Hi, good afternoon and welcome to our noontime symposium. I'm very happy to be joined by Dr. Herzog and Dr. Richardson. We're going to walk you through this afternoon in about an hour and a half learning the ABCs, a different type of ABCs. We're going to be talking a little bit about advancements in biomarker-driven care for gynecological malignancies. Now, I am the moderator. My name is Susanna Campos. I'm a medical oncologist at Dana-Farber Cancer Institute. So I'm going to walk you through what we hope to achieve today in an hour, an hour and a half. We do have a bit of a task. We're going to review basically what we've learned. We're going to talk about major milestones in biomarker-driven management of both endometrial cancer as well as ovarian cancer. We're then going to transition to applying our knowledge. We're going to talk about current opinions for biomarker-directed therapy. And then we'll walk back into what we've learned but actually talk about future developments and actually what are the next steps towards challenging, you know, the current treatment landscape. So, and then we're going to do a whole bunch of questions and answers both from the panel and I hope from the audience. So we are looking forward to having, you know, very good audience participation. So as I mentioned, my name is Susanna Campos. I'm the moderator from Dana-Farber. I'm joined gratefully by, with Thomas Herzog from the University of Cincinnati Medical Center as well as Deborah Richardson from the University of Oklahoma. So welcome. So these are our conflicts of interest. And so let's talk a little bit about symposium objectives. Our job for the next hour, an hour and a half is to discuss advances in biomarker-driven management of patients with both ovarian and endometrial cancer. We're going to discuss how the currently actionable biomarkers impact treatment selection for these diseases. And most importantly, we're going to talk about the, what are the likely molecular biomarkers that could alter the current treatment landscape and usher in new standards of care. Now we can start by talking about precision medicine. And I think all of us probably would agree that is a term that is, you know, commonly used. But what exactly does that mean? Does that mean the right drug for the right patient at the right time? I suppose. But I hope what you will see through this symposium is that precision medicine is just not simply one element, but it's a constellation of many factors, including some of the biomarkers that we will discuss, combinations of biomarkers, and of course, most importantly, the host. What we are cognizant of is the statistics of ovarian cancer. And in this particular slide, I think I shared this with you, but I believe that we all are very much aware of this. If you look at the estimated number of new cases in the United States, it's about 20,000. And the estimated number of deaths in the United States in 2022, about 13,000. So that remains a very sobering statistic. And when we go back and reflect on what's happened in the last several decades, well, we know that there's been no improvement in progression-free survival, which is standard therapy, platinum and paclitaxel. We know that the addition of bevacizumab did not improve overall survival, albeit that it did improve progression-free survival. And what we know, that still, all patients are treated in a very similar fashion, regardless of different histologies, and often without biological markers. But this did change in 2005, and that's when the PARF inhibitors actually entered clinical trials for patients that were BRCA mutation ovarian cancer. Now, as a clinician for, I'd like to say, two decades now, I think we've learned very much the hard way, and we know that ovarian cancer is histologically heterogeneous. We've seen this not only in the literature, we've seen this in our patient population. Patients don't always respond the same way. But I think what's been very exciting in the last decade is now we're starting to understand the heterogeneity, but in terms of the molecular genomic aberrations. We know that the histological subtypes impact prognosis. We know that there's been several key molecular aberrations that have been defined, most notably the BRCA1, BRCA2. We know that deficiencies in homologous recombination are common. We know that there's a high genomic instability and a low immunogenicity, which can contribute to tumor genesis. So where are we today? Well, in essence, the BRCA mutations did open the door to biomarker-directed therapy, and this is just a nice little timeline of what we've been doing the last couple of decades. The PARF inhibitors have come into our world in the early 2000s. In 2012, PARFs became very important in platinum-sensitive recurrent ovarian cancer, and they are currently incredibly important and very monumental as maintenance therapy at post-induction therapy. And you've all heard of our presentations, not only presentations here, but also recent presentations at ESMO in Paris. So in a likewise fashion, and also quite sobering, endometrial cancer. And if one takes a look at the statistics of endometrial cancer, there's about 65,000 new cases in the United States with a projected about 13,000 deaths. The common issue here is that this is the only gynecological cancer that has a rising incidence and mortality. And as you can see from here, endometrial cancer, over a course of 10 years, there's been a delta change of 19% compared to ovarian cancer and compared to cervical cancer. So where are we going with endometrial cancer? It's equally as exciting when compared to ovarian cancer. And what we know, and we've known this clinically because we've done this for a while, is that endometrial cancers are not the same, and that there are current and emerging endometrial cancer prognostic biomarkers. Histologically, these are different cancers, endometriosis, clear cell carcinoma. But it's almost been a decade now since the TCGA data, where we reclassified endometrial cancer and we're looking through a completely different lens. We're looking through a molecular lens, namely the pole mutations, the mismatch repair deficient, the MSS group, copy number low, and, of course, the copy number high. There are also clinical prognostic biomarkers, such as age and comorbidities. So with that in mind, I think we have some challenges in the next 10 to 20 minutes. And I'm going to introduce Dr. Herzog, who's going to take us into what have we learned in the past several years. So please welcome Dr. Herzog. I feel so far away from everyone, so this is the group that is over by the podium, so thank you for walking the extra bit. Appreciate it. All right. So the question is, what have we learned? We've learned quite a bit. So what are the major milestones that are driving management in endometrial cancer and ovarian cancer? That's really what I'm here to talk about today as we look at what the biomarkers that have been developed. And developing biomarkers, by the way, is no easy task for those of you that have been involved in that. It's quite complex, much more complex than what I think a lot of people appreciate. So this is looking at where we are right now in terms of the evolution biomarker-led care. And on the top you see the ovarian discoveries, if you will, and then on the bottom you can see the uterine discoveries. And it gives you somewhat of a timeline, and for the sake of time I'm not going to go through all those, but CA-125 discovered all the way back in 1985 for ovarian cancer, and then you start getting up into BRCA mutation in 1994 that was reported, and then you start seeing some changes in, you know, uterine cancer, which I guess if you took the timeline back to 1983, that's when we did our type 1 and type 2 endometrial cancer, a long-time board questions, right? Then we went to the dualistic classification, and then finally the modern molecular classification that we now use. So a lot of things, as you can also see, the acceleration of discovery has increased as well as you move to the right. So it's exciting to see that we have a lot more landmark points on the scale than what we used to have for either of those two diseases. So very encouraging in terms of looking at the rate of discovery. Just looking at the new targets there, we could have gone on for probably a ten-minute talk just on that. So let's look a little bit about ovarian cancer, and I think most of this audience is very familiar with the outcomes of the Cancer Genome Atlas Project that was launched in 2005, and this really was to look at and try to gain a comprehensive understanding of genomic alterations that underlie most of our major disease-site cancers, and what was really key about this is they did have some treatment data on this, but most of these patients were untreated that are in the data set, and you can see here survival analysis of BRCA1 and 2 patients, and one thing that became very clear is that this was a prognostic biomarker from the get-go in terms of predicting how patients would do in terms of being treated even with chemotherapy or any DNA-damaging drug. We know that up to about a quarter of our patients harbor either BRCA1 or BRCA2 mutation if we add up our germline and our somatic mutations together, and you can see that here in terms of the origins of the mutation, so I think most people are very familiar with that. My second bullet point there is tumor testing picks up additional cases, which is true anywhere between 7 and 9 percent. The important thing, though, to remember is if you're testing the tumor and it's positive, you still need to go back and sort out if it's a germline mutation or a somatic mutation to allow cascade testing and everything else that needs to occur with that, because it's a lost opportunity to actually save lives in the patient's family, so it's extremely important. So this is the first biomarker-led therapy for ovarian cancer with