This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Ursula A. Matulonis, MD: Hello. I'm Dr Ursula Matulonis. Welcome to season 2 of the Medscape InDiscussion Endometrial Cancer podcast series. I am honored to have as my guest Dr Gini Fleming, who is a professor of medicine at The University of Chicago and is the medical director of gynecologic oncology at The University of Chicago. Dr Fleming is an expert in advanced breast and gynecologic cancers, and she has authored and co-authored more than 200 articles for a variety of medical journals in addition to a number of textbook chapters. She is a pioneer in the field of gynecologic oncology. She also serves as an associate editor for the Journal of Clinical Oncology. Dr Fleming, welcome to the Medscape InDiscussion Endometrial Cancer Podcast.
Gini F. Fleming, MD: Thank you so much. I'm delighted to have been invited. As you know, talking about endometrial cancer is one of my favorite things.
Matulonis: As I mentioned, you are truly a pioneer in the field, and you are really doing so much seminal research. We're going to go back down memory lane a little bit, but also we are going to cover a number of different topics, including getting Dr Fleming's thoughts on the state of uterine cancer in the United States, the role of immunotherapy in endometrial cancer, and what her priorities are for research in this field, and we'll talk about what she sees as new and promising therapies for endometrial cancer.
My first question to you is that, as you know, the 2025 cancer statistics were just published in CA: A Cancer Journal for Clinicians. And once again, they indicate the emergent situation with endometrial cancer. Over 69,000 new cases are expected to be diagnosed in the United States this year, and the paper points out that the only cancer for which survival has decreased over the past four decades is uterine cancer. Uterine cancer is one of the few cancers that has increasing mortality, and it also has one of the largest Black-White mortality disparities. It's really amazing that year to year, the statistics for this cancer continue to worsen. What do you think about these statistics? And why do you think the stats are getting worse for this cancer year to year?
Fleming: That is the 6-million-dollar question. I think all of us had noticed for many years that every time we give the annual fellows talk on endometrial cancer, we had to update the slides for the numbers, which wasn't true for all the other cancer types because they were changing so fast. But what hit me like a lightning bolt was an article by Dr Clarke and colleagues in 2022, where they published an overview showing that adjustment for hysterectomy rates — and of course, hysterectomy rates in the United States have been decreasing and it's not possible to get endometrial cancer if you don't have a uterus — could produce an artifactual rise in endometrial cancer rates. But, when you adjust for hysterectomy rates, the mortality from the more common endometrioid endometrial cancer over the past years has been stable. The mortality from nonendometrioid cancers, such as carcinosarcoma and uterine serous carcinoma, as well as their incidence, has been steadily increasing year by year.
Both uterine serous carcinoma and carcinosarcoma are much more common in Black women than in White women. For example, if they get endometrial cancer, Black women have about a fourfold chance of getting uterine serous carcinoma compared with White women. This has also resulted in a rising increase in the disparities of outcomes from this disease because outcomes for women with uterine serous carcinoma and carcinosarcoma are so much worse than those for the more common low-grade disease.
Review articles, which raise my hackles constantly, are always citing that it's a rise in obesity that is the underlying cause of rising mortality rates from endometrial cancer. But this makes no sense to me. While all endometrial cancer is clearly somewhat obesity-related, low-grade endometrioid tumors are more related to obesity. One very good analysis noted that if you look at per 2 kg/m2 increase in body mass index, you have an odds ratio of 1.2 for low-grade endometrial cancer, but only 1.1 for the aggressive subtypes. So, if this were the cause, then we ought to be seeing a concomitant or greater rise in the low-grade endometrial cancers. This can't be the main cause of the rise in rates of death from endometrial cancer.
However, so far as I can find, any actual information on what contributes to the development of high-grade endometrial cancer is lacking.
I mention, and many people mention, that there is an increase in endometrial cancer in younger women, but this is general low-grade endometrioid endometrial cancer. It is probably obesity-related, but I don't think it's what's driving these mortality figures that are so alarming.
Matulonis: It really is remarkable — the number of endometrial serous cancer cases, carcinosarcoma. Certainly, when I started my career, these were really rare entities. And now, in our tumor boards, they're quite a common diagnosis. As you mentioned, just more aggressive and less treatment-sensitive, and I know we're going to talk more about treatments in a little bit.
