Hi, my name is Dr. Brian Slomovitz. I'm the Director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida. And I really had the great fortune to serve as the moderator for this industry sponsored symposium. I'm really thrilled to join you today to share the first installment of personalized management of advanced or recurrent endometrial cancers. In this center, we learned how to navigate PMMR, DMMR subtypes or molecular classifications. This industry sponsored symposium was presented at the IGCS in 2024. A really great meeting where we got to see our colleagues and our friends and to learn a lot. This was in Dublin, Ireland. This first segment, Dr. John Chan will be discussing PMMR or proficient mismatch repair protein versus DMMR or deficient mismatch for protein. Two of the most important, obviously, molecular subclassifications of endometrial cancer and how they come into play for the management of both first line and recurrent disease. Thanks so much, Brian, for having us. I have about 20 minutes. I wanna cover something that we're passionate about. We're talking about how uterine cancer has become the new princess. Unlike ovarian cancer, now uterine cancer is getting a lot of attention that we are working with in gynecologic cancer. I'm gonna start off by talking about why this has become such a big problem, particularly not just globally, but also in United States and also discuss some of the disparities that have been observed throughout the 20 years and 30 years of our experience working with this cancer. So our objectives are here. I'm gonna try to differentiate difference between how our group practices with respects to using these different biomarkers, with respects to DMMR and PMMR, how we select for different immuno checkpoint inhibitors, try to understand how to apply some of these findings, not just at looking at the upfront treatment, but also in the recurrent setting. How does this affect the treatment journey of this patient when the patients relapse based on what you chose in the upfront treatment paradigm? And then I'm gonna look at some of the real world case scenarios and also discuss some of the disparities associated with this. Clearly, this problem is not just a problem within the United States, it's in many of the westernized countries, but in the US, the scope of problems here. It is clearly now the most common and most lethal gynecologic cancer. Ovarian cancer, as of 2024, has become the second most lethal gynecologic cancer that we deal with. When I was in training, and Brian and I started training near the same time, actually, I was introduced by somebody one time, and he said that Dr. Chan trained in the 1900s. Really made me feel old, but it's true. We did graduate in medical school, probably in the late 1900s. But when we were learning in medical school in the United States, the number of new cases of uterine cancer was about 30,000. Look at this slide today. It has now doubled. Nearly 70,000 new cases in the United States. But what's worse is the number of patients that die every year from uterine cancer. It was about 3,000, now it's almost near 14,000. This is not happening in ovarian cancer and in cervical cancer. This is specifically for uterine cancer. It is currently the fourth most common cancer in women, but maybe in five years, we will actually take over colon cancer as one of the top three cancers in the United States. Clearly, there's increasing number of new cases and deaths per year. Is there a disparity? Are we seeing differences in race? Since this is an international meeting, we've done a lot of work looking at not just the African Americans, but also subgroups of Hispanics and subgroups of Asians within the United States. And this is based on a lot of our United States cancer registry data. We're able to show that in the last 50 years, who are the patients who died from this cancer? And you can see clearly, even in beginning of the 50 years, African American or black women are much more likely to die from uterine cancer in the United States. And that, over the next 50 years, has been increasing, as you can see from this slide. And the highest increase is in the Hispanic, in the non-Hispanic black, and the largest increase in mortality is actually in the younger black and Hispanic women that reside in the United States. We try to look at why. Is it all about obesity? Is it all, many people say, of all the cancers that are related to obesity, uterine cancer is actually maybe 60, 70% attributed to social determinants of health, such as obesity. So we looked at this line here. You can see the line is the obesity. And then we looked at the type one, which is the blue bars, and then the type two cancers. This is based on the old paradigm of type one, type two, which we still have in textbooks in the United States about this type one, type two paradigm. And then the 0% is over time, how much has increased with respects to the blue, which is the type one, and the red, which is type two. So you're seeing significantly more the aggressive histologies. But nonetheless, this classification may be outdated. Let's look some more in terms of some of the details that we have in terms of the cancer statistics data that we have. On the top, we broke it up for you with respects to serous cancers. On the left corner is the white patients. On the right corner is the black patients. Look at that increase over the last 20 years. In the black women, the patients that have serous cancers have significantly increased, even up to four-fold increase in these high-risk subtypes, particularly the serous papillary cancers and the carcinosarcomas, compared to the white women on the left. In endometrioid cancers, you don't see that much of a rise in endometrial cancers in the black. In fact, there's more endometrioid uterine cancers in white women compared to black women in the United States. Then we started looking at differences with respects to the molecular markers. And this