treating with a PARP, and you can see the difference there in outcomes between PARP versus chemotherapy, and the key really here is that you see hazard ratios unlike what we've ever seen before, so hazard ratio here was 0.3. We've seen hazard ratios as low as 0.19. I mean, it's really remarkable what we've been able to see with PARP inhibitors, and I think that sometimes is lost on people. I unfortunately grew up in the age of anything under 0.8 was a win, so to start seeing these numbers of 0.5, 0.43, 0.3, 0.19, it's an aha moment. What about endometrial cancer? So quite a bit has gone on in this area. We used to consider this as a monolithic disease, and just like ovarian cancer, we're splitting it out into different types based on histology, but more so now molecular phenotype or genotype, rather, and we went through the type 1, type 2, and then the sort of separating out, if you will, the histologies as we went through this, pulling out the serous first, understanding that that was distinct, but also clear cell and carcinoma, sarcoma, and certainly starting to then understand for the more common cancers, the endometrioid, what were some of the biomarkers that were associated with this, and what would that pattern look like, and so we got a much better understanding, especially with, for example, PI3 kinase AKT pathway in which the mutations are fairly prevalent with up to almost half of the patients having P10 mutations or loss, and so we see a number of very interesting ways of being able to interdict therapeutically, and so this was our early exposure, for example, to mTOR inhibitors and so forth, being able to use a different class of therapies that would actually go after a specific pathway. What we found out, unfortunately, is that these pathways are very complex and that there are workarounds and so forth, so there's other means that we would need to inhibit to probably have the clinical outcome that's desired, but we're learning more and more about this, and again, biomarkers are really leading the way for us understanding this. Well, that gets us then to really where we are with the TCGA classification that we use with the four distinct types, so POLE, unfortunately, a small percentage of our cancers because they have the very best prognosis. You can see there on the right, the top light blue line, remarkable in terms of what we see there, and I think, Matt Powell, you made a pretty good point at ASCO of do we need to even really think about de-escalating therapy with these patients, and I think that there's a lot of data that gives pause to treating these patients aggressively and giving them toxicity when we're looking at these outcomes. We probably need to learn a little more about different subtypes of POLEs and so forth, however, that certainly makes a lot of sense, and then we have the MSI hypermutated, and we have traditionally treated them with chemotherapy, and they have done okay, but it's a treatment that's okay, but it's not great, and it may be that IOs are the way to go, and with this group, whether that is to supplement chemo and or replace chemo, and we have trials underway to look at that, and then we have the most prevalent group, the endometrioid copied number low. It doesn't have a great response to chemotherapy either. Hormonal therapy is an area that's being investigated as well as a lot of other different therapeutics right now, so there's a lot of development in this area as well, and then we look at the serous subtype, which has the worst prognosis because, again, we've been treating it with chemotherapy, trying to basically say, well, it's just like a serous ovarian cancer when it's not, and we do know that HER2, for example, is something that we need to strongly look at in that group, so this is a comparison here that looks at the different, again, molecular subtypes, the four molecular subtypes, and then looks at mutational frequency, and, of course, you can see the difference between Pol E, for example, versus the copy number low, which is the third one over there, so less than 10 mutations per megabyte for copy number low versus greater than 100 for Pol E, so you can see the difference there, and you can see some of the most common genes that are mutated with each of those, and obviously with P53, copy number high, you're looking at almost 90 to virtually 100% depending on what database you look at. You can see some of the associated clinical and histologic features and how you test for those as well, so quite a bit of work's been done in this area since this data's come out, and it has changed clinical trial design, and it's made a big difference in terms of our therapeutic approaches by these subgroups, so very important that we're able to understand what the molecular classification is, and so what's been traditionally done is the PROMIS tool, where you sequentially test, looking at MMR initially, then looking at Pol E, and then looking at P53, some done by next-generation sequencing, and others done with IHC, and so when you look at this, it's been the traditional approach. What I think's been exciting is even this morning, we saw a presentation from Canada that looked at what they call PROMIS 2, where it was actually a single-step DNA sequencing, and they saw high concordance rates with the IHC. Obviously, in some of the subsets, some small numbers, and so it certainly needs more in the way of validation, but I think we're very close to being able to do much of this in a single step, which will obviously be helpful and make the information available quicker for the patient and for the treating physician. In sequencing 2, they looked at even endometrial biopsy in correlation with hysterectomy specimen, and the correlation was very high, so you could probably get this going even earlier in some cases where there's adequate tumor. In terms of sequencing, lots of companies out there that are able to provide these services. These are the big ones, if you will, that are able to do that, and you can see the number of genes and the tissue type that they're using and what they are able to do in terms of figuring out if you have HRD or microsatellite instability, tumor mutational burden, and, of course, PD-L1 staining. Lots of great things ahead in terms of molecular-driven therapeutics that are coming out for both ovarian and endometrial cancer, and it really is an exciting time. Susanna, I think we go to a panel, right? Yes, absolutely. So we have a couple of good questions, and I'm hoping that perhaps individuals might also have questions so that we can all address them collectively. But just to start off, thank you very much. That was an excellent review. I'm going to start off with you, Tom, since you gave the lecture. How is understanding around biomarkers, how do you think that's actually improved our care for women with the ovarian cancer and endometrial cancer? Well, I mean, I think that it's really, you look at the new standards of care in terms of frontline maintenance for ovarian cancer, for example, and some of the trials that are out now that are practice-changing. If you look at second-line endometrial cancer treatment, all these have been based on biomarkers, and I think that we're going to continue to see that with the trials that are out there. In other words, if you look at stratification factors and even inclusion and exclusion criteria, they're really based around biomarkers now which was unheard of, you know, 15, 10 years ago. Great, yeah. Dr. Richeson? So, around the biomarkers. Biomarkers, please. Yeah, I mean, I would agree with what Dr. Herzog said. I think it's very important. You know, I don't think that we germline test everybody that we should be testing because every patient with ovarian cancer deserves a test to see if they have BRCA mutation or not, and also other genes that are important both for their care but also for their family for the cascade testing that Dr. Herzog had mentioned, so I just want to emphasize that. But then, you know, for tumor testing, we're picking up at least another 7% of patients who are BRCA somatic mutation, and as far as the data shows, they do just as well with PARP inhibitor maintenance as patients who have germline mutations, and so we really need to offer them that care, especially after we just saw the updated data from ESMO showing potential, I hate to say it, but maybe cure in some of our BRCA patients, and that could extend to our tumor mutations as well. And obviously, HRD also really important in identifying those up front. Yeah, I completely agree. I mean, I think about this as my clinical patients. I have patients that I've treated over the course of years and who've treated for upfront with induction chemotherapy. They relapsed, one particular patient relapsed almost six years after we treated her again. She had a shorter disease-free interval. We treated her again. She was platinum sensitive. She's out four and a half years on a part, and that goes against everything. And when you see that, you realize what a monumental difference this has made for us. In the endometrial cancer arena, I think, you know, it is, it's important. We have deficiency in MMR. We have MSS stable. We have clinical trials now that have shown us pretty amazing responses from immunotherapy or immunotherapy plus combinations of VEGF. I think I'm excited. I'm gonna talk a little bit about this, about some of our future trials in terms of how do we bring immunotherapy earlier into the equation? Do we really need chemotherapy? Do we need radiation therapy? I think these are gonna be incredibly important questions, and there are some studies that are actually starting to address this, so it's actually quite exciting. It really has changed things for women with both endometrial cancer and ovarian cancer. Next question is, and I'll start with this one because I just gave this whole lecture to our fellows on this one, okay? What are the limitations of the TCGA