And welcome to the master session of uterine cancer. This is Domenica Lurusso. I am a GYM oncologist in Italy and I'm honored to co-chair this session with Dr. Xavier-Matthias Gouillou from Spain and Dr. Brian Slomowitz from the United States. So this master session is usually very helpful for our delegates and our colleagues because the goal of the session is to hear from high-level experts on the state of the art but also new perspectives in treatment of uterine cancer. This session in particular is a little bit different from those we used to have in the past. We have in particular three topics to discuss with the three panel discussion for one for every topic. So please use the Q&A possibility to ask our colleagues a very expert panel of specialists all the questions you have in this moment because this is a unique opportunity. We will start very soon with the first section which will be dedicated to the new molecular classification of endometrial cancer which is really a challenge for the pathologists and I want to invite my co-chair Dr. Xavier-Matthias Gouillou to take the stage. Thank you, Xavier. Thank you very much, Domenica. It is really a pleasure and really an honor to be here. I will share the presentation. I think this is and my name is Xavier-Matthias Gouillou. I'm professor of pathology in Barcelona and Jade in Spain and I have the honor of sharing this session that will include a short presentation on the issue and then the most interesting I think is the debate and we have I have the honor and the pleasure the privilege of having three outstanding pathologists with me. I have Talin Bosse from the Netherlands from Leiden who has contributed enormously to the molecular classification of endometrial carcinoma. We have also Russell Broados from the States who has an enormous experience on interpreting the molecular features of endometrial carcinoma at the light of morphology so thanks Russell for being here and we have also Gianfranco Zanoni from Rome. He's an expert gynecological pathologist and with you know a strong background and I think their contribution the contribution of the three of them together with my contribution are going to be I think interesting. So I'm going to start with that. By the way we have prepared a polling for you and probably it's going to be available for you and the poll the question in the polling is just if we are following if you are following the molecular classification right now. So let's start with that. The topic of the of the debate is molecular classification of endometrial carcinoma a new challenge for the pathologist as Domenica said this is a very interesting issue and these are my disclosures and this is more or less the structure of this initial presentation just to foster the debate. First I'm going to present to you remember a little bit what is the pathological classification and the molecular classification which are the possibility for application to clinical practice basically based on the ESGO, ESTRO, ESP guidelines and then finally we will make a debate with my colleagues on some issues that maybe we have to solve. So we have the pathological classification, the last W classification is very recent last year and in this classification obviously there is a review of the different histological types but in that classification the issue of the molecular classification was also introduced. This is the the structure of this updated molecular pathological classification I think I think it's quite simplified in comparison with the previous one and the input that I had from clinicians is that they like that we have endometriate, cirrus, clear cell, undifferentiated, mixed, other types of carcinoma. We have brought carcinosarcoma to the category of endometrial carcinoma and we have also neuroendocrine carcinomas. So we have pathologists have different types of tumors that have different morphological features, they have molecular features, they have risk different risk factors and they have even different precursor lesions. And pathological classification is strong. As mentioned there are different types of tumors with different morphological features, precursor lesions, natural histories, and very important the pathologic classification morphology allows distinction between low-grade and high-grade tumors which is prognostically relevant. So this is something that pathology, traditional pathology does very well. But pathology has limitations. So there is poor inter-observer reproducibility in high-grade carcinomas in a small subset of cases around 10% in the area between high-grade endometrial carcinoma and cirrus carcinoma. As we will discuss later on there are some histotypes that are heterogeneous regarding prognosis. The paradigmatic example is grade 3 endometrial carcinomas. And the data that we have, the most recent data, show that in the high-grade group maybe histological typing is not as relevant as in the low-grade group and in this area, particularly in this area, the molecular classification is important. So this is the general picture and this is the 10% tumors in which we really have problems in reproducibility. And then I think it's nine years ago the TCGA provided the molecular classification of endometrial carcinoma in these four prognostically distinct group of tumors. Poly-mutated tumors associated with very good prognosis, the ultra-mutated tumors, the copy number