I want to move to a hotter topic in endometrial cancer, and that's really around immunotherapy. You gave the invited discussant presentation at the Society of Gynecologic Oncology (SGO) meeting in 2024 on updated NRG GY-018 and the RUBY overall survival data. Of course, you did a really wonderful job. There was an overall survival trend toward benefit for the use of immunotherapy added to carboplatin-paclitaxel in both trials for patients with mismatch repair–proficient advanced endometrial cancer. But as you said, it was not as "dramatic" as seen in the mismatch repair–deficient advanced tumors, but that immune checkpoint therapy should be considered to be added to chemotherapy in the front line.
I think for mismatch repair–deficient disease, everyone agrees it is the right thing to do unless there's a huge contraindication, but for mismatch repair–proficient disease, we still grapple with this. Can you talk about predictive biomarkers to help you decide the use of checkpoint inhibitors in mismatch repair–proficient cancers? And then can you talk about the clinical situations of patients who have a mismatch repair–proficient cancer where you would consider recommending adding a checkpoint inhibitor to chemotherapy, or do you discuss it with all of your patients?
Fleming: I am not perfectly consistent on this topic. I think that you may well remember after I gave that talk at SGO, your colleague came up to me after the presentation and very passionately opined that I was not correct and that I said that I thought that the major reason that patients with mismatch repair–proficient disease had some benefit or that some patients had a benefit from immunotherapy was probably not the subgroup with high tumor mutational burden despite mismatch repair–proficient disease, and he said that he believed this was wrong. So, I did a little bit more homework after that and reviewed the publication of the GARNET trial. The older people in the audience will remember the GARNET trial as a test of single-agent dostarlimab in women with advanced or metastatic endometrial cancer. In this trial, they accrued 161 patients who had mismatch repair–proficient disease and had a response rate of 15%. They actually published an attempt to tease out what might have accounted for responses in this 15% of patients. They looked at patients with a high tumor mutational burden. Eleven of these 161 patients with mismatch repair–proficient disease had a high tumor mutational burden. And of those, five of 11 had a major response. So that is, in fact, fairly convincing. Now, this excluded the patients with POLE-mutant disease, although one of them was POLD mutant. There were five patients separately with a POLE mutation, and two of them responded.
I think that if you try to add up the numbers as I did on the back of an envelope, it doesn't account for all the responses that are seen, but certainly, patients who have a high tumor mutational burden, even if they have mismatch repair–proficient disease and do not have a POLE mutation should be among those treated with upfront immune checkpoint inhibitor therapy, as should patients with a POLE mutation.
I think that all patients should have next-generation testing at the time of development of metastatic disease if it wasn't done before in order to help with this determination. What I see being done in the community largely is testing for combined positive score — that is, for programmed death-ligand 1 (PD-L1) expression. In the GARNET trial, they also looked at this. They found that if the combined positive score was greater than 1 (which is the cutoff, say, in cervical cancer; it has not been shown to be prognostic in other endometrial cancer trials), then 22% of patients had a response. If it was lower than 1, it was 7%.
So maybe there's something there, and for a patient with low tumor mutational burden and a low combined positive score, I would really probably discourage them from getting treated, although I might discuss it with them. Whereas those who have a high tumor mutational burden or a POLE mutation should definitely get immune checkpoint inhibitor therapy.
Now, for the in-between cases, I'm really not consistent. Sometimes, I use it in a nonscientific way if I think I don't have much time to get to a second-line therapy and I want to get every chance of benefit. That is to say, the patient is not going to make it to second-line lenvatinib-pembrolizumab. I discuss it with most patients since it is approved by the US Food and Drug Administration (FDA). I just don't encourage it in everybody. If the patient very much wants it, then I'm certainly willing to prescribe it if there are no contraindications. But I have no qualms whatsoever about not giving it in most of these patients, particularly if they're eligible for a different trial, for example, NRG-GY026, testing adjuvant anti-human epidermal growth factor receptor 2 (HER2) therapy.
Matulonis: There are so many factors that go into our decision-making. I think time, studies, and datasets will help us eventually make better decisions about who to use checkpoint inhibitors in and who not to, but I totally agree with your thoughts. I just did a podcast with Panos Konstantinopoulos a few weeks ago within this series about hormonal therapies for advanced estrogen receptor (ER)–positive endometrial cancer. Not infrequently, we are faced with the patient who has an advanced ER-positive cancer, lower grade (maybe grade 1), mismatch repair–proficient, and, let's say, tumor mutational burden low. We have to make that decision between chemotherapy with or without immune checkpoint inhibitor. So that's one decision. Then sometimes, especially if they've got metastatic disease, we're thinking about hormonal therapy. Obviously if someone has stage III disease, without evidence of metastases, then consider chemotherapy. But if they've got lung metastases or nodal metastases and are asymptomatic, how do we think about these patients?
