done so great. I need to go and dive into her NGS profile to see why. Then, we have a lot of studies that are available. However, I think what is really exciting is the ADCs that are coming about and the new medication, trastuzumab deruxtecan.

 

Dr Graybill: I agree.

 

Dr Chapman-Davis: I think for most of our patients who are in the pMMR space, I go back to your molecular profiling once they have gone after the measurable disease with Taxol/carbo and some sort of IO. We are sending more people up front to check for HER2/neu. Just 1 thing to clarify with what you discussed about the molecular profiling for HER2/neu, what type of IHC staining are you using? Because we had to make sure that people know in that trial, they use gastric-type IHC staining vs breast-type and FISH, which they have used for other combinations with typical herceptin vs the ADC.

 

Dr Graybill: We are using the gastric type. We had to clarify that to you.

 

Dr Chapman-Davis: Correct. I wanted to bring that up because that is something that we had to clarify with our institution as well. Now, they actually send us both FISH for the breast as looking at for Herceptin use and then gastric-type staining, because sometimes things that would be negative for breast are positive for gastric-type. Then you can make sure you have an indication to use the ADC.

 

Dr Secord: I think it is an important thing that you ask for both. Dr Fader and Dr Santin's study with trastuzumab evaluated it really based on the breast criteria. However, we typically try to call it the endometrial criteria that they utilize there. We use that to direct and make decisions about frontline treatment. I really strongly advocate for patients to be offered the GY-026 study. However, I think it is really important to make sure your pathologist is doing both and not just doing gastric only now. That is a huge rabbit hole to go down, because they approved it for that indication, but they did not approve it for a companion diagnostic biomarker.

 

Dr Chapman-Davis: Correct.

 

Dr Secord: We do not even know what antibodies that your pathologist is utilizing.

 

Dr Graybill: I am curious, if you have a patient with advanced-stage uterine cancer who has residual disease and is HER2-positive, are you using chemo with trastuzumab or are you doing immunotherapy combination?

 

Dr Secord: You mean somebody who is a candidate for GY-026?

 

Dr Graybill: Yes.

 

Dr Secord: I am going to offer them the study. I think that is a really important study. Most of the patients that are HER2-positive are going to have p53 abnormal cancers and they are going to have that pMMR group. I think the greatest magnitude of benefit with immunotherapy is in patients who have deficient MMR. The big issue here is, is trastuzumab or HER2-targeting agent better than what you are going to get with immunotherapy? We do not know the answer to that.

 

Dr Chapman-Davis: We do not know the answer to that, yes.

 

Dr Secord: However, I strongly believe in the clinical trial.

 

Dr Chapman-Davis: I think there is 1 quick question in the Q&A. I am not sure for which study. Whitney, I am not sure if that one was from you.

 

Dr Graybill: I am sorry, I cannot. I am having trouble here.

 

Dr Secord: Is that the question about whether you would go with the chemotherapy and immunotherapy or lenvatinib plus –

 

Dr Chapman-Davis: No, it is in the QA. It says, what is the additional info that we get from TTST time 2 and not PFS2?

 

Dr Secord: I see it. From a clinical point of view, I do not think it offers me too much. However, I think from a regulatory point of view, it is supportive.

 

Dr Chapman-Davis: I agree. I do not think clinically it really matters. It is just more to have another piece of information. I think the next question said, in a patient with oligometastatic disease presenting with adenopathy, but no evidence of the oligomets, should we prefer curative surgery and local treatments directed at the oligomets? Or would it be more appropriate to manage this case as metastatic disease and initiate IO plus chemotherapy, especially in consideration when you have tumor biology and prognostic expectations are favorable?

 

Dr Secord: Oh my gosh, so hard. Basically, just grossly enlarged lymph nodes on imaging. Oh, my gosh.

 

Dr Graybill: If it is oligometastatic, there is a lot of factors that go into it. Like, time since initial diagnosis and all those things. However, I tend to surgically resect and do local treatment.

 

Dr Secord: I would say if it is just an enlarged lymph node and it looks like it is something that is resectable, that is still my option, to go to surgery. However, time is changing. Who knows what the future will bring, especially if somebody has deficient MMR disease. Do you want an oncology surgeon? I am actually really worried about even saying that statement.

 

Dr Chapman-Davis: I think a lot of times we are still doing some surgery, if we can, small, because knowing that they probably will still occur and we will be using the IO and chemotherapy shortly thereafter, even if you give them another year.

 

Dr Secord: Great question. Very provocative. We had to take that into consideration for future debates. I hope we answered everyone's questions.

 

[01:43:58]

 

Ongoing Trials of Interest

 

This was great to continue to go over the new data that is coming out about all these different treatment options, the biomarkers, and drug therapy. I just think 1 of the most important things is ensuring that all of our patients have access to care and access to some of these exciting trials coming out. I see the table up there with some of these really exciting antibody-drug conjugates like SACI-G and SACI-T and ADAPTO drugs that hopefully will add on opportunities for us to help our patients live longer with recurrent disease. Maybe we can move some of these up to the frontline setting and impact cure rates.

 

Dr Graybill: I want to thank everybody for being here. We really enjoy doing this. We thank you for your participation. For CME credit, please complete the program evaluation. You will also have access to the slides that will all be under the Resource Center.

 

Dr Chapman-Davis: Thank you, again, for joining us.

 

Dr Secord: Bye, everyone. Happy Friday.

 

Dr Graybill: Happy Friday.

 

[END OF TRANSCRIPT]