high associated with bad prognosis, and two groups in between those tumors with microsatellite instability and those that are called low copy number or non-specific molecular profile that do not have poly-mutations, do not have MSI, and do not have copy number high alterations. And that classification was very important because allowed us to recognize this group of tumors, the poly-mutated tumors, that are tumors that are the morphological level, they are usually aggressive, they are heterogeneous, they are sometimes difficult to diagnose, difficult to handle, but they have very good prognosis. And now we know, and I think I have to acknowledge the work by Alicia Leon and Talin Bose in making the first catalog of pathogenic mutations of poly, that are the mutations that are associated with high tumor load and they are the mutations that are associated with good prognosis, but this is a little bit tricky because we have pathogenic mutations and non-pathogenic mutations as we will discuss later on. And then we have the bad group of tumors, the copy number high, they have deletions, amplifications, and they have frequently p53 mutations. But sometimes there are some tumors that do not have p53 mutations and maybe we will discuss that later. So basically two groups, it's important to give credit to them, the group in Leyden and the group in Vancouver proposed a surrogate to bring that molecular classification to clinical practice. And just by performing one molecular test, poly-mutation testing, and three immunochemical tests, two for mismatch repair genes and one for p53, that allow us to stratify the tumors. And this is the paper from Vancouver, but there are similar papers from the group in Leyden showing that by using the surrogate we could stratify the tumors in this, more or less, in these four groups. And the molecular pathology is strong, it's a good risk stratification in general, but particularly in high-grade endometriic carcinoma. And as I mentioned, as I referred before, in the high-grade group molecular classification is probably more important than histological typing. And this is more or less the contribution of the molecular subtypes in each of the pathologic subtypes. And you can see that the vast majority of serous carcinomas are p53 abnormal, so high copy number, but there are a few that are not. The same for the mixed, which are usually the serous component predominate. Then the endometriot carcinoma grade three is the area in which the four molecular subtypes are more represented. There is promising data, and we will discuss that later on, for clear cell, for undifferentiated, for carcinocercomas. And in low-grade endometriot carcinoma, the vast majority of the tumors are non-specific molecular profile and mismatch repair deficiency, but there are a few that are polymutated and p53 abnormal. And as mentioned, the molecular classification in the surrogate allows us to identify different prognoses in tumors that look similar. And in my opinion, the paradigmatic situation is grade three endometriot carcinoma, they look similar, but depending on the molecular subtype, they behave really different. Obviously, we can expand that to the whole group of high-grade tumors. And that's very important. There are also similar results from later and from Memorial, but it seems that the molecular classification is particularly relevant in this group of high-grade tumors. And when we are dealing with a high-grade endometriot carcinoma or a serous carcinoma, this differential diagnosis is not easy always for us. Really, it's not very important because when the tumors are p53 abnormal, they behave in a similar way regardless of the morphological features. And this is now very important. The molecular classification also allows identification of the tumors of the patients that can benefit from immunotherapy. And we will discuss that. There are some tumors that do not fit with the isolated categories, and we call them multiple classifiers. So at least there is one attempt to bring the molecular classification to the clinical practice, and that has been proposed by the ESGO, ESTRO, ESP guidelines so far. And according to these guidelines, it is encouraged to perform the molecular classification in all endometrial carcinomas, but particularly in high-grade tumors. And because, as we will discuss, maybe polymutation analysis is not available in all pathology departments across the world, maybe we can skip polymutation analysis in some subsets which are low-risk and intermediate-risk endometrial carcinomas with low-grade histology. And this is a diagram that was sent to me by Antonio González, who is a friend in Spain, who also was a member of the panel in the ESGO, ESTRO, ESP guidelines, showing how important it is the molecular classification in risk stratification, this guideline, when the molecular classification is known, and the consequences that this has in treatment. So now it's time for me to finish my talk, and these are the four questions that I will share to my colleagues. But then, obviously, please send us more questions through the question and answer section, so we can discuss them, all the questions, with the panel. So the four questions, general questions, that I would like to discuss with Talín Bosé, with Russell Broadus, with Gianfranco Zanoni, the first one is, are we really ready to implement the molecular classification in