is the prevalence of markers in endometrial cancers adjusted by race. And you can see the bars on the top shows the African-American women's. They actually have a lot more TP53 cancers. Similar in terms of MMR mutations. But if you look at the bottom graph there, you can see those are tumors adjusted based on cell type. So the African-Americans are getting more serous cancers, and these serous cancers clearly have much more P53 mutations, even after you adjust for the cell types of endometrioid and also the cell types of papillary serous cancers. All right, so now we're moving into the molecular world, from epidemiology to looking at the type one, type two, this really crude classification of uterine cancer. And now let's look at the molecular world. You can see the top two cancers, these are about half of cancers. They're either POE or MSI hypermutated. These are the hot tumors. And Professor Vogelstein from Hopkins University basically wrote a very nice paper when he actually categorized different tumors based on environmental damage. For example, uterine cancer may be damaged by social determinants of health and obesity, cervical cancer by human papillomavirus. These are hot tumors, because they're environmentally induced tumors. Then the immune checkpoint inhibitors work. Cold tumors like ovarian cancer, when there's not much of environmental influence, those tumors may not respond as well. They don't have higher mutation burdens, more neoantigens, therefore checkpoint inhibitors and immunotherapy doesn't work well in ovarian cancer. But you can see how these are the differences between the hot and cold tumors. And the TCGA, in addition to PROMIS, looking at the GOG210 data, and also looking at the PORTEC3 data, basically did this molecular classification that maybe the PORTEs, the MSIs, we can treat less, and the other copy number high tumors, these are the patients that potentially need additional treatment or adjuvant therapy. And this is the PROMIS that we showed you, basically doing very similar thing, taking another data set and basically replicating what the TCGA showed, looking at which patients that we need to treat less and which patients we treat more. Like I said, the PORTEC data also show very similar characterization, classification, showing the difference in prognosis. In terms of PORTEC, they even looked at abnormalities in P53, and maybe some tumors, like the abnormal P53 tumors clearly deserve more chemotherapy and systemic treatment associated with this. GOG210, in our own NRG cooperative group, we also show very similar findings. So you can see, based on four or five different tumor banks, we're able to look at these different characterizations and potentially further define how we can treat these patients with uterine cancer. In addition to that, HER2 has also been shown, based on Dr. Fader's trial from Hopkins, that potentially these are also patients that can benefit from some targeted therapy with respects to HER2. Now, the next two slides I'm gonna show you talks about how the NCCN guideline, as of 2024, has classified these tumors. They say, first, do the PORTEC sequencing, then you do the MMR classification, and then subsequently break that P53 immunohistochemistry down in terms of defining the P53 aberrant or the NSMP group. Similarly, the ESMO did this clinical practice guideline. Dr. LaRusso was involved in it. I actually like this a little better than ours. It's much more neater and organized. So I applaud the Europeans for doing that. But please don't tell that to my American colleagues. I won't have a very promising career in ASCO or SGO. All right, but the SGO did do something really nice. They looked at the different markers, and Dr. Christine Walsh published this no more than a year ago, looking at the different FDA-approved biomarkers on the left side here, the DMMR-MSI and the TMB-HI, looking at markers that are potentially predictive, such as the P53 HER2, in terms of predictive responsive to maybe Avastin, if you have P53, Herceptin, or in HER2, if you have HER2 marker, or estrogen blockers like Tamoxifen, Magase, if you have ERPR tumors. And then there's a smattering of these other prognostic and also exploratory markers that you can use. But how do we apply these markers in terms of upfront treatment of ovarian cancer, which is what I'll cover in the next five minutes? All right, in uterine cancer, over the last three years, there's just been a huge paradigm shift. The first paradigm shift is this introduction of this tyrosine kinase inhibitor, Limbatinib, with Pembrolizumab. And that occurred about four or five years ago in 2021. In 2023, this moved from using immune checkpoint and TKIs in the recurrent setting to the upfront setting, where we actually approved two drugs based on the RUBY trial, which is the Starlimab. And then in 2024, this broke open more. We now can use Pembrolizumab in all comers, whether you're DMMR or MMRP. In the RUBY trial, they also opened up to all comer label. And DOE trial was also approved in United States for the DMMR. But in Europe, you guys had it approved now for both to use the Laparib and Dorvalimab in combination as of two months ago here. So we put this together and published this in GYN Oncology, looking at how we can select out these different trials and how do we determine which treatment option may be preferred in patients who have advanced or recurrent endometrial cancer. So we put these four trials together in a table and we try to look at differences. And I highlighted some of these differences with looking at the red mark here. And you can see, with respects to GY018, which is the third column there, it's only two years of maintenance, whereas RUBY is three years and DOE is treatment until progression or maintenance until progression. There's little slight differences in terms of the proportion of patients with stage three, stage four versus recurrent disease. But it's clear that the RUBY trial included