data? We quote, and there are, of course, TCGA data, 2013, it really revolutionized the way we think about endometrial cancer, but we have to remind ourselves that it was actually small. It was only 307 endometrioid patients, and there were some few serous, but there were no clear cells, and there were no carcino-sarcoma, so in terms of the TCGA, what I think some of the limitations are is I'd like to see it expanded to all these histologies. Dr. Richardson? I would echo what you said and also mention de-differentiated and undifferentiated cancers, which I think are very under-classified and actually may look a lot like grade three endometrioids, and that's definitely lacking from the TCGA data. My other question, and Dr. Weston kind of addressed this a little bit during her distillation earlier, is what do we do about the patients who have more than one classification? Because we do pick up maybe up to 5% of those patients. How do they behave? And then, obviously, tying that to outcomes, we know Poly does well, but do they do well because we treat them? Or would they do equally well when we don't treat them? And I think there's a lot of clinical questions that still remain to be answered about that. Yeah, I think I agree with all those points. I think the one thing you have to understand is that it took a while to do the project, so it initiated over almost 20 years ago, and then the data is almost 10 years old when it finally got reported, and so there was no IO treatment data in there. As I alluded to in the talk, there wasn't a lot of treatment data, unfortunately. It was mostly untreated samples, and so you're missing that. The other thing is no one really recognized at that time the importance of HLA, so that wasn't in there as well as I understand it. And then RNA expression data, that's what we're missing now. Now we understand the transcriptome, and we've gone beyond just looking at gene expression. Some of those genes we can understand if they're making protein or not, but in others it's not the case or what the degree of deregulation is or downregulation, so it makes a difference. But a very good start. So what do you think that the outstanding questions are for ovarian cancer? Like what are the burning questions? Are we ever gonna make immunotherapy work for ovarian cancer? Are we ever gonna make it for all? Maybe clear a cell, who knows? Yes. And if so, who are those patients? I actually think there are some patients, but we use the TCGA data to subgroup our uterine cancer. We don't really use it in ovary cancer. We kind of stick to our HRD BRCA, and I feel like that's a large area that remains to be answered for ovary cancer. I'm concerned about what's going on in the PARP space right now with what appears to be some label-limiting behavior by the FDA in terms of looking at OS, that these powers, the studies weren't really powered to look at OS as a primary, and so that's a problem, because now you're taking non-analytical endpoints where there was a major crossover, and there's not balance, and you're trying to draw conclusions. I think for those that saw Panis' discussion this morning, you can see how confusing all that can be. I'll leave it at that, so yeah. It is, and it seems the pendulum has swung a little bit too far in either direction, absolutely. My question that I have is, we talk a little bit about this, and I don't know that we have data that we can glean on very heavily, given that the trial was done at a certain time. Do we treat PARP after PARP? Is there any role for a PARP after a PARP? And in many cases, we have patients that have been on PARPs for two years. They go on, and they don't relapse, and then they relapse. I'm perfectly comfortable in introducing a PARP based on some of the studies that we've had. Dr. Richardson, your thoughts? Yeah, I think that's an excellent question. I agree that those patients are probably eligible for another PARP, but we don't have a lot of data about that, and the data we do have don't look great yet. So, and then the question is, can we overcome PARP resistance, and how do we do combinations? Again, you mentioned Panis' distillation. That was quite a great distillation this morning. There's polthetas, there's drugs that we might be able to combine, and I think we're gonna have to get very strategic about how, you know, when to use which drug to maximize benefit for our patients. Dr. Rizal? Yeah, I mean, I think, you know, looking at Rhea, it was helpful, and if you believe that you can do PARP after PARP, it reinforced that, and if you were someone who didn't think so, it somewhat reinforced it as well, because the medians weren't that different. What I would say about it, though, is that it's easy to sit here and opine when you're on the stage, but when you have a patient who's actually in front of you, and they have, for example, a mutation, or you know that they have homologous recombination deficiency, to me, I'd like to have the patient prove to me that the PARP's not gonna work, rather than just dismiss that the PARP's not gonna work. That's just looking at it more from a clinician. Absolutely. So, and we welcome questions. You know, we're just going through with some of the questions that we kind of came up with that we thought were important, but anyone who has a question, please come to the podium, by all means. Now, we have these milestones. We have the PARPs in ovarian cancer. We have the TCGA data in endometrial cancer. How do you think that's gonna influence clinical design? Well, I think it's important. You know, a lot of clinical trials now mandate BRCA testing, for example, germline for ovary cancer, which we didn't do in the past. I think that's incredibly important. I think a lot of the trials are utilizing a tumor biomarker and collecting that data. Again, I think, you know, we know what is predictive, and we need to be collecting that data, as well, to know which patients are benefiting from what, and so then the next questions are, you know, you have to define the standard of care, and then ask, what's your question, as far as how can we move the science forward? Until we cure all of these patients, we still have a lot of work to do. Yeah, I think what, sort of a gap in that area, in terms of clinical design, has been, you know, which of these endpoints, for example, for IOs do you really lean on the most? Because we know that PD-L1, and then how are you gonna measure that? How are you gonna report it? Is it combined positivity score? How are you gonna report that out? What's the method that you're using? And then, beyond that, what is the role of tumor mutational burden, you know, and then microsatellite instability? And so, in sort of a Venn diagram, I think it seems to differ a little bit between disease groups, and I'm wondering if it does even with subtypes of cancers within those specific diseases. So, I think we need to do a little more work, but in answer to your question, I think everything you said, Dr. Richardson, was spot on, you know, and I said earlier that it really is, it's influencing trials tremendously, because it's involved in the inclusion-exclusion criteria, as well as stratification now. So, these biomarkers are really important. And it's making us think, I think, and we'll talk a little bit about this, you know, about some upcoming trials, like, you know, Dr. Box, you know, B20 trial that's asking the question of an anti-PD-1 with radiation therapies, the C93 data, which is actually asking, I think, a very important question is, you know, in patients with advanced stages, stages three and four, do you, and are deficient in MMR, I mean, do you have to treat these folks with chemotherapy? Or can you treat them with simply an anti-PD-01? I mean, these are incredibly important questions that would change, actually, the paradigm of how these individuals are treated. So, I think some of these milestones have really let us think a little bit outside of the box, you know, clearly, because we've had success, and clearly, there's enthusiasm, but how do we do better with what we know today? Absolutely. We have a little bit of time left on this section. So, here's an open-ended question. Do you order next-generation sequencing on all your patients? And if so, at what time? I would say yes for advanced metastatic recurrent, not for my stage ones or twos in general, as far as uterine cancer is concerned. When it comes to ovary cancer, I do it on all my stage two, three, and fours. But in stage one, I don't typically order NGS up front. Dr. Herzog? That's an amazing answer. I do exactly the same thing. Good. I get it on everyone in those categories. We have an in-house next-generation sequencing, so we send that off, and then at the appropriate time, and sometimes the appropriate time is at time zero, we'll send off just one of the commercial next-generation. Do they do it on, just do it routinely then on your stage one endometrials, for example? No, we have to ask for it. We have to separately consent. In our stage one endometrials, well, on all the uterine cancers that we will have, our pathologist will actually deliver with a deficient or proficient, an MMR. We'll get her to new, if it's a uterine pap series. We have to reflex to ERP, our status. That's not routine at our institution. And when we meet the patient, we have to consent them to see whether or not they would like to do next-generation sequencing. You know, it's interesting, because that's where we get our poll information, our poll mutations at some times, because we're not going to get them very fast otherwise. What about your high intermediate risk stage one? High, oh, we get, I have a case, you know, no word of lie, I've had a case where it was exactly that. It was around pandemic time, and our pathologist kept saying there was something funky about that particular pathology, that they looked, it was a little bit more high-grade, and we did send it off, and she was more consistent