We've talked about this already. You mentioned that checkpoint inhibitor combined with chemotherapy is now FDA-approved for advanced endometrial cancer, regardless of mismatch repair status, and this makes us all feel obligated that we have to discuss checkpoint inhibitors, even in mismatch repair–proficient cancer. So my question to you is, what factors go into the decision to use a checkpoint inhibitor combined with chemotherapy for mismatch repair–proficient, advanced ER-positive endometrial cancer vs starting with hormonal therapy? If you do decide to eventually use a hormonal therapy before starting chemotherapy, how do you decide which hormonal therapy to use?
Fleming: I have no qualms whatsoever about starting with hormone therapy, perhaps because I also treat breast cancer and that is the standard pathway in breast cancer, and perhaps because when I started treating endometrial cancer, endocrine therapy was the first-line standard. Chemotherapy plus immune checkpoint inhibitor is not curative.
For patients who are not symptomatic from their disease and whom I believe may do well for a while in endocrine therapy, I will generally start with endocrine therapy. I'm fairly old-style about how I decide who to start at endocrine therapy. That is to say, if the tumor is strongly ER/progesterone receptor (PR) positive, I consider that a better candidate than someone who has, say, a weakly ER-positive, PR-negative tumor; patients who don't have any symptoms; or patients with grade 1 or 2 endometrioid histology who have not progressed rapidly after adjuvant therapy. These are the general candidates. I think that prior endocrine therapy does not decrease the response to subsequent chemotherapy. Indeed, many of our current chemotherapy trials allowed prior endocrine therapy. I'm not so sure that the converse is true, in that I suspect that chemotherapy will decrease the response to endocrine therapy, perhaps causing the tumors to mutate more. I'm not sure. In any case, I use this fairly frequently.
If there's no trial available (and I look for a trial to put these patients on), I tend to use alternating progestin and estrogen. I don't have strong feelings about which regimen, but I do not use much single-agent aromatase inhibitors. In the single-agent trials, single-agent aromatase inhibitors have had the lowest response rates of any endocrine therapy. That being said, these are small trials that are conducted across many years, and I don't know that the data are very convincing one way or the other.
As you know, there are now three trials published showing reasonable response rates to endocrine therapy plus a cyclin-dependent kinase (CDK) 4/6 inhibitor. And because again, I treat a lot of breast cancer, I use this combination quite a lot. If I can get insurance to cover it, I will use that combination, but that's not always easy. I do occasionally use everolimus-letrozole, but my patients tend to have a high incidence of diabetes, making that sometimes a tricky regimen to use.
Matulonis: I agree on the everolimus-letrozole. I worry about its lung toxicity, and it's not easy. Especially, obviously, with the hyperglycemia.
I want to shift gears a little bit to hear your thoughts about future directions. There was a published report in December 2024 from the National Academies of Sciences, Engineering, and Medicine that talked about women's health funding and the National Institutes of Health here in the United States. The report really bemoaned the lack of funding for women's health and definitely called for increased funding for endometrial cancer. This cancer now receives about $15 million per year, which is far less than breast, ovarian, and even cervical cancer. I want to understand what you view as research priorities for endometrial cancer moving forward.
Fleming: It's an exciting time for endometrial cancer, and there are lots and lots of interesting directions, but as we discussed already, I think unless we address and research the causes of high-grade uterine cancers such as carcinosarcoma and serous carcinomas and the treatment of these cancers, I don't think we're going to address either the rise in deaths from this disease or the increasing racial disparities from this disease. So, I would have to say those would be my national research priorities. Not, however, that there aren't many other interesting directions.
Matulonis: I agree with you on that one. Tell us what you're most excited about regarding new or emerging treatments.
Fleming: I think for all of us, the DESTINY trial results, when they were reported, made one of the happiest days in a long time. For women with 3+ levels of HER2 in their tumor by immunohistochemistry, trastuzumab deruxtecan, the drug studied in the DESTINY trial, produced an 85% response rate, with prolonged time to progression. In those with 2+ HER2 expression, there was a 47% response rate. The drug is now FDA-approved for any tumor type with 3+ expression by immunohistochemistry. And the DESTINY trial is ongoing to accrue more data for women with lower levels of HER2 expression.