the more difficult-to-treat aggressive histology of carcinosarcomas, as did the DOE trial, but this was not included in the GY018 trial. Furthermore, you can see that the RUBY trial included patients who actually had recurrence within six to 12 months, whereas GY018 and DOE only looked at patients who had more sensitive tumor, possibly, with over 12 months of treatment. I know it's not right to put these trials together, but we have what we have, right? You get what you get, and don't be upset. This is what my son's grade school teacher told him once. So we're never gonna have a prospective trial that's gonna compare all four drugs together. But this is what we have, and don't be upset, but we're gonna put this together like you all do anyways at night, right? Looking at, on the left, the RUBY trial, it's clear that if you have the DMMR, those patients got from seven to 30 months with mature data with a HAZ ratio of 0.29. So is that the group that we should consider, DMMR, looking at the STARLIMAP? Well, if you look at the GY018 trial with PEMBRO, over 800 patients, they, in the PMMR group, look at the box that I put there in the middle for you, they improved the progression-free survival from eight to 13 months, about a four-months difference with a HAZ ratio of 0.54. And then the DUOE trial also did the similar thing. So is this how, potentially, one can look at the differences between these two trials? Clearly, other people I've talked to during this meeting, I go, how do you differentiate between PEMBRO? They said it's like Coke and Pepsi. There's no difference. But I believe a bunch of patients in this room here like Coke better versus Pepsi. So maybe this is how you select out the difference between Sprite and 7-Up or Coke and Pepsi. I don't know what DUOE is, because in Europe, you guys can use it in combination. So maybe that's like an Irish coffee, right, with whiskey and coffee put together with PARP and ICI. All right, so then I put this chart together, and we published this and got on commentary. We have the citation down there. DMMR, if you're endometrioid, the Starlamab, especially when they treated patients who had over six months. PEMBRO clearly is another one that you can use. For carcino-sarcoma, maybe those patients can use the Starlamab. And when the patients recur, what do we do? Of course, we're in a research meeting. Clinical trial's number one. But if they have a DMMR, you can repurpose some of these drugs. Potentially, you can reuse immune checkpoint inhibitor, PEMBRO or the Starlamab, or chemotherapy. What about in the PMMR setting? Then your options open up a little bit more, right? Because if you're in the PMMR setting with a progression-free survival of four or five months based on that group in the GY018, I put GY018 there. But you can also choose to use the Starlamab, right? Particularly in patients who have a HER2-negative carcino-sarcoma. If you have a serous cancer with a HER2-positive disease, then maybe those patients can get enrolled in a trial looking at addition of a HER2 blocker. Other histologies with P53 mutation, you can consider Bevacizumab with chemotherapy based on these two trials that we listed there, 86P and GOG209. And when the patients recur, right, with a PMMR setting, currently the standard of care is to use the combination of the checkpoint inhibitor with TKI-limbatinib, and that's PEMBRO-limvima over there. All right, to differentiate between the two and to look at personalized strategies, I think this is what we ultimately are able to review. In the last minute, I just wanna cover what else do we think about when we think about recurrence and looking at these patients in this setting. Well, I think first is discuss potential clinical trials. We have very exciting trials looking at these different markers from RAINBOW trial to other studies looking at the XPO inhibitor even against wild-type P53. And then we talk about the potential biomarkers. When you look at these patients in the recurrent setting, you look at if they're DMMR or they're MMRP. If MMRP, you can use the PEMBRO-limvima combination. Wait, but can we also repurpose some of these drugs? We reuse bevacizumab in GOG218 and GOG213, but can we also use some of these checkpoint inhibitors and repurpose them? How do we decide that? Well, we look at the past history of the patient, right? If they had a long maintenance, they had a long remission, treatment-free interval, would you restart again? Would you redo the chemotherapy and immune checkpoint? Or would you do a different checkpoint inhibitor? Does checkpoint after checkpoint, PD-L1, CTLA-4, PD-L1 with another PD-L1, does that something that we can offer the patients? And then last thing I think is proficiency, right? How comfortable are we with these drugs? And moreover, I think it's also pathways. Does your hospital cover this? Does their insurance cover this in the United States? All these things are possibly things that we can consider for the patients in that recurrent setting. I am done. Any questions? We'll take questions. Thank you. Thanks, John. Yeah, one question, please. Just one question. David Rader from Melbourne. The P53 group, they're considered as one group, yet we know what an interesting and peculiar molecule that is. And there's loss of function, of tumor suppressor function. There's also gain of oncology of oncogenic function. Have we teased that out in relation to the different mutations? Because they may respond very differently to treatment. Yes, I totally agree. I think P53 abnormal, we kind of put that in one category. But there's clearly a lot of differences within that P53 subset. We do have the trial open, the XPO trial, that looks at wild-type P53. And the patients who have P53 mutation, I think clearly there's a lot of opportunities for more research and more novel agents to be investigated.

endometrial cancer

molecular subclassifications

treatment strategies

disparities

immunotherapies

biomarkers