with the serous, and we elected to treat her. Early-stage high risk, and we elected to treat her with chemotherapy, with platinum and paclitaxel. And you know, and that is but one case, but I'm hoping that's probably what we start thinking more than just following an algorithm that we all know, you know. This has been great. Does anyone in the audience have any questions, please? We're right on time. So I'm going to turn this over to Dr. Richardson, who's going to talk to us about applying our knowledge. So thank you, and please welcome. Thank you. Thank you. It's great to be here back in person. So we're going to talk about current options for biomarker-directed therapy. And I think you're all aware in this audience that we can use Bevacizumab for ovarian cancer, and it improves progression-free survival. It does not improve overall survival, but you can use it in first line, followed by maintenance. You can use it for your platinum-sensitive recurrent ovary cancers in combination with platinum doublet therapy, followed by maintenance, or you can use it in platinum-resistant recurrent ovary cancer in combination with chemotherapy. And we've kind of just had quite a discussion about biomarkers in ovarian cancer, but we do know that germline BRCA mutations are prognostic. We also know that they are predictive in regards to outcomes and also in helping us choose whether or not we want to use PARP inhibitor maintenance, for example. And that extends to both germline and somatic BRCA mutations and then whether or not the patient is test positive for homologous recombination deficiency, and then whether or not they're MSI-high or MMR deficient. And then there are some exploratory biomarkers currently being worked up, including the PIK3 kinase, tumor mutation burden, which is actually FDA-approved for IO, irregardless of what cell type you have. However, whether or not that's important in ovary cancer is yet to be seen. And then moving into the space now is also the folate receptor. And we do know that many healthcare providers do use NGS at diagnosis to stratify patients for treatments and including maintenance, but there can be some confusion on which biomarker tests to order and the difference in the test technologies and methodologies. And centralized testing is in place in many markets and there are dominant labs based in the United States. And we also know that PARP inhibitors have shown benefit across multiple different types of homologous recombination deficiency-defined subgroups. You'll see on the left it favors PARP, on the right it favors control, and it never really favors the control. All the subgroups favor the PARP inhibitor, whether you're talking about first-line maintenance therapy or we're talking about relapsed maintenance trials. We do know that patients with a BRCA mutation do the best, followed by our HRD, which can include somatic mutations of BRCA, followed by our BRCA wild type, but they are LOH high in making them homologous recombination deficiency. And last, you have our patients who, this says HRP, which is homologous recombination proficient, but quite frankly, the tests are not that good to determine that. So many people moved to just saying not homologous recombination test deficient positive, which is a mouthful. So this kind of moves us to our biomarker groups in ovarian cancer. And as we know, you can use Bevacizumab, and there is really no biomarker to say who is gonna benefit from that therapy. PARP inhibitors actually can be used in any of these biomarkers. However, many people do use the test to help determine whether or not they're going to offer this, at least in first-line maintenance. And then finally, we have PARP inhibitor combination with Bevacizumab that, at least in the United States, can be used in homologous recombination deficient patients. And I think we all also know that there are multiple decision points to be made when you have a patient with newly diagnosed advanced ovary cancer. First, hopefully, germline testing is being done, and if the patient is not BRCA mutation, then followed by tumor testing to look for both BRCA somatic mutations and also their HRD status. First, you have to make a decision whether you're gonna give this patient neoadjuvant chemotherapy or if you're gonna do a primary debulking. Your second question is gonna be whether or not you're gonna give Bevacizumab with that chemo, and then follow it with maintenance Bevacizumab. And then finally, if you have added Bevacizumab, you get to the decision point of whether or not to add PARP, or if you haven't given Bevacizumab, whether or not you're going to give PARP inhibitor. So you can give PARP alone, you can do active surveillance, or you can give PARP in combination with Bevacizumab, depending on what the results of your test were. And so, you know, this is a conundrum, right? What do we do after deciding, you know, depending on what we did after first-line maintenance? So if you gave previous PARP inhibitor and the patient has not had Bevacizumab, then obviously for a second line, you can use Bevacizumab in combination with platinum doublet, followed by maintenance. It's unclear whether or not we can use PARP inhibitors, again, in this setting and what the outcomes will be. If the patient had previous Bevacizumab and was PARP naive, then for your second-line maintenance, you still can use Bevacizumab or you can use a PARP inhibitor. And I think many people, if the patient was having a CR or PR to their chemotherapy, would likely choose PARP in this setting. And then finally, if the patient has had both, Bevacizumab and PARP inhibitor up front, well then what do you do for second-line maintenance? Again, Bevacizumab is an option. Whether or not you can use PARP again, again, we need a little bit more data on that. And then are you gonna use PARP with Bev again? Or are you gonna do active surveillance? Or I will throw out there that there are gonna be a few clinical trials looking at novel agents in this setting. And as far as what are we doing now for platinum-resistant ovarian cancer, well, there are antibody drug conjugates and hopefully we're gonna have one soon. But the two that are farthest along in development for ovary cancer treatment include targeting the folate receptor and the second one would be targeting NAPI2B. There is some trials ongoing with immunotherapy, including anti-PD-1 plus a PARP inhibitor plus a multi-target kinase inhibitor versus standard-of-care chemotherapy, or a combination of an IL-2 plus an anti-PD-1 versus investigator's choice chemotherapy. And then obviously there are multiple trials, as you can see below, using weakly paclitaxel as a backbone. And that's because weakly paclitaxel is quite an active drug in platinum-resistant ovary cancer. And so there are ongoing questions about adding an anti-angiogenic gene therapy with paclitaxel versus paclitaxel with placebo. Again, paclitaxel with or without tumor treating fields. There's also a combination with an AKT inhibitor. And then finally, recombinant fusion protein. So as you can see, this is an area of interest. And that switches us to endometrial cancer. So biomarkers in endometrial cancer probably the one that is the best prognosis is POLI. Then obviously we want to know if somebody has MSI or DMMR, both for potentially treatment, including immunotherapy options, but also this potentially can help you figure out whether or not a patient has Lynch syndrome, which is also important both for them and their family. Also P53. I'm not gonna read the whole other list for you, but you can see there are other biomarkers potentially that are prognostic for uterine cancer. And you'll notice on this slide that endometrial cancer does have the highest rate of MMR deficiency or MSI high of all solid tumors. It's highlighted in blue. And if you go down about five things, you'll see that's uterine carcinosarcoma. And then if you go down a few more, you'll see ovary cancer is pretty low. Next to uterine cancer is colon cancer and also stomach cancer. And this is outcomes from the PD-1, PD-L1 inhibitors and recurrent or advanced MMRD or MSI high endometrial cancer. On the left is PD-1 inhibitor A, which has a median progression-free survival of 13 months. And you'll see an overall response rate of 48% and the median duration response was not reached. And it almost looks just like the one next to it, the PD-1 inhibitor B. Again, an overall response rate of 46%, median duration response not reached. This median PFS was six months, a little bit shorter in that but as you can see, these are active drugs in these patients. Then that brings us to the question about hormonal therapy for advanced or recurrent endometrial cancer. This was a trial that compared an mTOR inhibitor with an aromatase inhibitor compared to a Selective Estrogen Receptor Modulator. You can see small numbers, 37 patients versus 36. The objective response and the intention to treat in the mTOR aromatase inhibitor was 24%, not that different than the CIRM of 22%. And you'll see clinical benefit rate pretty high in both, 78% versus 69%. What is a little bit different is the progression-free survival with the mTOR aromatase inhibitor having a median PFS of 6.3 months compared to the 3.8 months in the hormonal therapy. And the OS has not yet been reached in the mTOR aromatase inhibitor compared to 16 months in the CIRM. And then anti-HER2 treatment with chemotherapy, this was in patients with serous carcinomas. Smaller study, but very important, and we're gonna have a confirmatory trial coming up. But basically show that if a patient is HER2 positive with serous cancer, that they did better if anti-HER2 therapy was added to their platinum-based chemotherapy with an overall survival median of 25.4 months in the control arm versus not reaching the experimental arm. It has a ratio of 0.49, which really makes HER2 testing really important for our serous cancers. And so it's difficult, the