As you know, it's approved for patients with levels of 1+ or 2+ in breast cancer. I've seen dramatic results in patients with 1+ levels in that disease. I would like to eventually see this moved adjuvantly for patients with high-risk disease — that's 3+ positive — despite the risk for pneumonitis. I think that it will increase the cure rates.
We need, of course, to await the results of the adjuvant trials of naked anti-HER2 antibodies in endometrial cancer, but having personally run studies of naked antibodies and endometrial cancer with zero response rate in multiple patients with 3+ immunohistochemistry results, I'm not so confident that those are going to be positive trials.
So that's one area that, again, is not the majority of patients, but it is a reasonable percentage of patients with serous carcinoma, which I think is a priority for us. There are other antibody-drug conjugates, potentially TROP2-directed agents, that are showing promise in endometrial cancer as well. I'm looking forward to larger trials with these agents.
There is also, I think, still the unanswered question about adjuvant bevacizumab or frontline bevacizumab in endometrial cancer. It's an old study, but in GOG-86P, patients were randomized to get bevacizumab or temsirolimus added to frontline chemotherapy. The patients who had p53-mutated disease had a hazard ratio of 0.61 in terms of benefit for the use of bevacizumab, whereas there was no benefit in patients who had p53 wild-type tumors.
I believe that NRG has an upcoming trial that will be comparing immune checkpoint inhibitor therapy vs bevacizumab added to chemotherapy frontline in patients with p53 mutant disease, and I think that should be a very worthwhile trial. There is still an ongoing trial of prexasertib as maintenance after frontline chemotherapy for patients with endometrial cancer, again in the p53 wild-type group.
There are many issues in the treatment of patients who have mismatch repair deficiency. Not all of them are cured with immunotherapy, and if they progress on their frontline checkpoint inhibitor therapy, what's the next best step? Should they just go on to lenvatinib-pembrolizumab? Should they get more aggressive immunotherapy such as ipilimumab, nivolumab, a CTLA-4 inhibitor combination, or another combination?
What should the frontline therapy for mismatch repair–deficient disease be? There are still ongoing trials testing single-agent immunotherapy vs chemotherapy, and those results may inform our practice. And there's an ongoing trial in the NRG, GY-25, evaluating ipilimumab-nivolumab vs single-agent nivolumab that I think is well worth accruing to. So there are a lot of promising directions. I think after many years of having none or one approved drug for endometrial cancer, things are finally moving in the right direction.
Matulonis: Yes. There's a lot of exciting avenues, but also, as you pointed out, lots of work to do and lots of trials to run.
I'm going to finish up by asking you if you'd like to talk about any endometrial cancer research that you and your team at The University of Chicago are working on right now.
Fleming: The one thing I'd like to comment on would be in a very preliminary area of working on, but the microbiome is sort of a wide open new Wild West area to me. There are fascinating findings with the microbiome. Numerous researchers are here at The University of Chicago, including one microbiome/immunotherapy scientist who has mouse models, and he's identified which bacteria promote antitumor responses to immune checkpoint inhibitor therapy in these mice. By changing the bacteria in their gut, he can make the tumors resistant or sensitive, and he's working on the mechanisms of this. As you know, there have been very intriguing reports of transplants of fecal specimens from responding patients to improve the efficacy of anti–PD1 therapy in patients with melanoma.
I think that relevant models in endometrial cancer would be very exciting. And this is, again, an area that I think is in its infancy. But immunotherapy, unlike antibody-drug conjugate therapy or chemotherapy, can be curative. I think that improving immunotherapy results is one way that we can definitely decrease the mortality of advanced disease.
Matulonis: That sounds really interesting, especially the microbiome, which sounds really cool. Gini, I want to thank you so much for being here today. It's been a real pleasure and honor.
Today we talked to Dr Fleming about the state of uterine cancer in the United States; the role of immunotherapy in endometrial cancer, specifically mismatch repair–proficient cancers, and her priorities for research in this area; and her thoughts on new and promising therapies for endometrial cancer. Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on endometrial cancer. This is Dr Ursula Matulonis for the Medscape InDiscussion Endometrial Cancer Podcast.
Listen to additional seasons of this podcast.
Resources
A New Vision for Women's Health Research: Transformative Change at the National Institutes of Health
Antibody-Drug Conjugates as Targeted Therapy for Treating Gynecologic Cancers: Update 2025
Medscape © 2025 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Endometrial Cancer Trends: Immunotherapy Insights and Research Priorities - Medscape - Apr 10, 2025.
Comments