one caveat is it's kind of difficult to accurately define frequency of HER2 expression in uterine serous carcinoma. It's estimated that maybe 25 to 30% of all patients with serous carcinoma overexpress tomorrow HER2, and maybe even 16% in carcino-sarcoma. So this is not just serous, even though that's what we talk about the most. I'd like to point out that it does happen in carcino-sarcoma and also clear cell uterine cancers, which are more rare. And there is no validated criteria currently for scoring HER2 in gynecologic malignancies, and so we've kind of extrapolated from breast cancer. And so currently the HER2 expression is defined as three plus by IHC is positive. If two plus IHC scoring, you have to follow that up with some kind of in-situ hybridization. And there is high concordance between next-generation sequencing and in-situ hybridization in breast, but not uterine cancer, 43%. And that brings us to our panel discussion. Thank you. Thank you very much. So again, if anyone has any questions, please come to the mic, that would be great. But a couple of questions. We have these actionable biomarkers, and what do we do every single day? Dr. Richardson, since you gave the lecture, how do you use these biomarkers every day for MSS, or deficiency in MRP53? How do you engage in your own clinical practice with these biomarkers? So I would say in general for my recurrent uterine cancer patients, if they're MSI-high or DMMR and they've recurred, I'm going to just give them single-agent anti-PD-1, whereas if they are MS-stable, I'm going to give them an anti-TKI with an anti-PD-1. It's very hard not to use names. So I think that is a really important thing. And also, we do IHC on all of our uterine cancer patients, and depending on what the results are, we follow that up with germline testing if we're concerned that a patient has Lynch syndrome. So I use it both to help guide whether or not somebody might have a germline mutation, and also potentially to help direct therapy. Yeah, as a poor man's test, I would use Lynch syndrome, absolutely, absolutely. And Dr. Herzog, how do you? Yeah, very similarly, the only thing I'd add is look for HER2 as well, which I know you do, yeah. Does your pathologist automatically give you HER2 new on all uterine pap series? They do. They're supposed to. They're supposed to. They don't always, and so then we remember at tumor, luckily, my fellows are really good about remembering it, so we present all of our cases at Tumor Board, and so if one is missed, my fellows usually pick that up and then the pathologist tests. And we're actually starting to test now for carcinoceratoma as well. You are, so yeah, exactly. And you alluded to a clinical trial that is upcoming. We have Dr. Fader's work with trastuzumab in patients with uterine pap series three, four, and recurrent. Maybe you can mention a little bit about the new trial that is coming to light? Yeah, so it's gonna actually include, I believe, stage one through four serious carcinomas and include, it's obviously platinum-based chemotherapy with or without an anti-HER2-directed therapies, and I believe there's two of them, potentially, in that trial that are gonna be investigated. And I guess what I would also point out is that if you do identify a HER2-1+, there are other drugs now that have, you know, that we've gotten beyond the first generation. And so there are ADCs and things that target. That was a huge thing at ASCO for breast cancer, and so even if you're identifying those one or two-plus, keep them in mind because there are some drugs that can be active, potentially, at least in breast cancer, so I'm hoping that also translates to uterine cancer. So I think we need to start being aware that it's not just gonna be our three-plus that might benefit from these therapies. I agree. Tom? Yeah, I was just gonna say there's been a revolution in our understanding of HER2 and how to use it clinically and what some of these newer drugs can do, so it's really an exciting time, and it's gonna make us relook at a lot of things. You know, it's interesting because now, because of the ADCs, you know, the work that's been done in breast cancer was pretty monumental, published in the New England Journal of Medicine. It hasn't grown to us, but there are clinical trials looking at these ADCs. I've started looking at HER2 new, and it's a little bit of a Hail Mary, I realize, but I looked at HER2 new in all my patient population just to see if I can get a signal in hopes of generating some thoughts in terms of a clinical trial. Absolutely. Now, in terms, we talked about endometrial cancer in terms of MSS and deficiency in MMR, P53, and here's the big question. In ovarian cancer, and we've talked about this a little bit already, how do you, do you do germline testing on everyone, and if so, when? And you alluded to this previously. When do you do somatic testing? Do you do them all at the same time? Do you do next generation sequencing? Do you look for LOH? How do you guys, what is your standard in your institution? So, I mean, at our institution, we do germline testing on every epithelial ovarian cancer across the board, and then if they are not identified to have a germline mutation, then we go on to tumor testing, again, in those more advanced cases, not necessarily in our stage one cases. So, I think that's. You test for HRD? So, it's in the NGS that we, so we don't, yeah, we try and make it just so that the patient only has to have one test, and so we do an NGS that includes HRD result. Yeah. Dr. Rizzo? Yeah, pretty similarly, we're a center of excellence from one of the sequencing companies, so the university has a relationship, and so we send, and they have a relationship joint venture with germline so that we get that as well from another company. So, it's all integrated. So, that's helpful. Yeah, I think what we need to think about is how to make it as simple as possible. And cost effective. Yeah, and then differentiating between HRD tests. You know what I mean? The gold standard has been the myriad and the foundation ones because they both have been involved in registration trials. They're slightly different tests in terms of even how the LOH is measured between the two, so that's interesting. And then you have the other aspects of the myriad test, which don't add a lot, but they add something in terms of large-scale transitions and telomeric imbalance in addition to the LOH, the loss of heterozygosity. So, from the data that I know, you know, there's a lot of correlation between LOH from these other companies now with what we see with myriad and so forth, but it hasn't been validated in real time. So, there's still some unanswered questions. So, in our institution, we have a little bit of a debate. You know, not all of us agree. I know it's hard to accept. We all do germline. I know, I know, it's shocking. We do germline testing on everyone. And there's a group of individuals, you know, and then we'll reflex. If that's negative, we'll reflex, obviously, to somatic testing to try to capture that 7% of individuals. There are some individuals in our group who will not send off next-generation sequencing. You might have heard a little bit about that this morning. Okay? They look at HRR genes, and there's some of us that actually look at, do send off HRD testing, just to try to understand, you know, where the patient may fall into that, mostly just simply to understand the magnitude of benefit. I happen to be in that latter group. I send off the HRD testing. I'd like to know, you know, when I explain to patients in terms of why we're giving them a PARP inhibitor, what the magnitude of benefit is. Not that we deny anyone a PARP inhibitor as first-line maintenance therapy, but I just sometimes, not sometimes, all the time, really like to try to tell them, you know, this is what you're investing in. You know, these are the side effects, but this is what you're investing in. And it goes far beyond what a hazard ratio is, really to try to explain to them. Because, you know, it's two to three years worth of drugs, not to mention the financial toxicity, and I think that's real. So I liked it. I know there are other views, and I certainly am cognizant of that and respectful of that, but it's very interesting to see how different people actually organize that in their own institution. Yeah, I think, for me, it helps with a patient who's having toxicity, for example, how hard to fight to keep them on. You know, obviously, if they have a HRD score that's very high, I mean, I really look at that as someone, I really want them on a PARP, very much so. And it doesn't mean HRP, that I don't want them on a PARP either. It's just that I may go, jump through a lot of hoops to try to keep them on versus someone who's HRP who's having a really rough time. I might try something different. No, agreed. I had a patient in my clinic the other day, I was a consultant, and she's BRCA mutation carrier, and she had a very difficult time with one PARP inhibitor, and she was really dose reduced to the most lowest level. And, you know, she was concerned. She was concerned that, you know, why am I taking this drug? Well, you're a BRCA, you know, you carry a BRCA mutation, so although I can't prescribe, or your clinician cannot prescribe the FDA-approved dose, I would rather have you on the lowest dose than have you on nothing at all, to be honest with you. So I think it's certainly a conversation piece in hopes of engaging that enthusiasm. Absolutely. Now, these are great biomarkers, but there are challenges with these biomarkers. So just out of curiosity, do you do IHC testing on all your, or do you guys, Reflex, do you guys do MSI testing? I know that it's different among institutions. Yeah, so this has come up actually recently. We do IHC testing, but the question is, sometimes should we be adding the MSI testing, and if so, in who? And so I'd be curious to know, both from either of you on the panel, or people from the audience, how people handle that, because it's been an area of debate, actually. You know, we don't want to miss those patients that are MSI high that were not identified on IHC. I know, usually it comes with, you know, just really kind of trying to detail what their family history is, which is sometimes a bit of a task, but if there's any cause for concern, we just send them to genetic counseling, or we would, like, send us out, yeah. Yeah, one of the things that, you know, I mentioned in the talk, but I thought Amy Jamison's talk this morning at the first plenary session was very interesting, where she did the next-gen sequencing, and all that, and saw very high correlations, but the numbers were not that big, so, you know, as I said, we probably need to validate that further, and see how many patients were, because you don't want to miss that knowledge, either. But the tests are going to get better. We started looking at protein expression, and then it's going to paint a clearer picture, as well. I just learned a new term from ASCO a couple of months ago, epigenetic constitutional hypermethylation. You know, I had to look that one up, but then I had a patient in my clinic who actually had that. It's quite interesting, where, in essence, you really test negative for Lynch, but you really are going to behave like Lynch. Completely quite rare, but it exists, yeah. So, it keeps on growing. And in our last 23 seconds, if we can try to answer this, I mean, are you an, are you a LOH fan, or are you more of a Myriad fan, the three, how do you measure your HRT? LOH. LOH. Because I want to add the same time as NGS, because otherwise you have to send two tests. Yes, yeah. A little bit of both. A little bit of both. In the sense that, usually, we get the LOH from the testing, but there's times that I will send it to Myriad for different reasons. Do you ever send them to both? Occasionally. I have. To see the concordance, absolutely. Does anyone have any questions in the audience before we actually move on? There was somebody back there. Hello? Yes, thank you. Hi, it's Bruce Howard from Cape Town, South Africa. Thanks very much for an excellent session. We have a problem sometimes with our germline testing that it takes quite a long time for us to get the results. Do you think it's a reasonable approach to do the somatic testing and to follow up or wait on the germline at a later stage and to respond for that? Because we often have to send it away. And we have quite a lot of delay, which can then affect our clinical management of the patients. Yeah, for me, I think that's a fine approach. So fine that that's what I do. So the reason I do that is because, for the reasons you said, we get that information back very quickly. And while it's important to sort it out, and it's critically important to sort it out if they have a germline, if it tests positive on a tumor, you have time to sort that out. But then you can get going with your treatment, which is really directed. So I think it works out well temporarily. How long, just on average curiosity, does it take to come back? Sorry, what was that? How long? What's the turnaround time? Probably about four to five weeks. So for the germline, yeah. So that's a bit long for us. But the somatic, obviously, we can get much quicker and cheaper, yeah. Hi, good afternoon. Kevin Holcomb from New York. I had a question about mucinous ovarian cancers. And we test them all germline, because it's recommended for epithelial. But I was just wondering what the pickup rate for BRCA mutations, I imagine they're low. I was wondering if you can give me a number. And then I was wondering about chemotherapy for those patients as well. I've seen some studies using GI regimens versus platinum-based regimens. I don't believe they've been proven to be superior, but I was wondering, do any of you use GI regimens as opposed to standard ovarian? In terms of your first question, I don't think I've ever seen a BRCA mutation in a mucinous ovarian cancer. Although there are other mutations of interest. HER2, for example, can be positive in mucinous. In terms of chemotherapy, we struggle with this also. I think the clinical trial that was faithfully tried to execute was very hard to deliver. And if you look at that publication, it's quite hard to decipher which one you should be choosing. In a very, very select group of people, the GI regimen was in essence better. But the end of that study, the end of that particular group was quite small. And if I recall correctly, it was on the order of 18 people. So I have to say, in my institution, we tended to stick with carboplatinum and taxol and not the GI regimen. I think the GI regimen may have a little toxicity, but I think both are very reasonable to try. Yeah, I would agree with that. I test them because mucinous can have Lynch syndrome, and I don't want to miss that. And I also, we typically would go to the carboplatinum-paclitaxel and perhaps use a GI regimen after relapse. But they are more toxic. Kevin, good to see you. Thanks for having us in New York. So I have seen some reports where there are cases with BRCA mutations, but it is very, very rare. It's probably on the order of 1% or less. So why would they be excluded in terms of all the societies have recommended all epithelial cancers be tested? The reasons that Dr. Richardson said, as well as the fact you will pick up an occasional one, and probably the biggest reason is because when you start telling people that there's subtypes you don't need to test, that'll probably decrease testing for all patients. So it's probably a combination of all those. As far as GI regimens, we've gone back and forth on that. I just think we need to do better in terms of finding out things that work better, maybe IOs and things like that in the mucinous because just the GI chemo regimens have not been all that effective. I've seen studies where they've been slightly more effective. I've seen others, and they've done quite a bit of this work in Japan, where it hasn't been any more effective than carboplatitaxel, so. Next question. Hey, Susanna. Hi. Thanks, Tom. Excellent talks. I have a question regarding recurrent uterine cancer. We have the TAPR trial open from ASCO in our institution, and occasionally we get really lucky, and we have certain patients that have like three or four mutations that are targetable. TNB high, PI3 kinase, and then they got HER2, so we could use Herceptin and Progetta on them. How do you choose which one to do first, and how do you sequence it? Because ASCO allows us to do any of them. We could put them on tendrolimus with PI3, or we just put it on PEMBRO for TNB. Can you enlighten us on that? You're gonna use every one of them at any given time, so I think that, I think I would be more partial to using the anti-PD-1 first, okay? It's easy, it's every three weeks, or every six weeks, we can certainly do that. And then HER2-neu would have to be, is it really, is it FISH positive, you know? Or is it an amplification, or is it a mutation? But at the end of the day, I think we're going to gravitate. As a clinician, I would imagine that you could gravitate to all of them, you just have to pick the sequence you think is most important, or perhaps if a clinical trial, for example, an ADC that we were talking about, you know, an ADC would be appropriate for that individual at any given time. And also toxicity profile, in terms of the patient, you know, what can the patient handle at that point in time? And also, have you used them in combination? Used them, well, I would have loved, perhaps, to use them in combination, but insurance-wise, formulary-wise, I would not have been able to do so, unfortunately, yeah. I would just say, sorry, I didn't mean to interrupt you, but, you know, these are really, actually, great cases for molecular tumor boards. And one thing that I usually, actually, will ask the NGS company, if they haven't provided it, is what the variant allele frequencies are, and try and sort out, what do I think are the driver mutations? You know, obviously, that's a little bit of an art, not necessarily fully validated. So I'd probably go with my TMB first, because that is FDA-approved. The others are kind of, you know, we have some literature to support their use, but it's off-label. And so, that's probably how I would look at that, because the TMB is probably legitimately real. The issue being that PIK3 kinase might be interfering them with your ability to respond to your IO, and that's where I feel like molecular tumor boards can be really helpful, to help you strategize what your next line should be. Yeah, John, I refer to these as dartboard cases, because I just don't think we know yet. But the idea, or the concept, that, if you could understand what the driver mutation is, I think is really a sound one. I think that's a really smart comment. Thank you. Thank you. Well, I'm gonna introduce myself, because we're moving on to the last section. So we've had a great review of all of our actual mutations, both in ovarian, as well as uterine cancer. And the question that we've alluded to over the course of the last hour has not only been a review of that, but our enthusiasm for where we're actually going in the future. And so what I'd like to share with you is, you know, some next steps towards changing the treatment landscape for both ovarian as well as endometrial cancer. And you know, what you can see from this slide, and it's a busy slide, but this is basically all the trials that are in existence that we are testing these new promising therapies for ovarian cancer. And you can tell that, you know, some of these trials in terms of patient population, they're biomarker unselected. And there are times when they're selected like HRD or non-BRCA mutation. And there are different biomarker stratifications for all of these trials, which is extremely important. We've tried to summarize that here, but indeed, they're much more complicated than this chart even tries to allude to. But in terms of biomarker unselected, looking at HRD status, there's the first trial, which is actually ongoing, and it was an adaptive trial. And it was basically the standard of care of chemotherapy, plus or minus BEV, plus or minus an anti-PD-1, followed by maintenance therapy, either to BEV or an anti-PD-01 plus of PARP. And this was adapted as the PARPs were coming into the equation as part of the previous trial. There's the NIRVANA trial and the AGO trial, the 20A trial, which looks at chemotherapy plus BEV, followed by a PARP inhibitor plus BEV. There's the ATHENA trial. We heard a little bit about the ATHENA trial at the American Society of Clinical Oncology meetings, but what we're really interested in is, clearly, we're interested in the data that they presented, and they did a wonderful job, but we're really interested in that question of immunotherapy. And this particular trial looked at chemotherapy, standard chemotherapy, followed in sequence. There was four arms of that particular trial, but in this case, the PARP plus the anti-PD-1. There's the NPLUS trial, which is looking at three cycles of chemotherapy versus six. And there are other more elaborate trials, also the DUO-O trial, which is looking at chemotherapy plus BEV plus an anti-PD-01. And then there's the KeyLink-O001, which is the chemotherapy plus anti-PD-1 plus or minus PARP maintenance therapy. So as you can see, all of these trials have different stratification factors. They may differ in terms of biomarker selection, but they all have a common theme, and they're asking the question of whether the PARP, as well as perhaps IOs, have a role in the management of patients with ovarian cancer. And the question's unknown, but hopefully we'll start getting some indication in the next couple of years, if not months. Now I think we alluded to this, and we all talk about HRD, and I think we would all agree that knowing HRD is purposeful. It has been validated in many different studies. But do the tests that we have now, are they picture perfect? They are not. What I think has to also happen is these current tests have to show us, how do we measure clinical resistance? We're not getting that from any of the tests that we have now, and I think it's quite important to actually also know that. Now, not to be undone, endometrial cancer, there's a whole slew of clinical trials that are being looked at in endometrial cancer. And once again, this is a particular slide that kind of goes through many a different trial. The RUBY trial is looking at an anti-PD-1 plus chemotherapy, followed by an anti-PD-1 maintenance therapy versus a placebo. The RUBY-2 brings into the equation of a PARP inhibitor. The LEAP trial is an extension of our Keynote 775, which was an extension from 146, which is actually looking at a TKI plus an anti-PD-1. And so that's going to be versus chemotherapy. And then we have our NRG018. That again is the backbone standard of chemotherapy plus or minus a PD-01 versus a placebo. And then we have other trials that are looking specifically at the MMMR, the DOMINICA study, and also Keynote C93, which is actually a very interesting study, which is actually looking at stage 3 and 4 and asking the question, can you treat patients with an anti-PD-1 versus chemotherapy? There is a crossover effect in the C93, but I think that's an incredibly important question and to imagine that we don't have to navigate these cases with chemotherapy or radiation therapy, that it could be achieved with an anti-PD-01. It's a question at this point in time. And then the PD-01 all comers in terms of patient populations, we have the DOE trial, which I will let you read because it's awfully complicated and there are multiple arms. And of course the ATTEND trial, which again is looking at another anti-PD-1 plus chemotherapy plus the anti-PD-1 for maintenance. So you can see there is no shortage of clinical trials that are ongoing that will hope to address and will carry forward with some of the earlier data that we just actually heard. And importantly, and these are trials that I would ask you to all look up because they're super complicated trials, but they're incredibly interesting trials. And again, they're biomarker-directed therapy. There is the ENDOMAP trial, which is looking at an anti-PD-01 in combination with BEV or in combination, for example, with a biomarker-driven therapy. And tumors will be tested for PIK3CA mutations, they'll be tested for loss of heterozygosity, PDM1, MSI-HI, and the tumor mutational burden. The BOUQUET trial is exceptionally interesting because this is a trial that looks at all those cases, those rare tumors that we don't really have prospective clinical trials. So it includes CIRUS, it includes many different histologies that are not as frequent as, for example, our epithelial ovarian cancer. And again, this is biomarker-driven. It's an extensive, so I'm going to have you look that up, but again it's biomarker-driven therapies. In some combinations it's anti-PD-01 plus a BEV, but in other times it's just targeted agents, targeted agents that will address PIK3CA, AKT, P10, other times BRAF, KRAS, NRAS, ERBB2, PIK3CA, estrogen receptor positive. So extremely important. So that's the ENDOMAP and the BOUQUET. The BOUQUET is ovarian, the ENDOMAP is uterine. Very interesting is the trans-PORTEC rainbow trial, and this is a way of trying to really think about all our patients and how can we do best for our patients. We have trials ongoing, we have trials that haven't been reported, I should say. We have the PORTEC trial, we have GOG258, and it still left us with several questions when we see patients in our clinic with stages three and four. Can we narrow the treatment course for these individuals or maybe perhaps completely take away, de-escalate treatment? And in this particular trial, the trans-PORTEC trial, as you can see, the first arm is the stage one, stage four, and this is in P53 abnormal cases, because this is a randomized phase three, randomized to chemo-radiation therapy versus chemo-radiation therapy plus a DDR targeted agent, specifically for P53 abnormality. Second cohort is a stage two, LBSI positive to stage three, and they're looking specifically at MMR deficient tumors, and the randomization will be through pelvic radiation therapy versus pelvic radiation therapy plus a PD-L1 followed by a PD-L1. And the third cohort is the no mutations that are identified, nonspecific, and this is stages two to three, and patients will receive chemo-radiation therapy versus radiation therapy plus hormonal manipulation. And then talk about the de-escalation of treatment. If we identify patients with pole mutations, stages one to three, the patient will receive no adjuvant treatment. So these three trials, in conjunction with all the other trials that we've just mentioned in a matter of seconds, okay, I think will really take us into the future in terms of some of the things that we've talked about today. So all the trials that we've mentioned, both for ovarian cancer, clearly endometrial cancer, and here are some very interesting studies, the endomap for uterine cancer, the bouquet for rare tumors of ovarian cancer, and the RABO for that of uterine cancer. Now these are not the only ones, and this is a slide that has many words on them, and I'm going to talk to you just briefly about biomarker-directed targets for both ovarian and endometrial cancer, and as you can see, these continue to expand. Dr. Richardson highlighted a few of them, but as you can see, there are agents for individuals with a high CA-125, there are individuals for platinum-resistant tumors, we went through a whole series of these, we're looking at trials, many of the trials now are looking at ATR mutations, ATM mutations with ATR inhibitions, what about the MUX16 plus tumors, there's a MUX16 CD3 bispecific antibody. And in terms of uterine cancer, as you know, there's been several work, you know, looking at V1 inhibitors specifically in patients that have P53, they're fully receptor antagonists also in uterine cancer, in combination with PD-L1 also. There is for platinum-resistant tumors, combinations in PIK3CA, AKT, and mTOR inhibitors, and we talked a little bit during our conversation regarding HER2NU, and the anti-HER2NU ADCs, which are bispecific, which have been incredible data in the breast literature, the question is how can we navigate this and can we expand that to the gynecological arena. And in terms of estrogen receptor tumors, and borrowing from my friends in breast, again, the role of CDK4 and 6 inhibitors, it's been monumental, they have been monumental in breast cancer, and the question is can they in essence also navigate certain hormonally driven tumors. So as you can see, we are not short for trials ongoing, so it is an extremely exciting time both in the world of ovarian cancer as well as in uterine cancer. So we're going to talk a little bit more about, we'll go back to our panel discussion here and ask each other a couple of more questions. So what are you guys most excited about in terms of clinical trials, we went through about a million in about 2.5 seconds, understood, but what are you most interested in in terms of, I'm going to give you uterine cancer, what are you most interested in? I am really interested in that RAINBOW trial. I am too. I think that is really, we're really starting to get to the heart of the matter of how should we be thinking about uterine cancer and actually doing directed therapy based on their TCGA classification, molecular classification, and I think the second thing I'm most interested in for uterine cancer is, is chemotherapy going to remain first line or are we going to replace that with non-chemotherapy front line? I'm actually looking forward to B20. I would very much love to see us do away with chemotherapy, yes. Yeah, I think that's an important question that we will hopefully know soon and would obviously change the standard of care tremendously. I guess then, what would you predict then for second line? So would chemo be it again? Yes, so that's where we would plot. I'm a medical oncologist. Move chemo down the line. Move chemo down the line. I mean, especially when we see, granted we don't see this in all cases, albeit, but when you see the most amazing responses that you sometimes can get from anti-PD-L1 that you'd never, ever expect, there's such great questions that can be asked in terms of how you can navigate that earlier into the sequence of patients with uterine cancer. I'm actually quite interested in the Bouquet trial. I think that is a really cool trial. I mean, I had to look that up, okay. I will tell you honestly, but to actually be able to address these rare tumors that we all see in our clinic and we have absolutely very minimal treatment options for, you know, whether it be the granulosa cell tumors, the clear cell tumors, and the like, so I think, you know, having that kind of a basket trial, especially for that type of disease, is actually wonderful. So, yes. So, what do you hope for in five years for our patients? Well, I mean, I hope that we start moving towards cure, and maybe if we start sequencing treatments differently, we actually can get there. You know, I think maybe some parts are curing, maybe some are up front patients. I'm really optimistic about that, and then I also think we need to, again, like work on maintenance after you've already, say, used PARP inhibitor and bevacizumab. Where do we go from there? Are there combos, and how can we reverse some of these resistances that we're kind of coming up with? Yeah. Tom? Yeah, I think biomarker development is going to be a big part of the future in terms of, you know, we'll probably, you saw that timeline at the beginning of my talk in terms of the acceleration of biomarker development, and over time, and I think with all the new molecular techniques and everything that we have out there, this idea of smaller portions of the population being treated differently even within a disease group will take hold even more so than what we see right now, so there'll be a lot of different buckets, if you will, in terms of looking at that, and I think that's exciting. I think even if, you know, you looked at your last slide, Dr. Campos, you had a slide showing a Venn diagram, basically, of, you know, where there's overlap between endometrial and ovarian cancer, and that's a whole different way of thinking about it based on the molecular profile rather than the tumor of origin, and, you know, whether that's ADCs with folate or other targets or whether it's HER2, whether it's hormonal. We can borrow from our colleagues. PARPS. Yes. It goes on I.O. I mean, it's really amazing, so there's so much, you know, you outlined the endometrial trials in FRONTLINE that are going to be coming out, and they're all, you know, there's some similarities, but there's differences in the time that they report out and how they report out and how the standard of care will be flexing over that time period before they all roll out is going to be very interesting. Very much so. I think in the questions, you know, the questions that we're trying to answer now, are we going to answer the questions or are we going to have more questions at the end? You know, when you think about it, you know, if NRG018 is positive, if RUBY is positive, you know, how is that going to change and for whom, you know? I think we're going to become quite more select in terms of how we treat individuals and, you know, getting back to, you know, that term precision, which I, you know, we use so loosely and I don't even know what that means in more often the case, but perhaps that's exactly what we're going to be focused on is really understanding that if this is a person who has a deficient tumor, I'm going to be treating them with a PD-L1. I don't need to go down the chemotherapy and really selecting alpha therapy. Opens a bag of questions, of course, you know what I mean? In other words, could I do this earlier on in my early stage high-risk individuals such that they never get to metastatic or what have you? I think it's exciting. It's, you know, it's going back to, it's emulating also of the disease disciplines, you know? You know, in the breast world, it's very different. You know, they're classified very differently. You're very selected in terms of who you're treating and this is what I'm hoping that we're looking through a completely different set of lenses and that's exactly how our patients are going to be treated in the future. Yeah. It's an exciting era, right? Well, it's not sleepy anymore, okay? It's definitely not sleepy. Well, the other thing it speaks to is, you know, in the field of medical oncology, how people can be generalists with all the different diseases, having so much in the way of new knowledge that's coming out at every one of these meetings and fairly rapid changes in standards of care and it could, I don't know, I'd be interested to hear what you think. Is that going to change at all the need to drive some type of specialization within medical oncology? It's a great question and it comes up every time I have to board certify in my oncology boards and thank God that it's still a couple of years away because I don't know anything about lymphoma anymore. But no, to your point and being very serious, it's very hard and I give tremendous credit to those in the community who are doing general oncology because I think that is such a difficult job given the data that actually has arisen. But I do think that in time that perhaps people are going to be coming more specialized. We're used to that at centers. That's a luxury. That's a huge luxury and that is a luxury that our colleagues sometimes in the community do not have, you know? But I do think that as time goes on, you know, I see communities often that there may be one or two individuals who focus more on GYN and breast and others who focus on GU that within even a community practice they're more, you know, more narrow. But I think it's mind boggling to think that with all this information that any one particular person could really encompass all of that. Yeah, I mean we're all from large academic centers and clearly that's already happened where subspecializations occurred, you know, and frankly the knowledge you get at a tumor board like that where you have subspecialization, even our imaging people and our PATH people are subspecialized. And so you have someone that does nothing but read abdominal pelvic CTs and that's all they read. They don't read head. They don't read chest. They don't read soft tissue. And so I think that it's going to be a challenge for the community physicians without some way of being able to address the large amount of knowledge that's being dumped into the system that you need to know how to treat patients properly. Yeah, and you know, CME, CME, CME, CME, absolutely, absolutely. Any other questions? We have about two minutes left. Any other questions from the audience that we haven't addressed, please, we'd love to. It's a quiet group. It's a quiet group and I'm blind. Okay. How about any other questions that perhaps we should have addressed? Dr. Richardson, you know, other things, burning questions? No, I mean, I would just like to see us reverse what's happening with uterine cancer. It makes me, you know, sad basically that we have an increasing incidence in mortality in uterine cancer and we need to figure out a way to reverse that. And I think, I think a lot of that has to do with inequities in medicine. And I think, you know, we really need to make sure that we're getting our trials to all of our patients, not just some of our patients, that we're making sure that the outcomes represent all the women that come to us for care. So I think that's what I would part with. Yes, I totally agree with that. And I think I'm encouraged by the fact that the FDA is now demanding diversity plans within clinical trials in terms of, you know, what's the prevalence of the disease in a underrepresented population, minority population. And we've never asked those questions and held it to a standard of trying to at least equal that. Not only is it the right thing to do, there's also biologic reasons that we may find and we have found in the past, either efficacy changes based on different biomarkers or different gene pathways being activated, but also toxicity tolerance. It can be different. And if we don't have representation across our total U.S. population, we're leaving people out, we're leaving them behind in terms of that knowledge. So that just cannot continue to happen. You know, I'm also very grateful that, you know, I had a patient many years ago who told me that she did not have the disease. I will never forget this. I was a fellow. She said to me, I don't have the disease that's in vogue. And I said, what do you mean by that? And really what she meant to say is her disease wasn't a disease, but there was a lobby group for it. And now what we're starting to see is that that's changing. You know what I mean? That people are speaking out about ovarian cancer. They're speaking about uterine cancer. There's a presence. And I'm very grateful for that. But I will never forget that patient said, I don't have the disease that's in vogue. Well, it is in vogue right now. So. Well, thank you very much. This has been really a pleasure to moderate. And thank you both very much. And thank you for listening to us for an hour and a half. I hope that you've taken away some of some bullets that actually make us excited. And I hope that makes you excited. So thank you very much. Thank you.

biomarker-driven care

gynecological malignancies

ovarian cancer

endometrial cancer

biomarkers

treatment decisions

patient outcomes

clinical trials

PARP inhibitors

immunotherapy

personalized treatments