endometrial carcinoma in 2021? The second one is, should the molecular classification be applied to all endometrial carcinomas? Maybe we have to prioritize some of them. Is it cost-effective in early-stage low-rate tumors? The third is, which is the main limitations of the molecular classification? Poly non-pathogenic mutations, wild-type high copy number tumors, we have seen examples, double classifiers. And finally, which is the place of traditional pathologic classification at the time of molecular classification? But as mentioned, obviously, you can have also you can pose also questions. So Talín, Russell, Gianfranco, we will start with the first question. And Talín, if you don't mind, you can start. Are we ready to implement molecular classification in endometrial carcinoma? I think you said that I could start. Is that correct? Did I correctly? Fantastic. Now it's time for discussing. So you can interrupt. You can discuss. I see. I see. I see. But you want me to start to answer the question, right? So for example, are we ready? So the first question is, who do you refer to when you say we? As we are a panelist of pathologists, I guess, is the pathology community ready? So let's select that. And then it's, of course, a little bit difficult to answer for the whole world, right? I think there's diversity around the world and pathology labs and equipment and possibilities for molecular testing. If you ask me from the Netherlands, are we ready for molecular classification? I think we can say yes to that. Of course, it takes courage to make a change like that, but the WHO has taken that step, and the WHO is generally considered the Bible of pathologists, and it gives good guidance to the molecular classification. And it has taken that courage, I think, because the WHO editors have decided that there was sufficient evidence that this is a robust classification that can be applied in clinical practice on pathology material on paraffin embedded tissue. Furthermore, it's a good basis for treatment, and I think, given that the clinicians have also now integrated it in their guidelines, that means that the clinicians also know what to do when we put it in our conclusion text. So, I would say the answer is, from my point of view, yes. We, as a pathology community, can take this change. We can implement this. Okay. Russell, thank you for coming. What are your feelings about that? I'm going to take a slightly opposite perspective on this. In my heart, I absolutely agree that pathologists can do this and, frankly, should be doing this. However, I'm not convinced that oncologists in the United States evenly understand the implications of the molecular data, and I'm not convinced that pathologists adding the molecular data would change in any way the oncology treatment approach. So, I see this from a little bit different perspective. I will put anything in a pathology report if I know that it will help to influence oncology treatment approach to the patient, and I'm just not seeing, frankly, right now, in our practice in the United States, that oncologists would really incorporate this on a routine basis. So, Russell, are you using and reporting in your clinical practice that molecular classification? We are not. We do the mismatch repair immunohistochemistry routinely on all patients. The p53 immunohistochemistry, you know, it's mainly in patients that have high-grade tumors. Some of the pathologists use this to help push them to either, if it's positive, serous carcinoma rather than endometrioid, even though I, frankly, think that's flawed logic because there are endometrioid tumors that can have p53 mutations. Okay, thanks. Thanks a lot, Russell. And Gianfranco, thank you very much for coming, Gianfranco. So, what's your feeling? Are we ready? Because we had a webinar, remember, in the Italian Society of Pathology, and there was a discussion, and you are very well aware of Italy as an example of Europe. Which are your feelings on that? My personal feeling is that we need to perform molecular classification, and I think that culturally we are ready. We pathologists are completely ready to face the new classification. The problem could be the presence or absence of money to do that because Italian health system doesn't reimburse the exams. For this reason, we have some problems in order to perform them. But in Italy, the situation is patchy because in some centers, we perform a polymutation in every case, also in low-grade, in all cases. But my point of view is similar to your point of view. I think that in low-grade, we can omit the poly in this context. We don't have a lot of money to perform the exam in every case. But finally, I think that we have to do that because we need to have histological classification and molecular classification and put them together. But I think it's the last question that you do. Yeah, okay. So, thank you. So, I think that all of us think that the molecular classification is interesting. And Russell expressed the problems of interaction, of getting a practical objective of this. And you also mentioned the financial problem related to polymutation analysis. The second question. Xavier, since it's a discussion, can I just respond to at least what Russell was saying? It's a bit of a pity that the clinicians are not on this discussion bit because, I mean, Russell is saying, well, I'm not doing it because the clinicians don't act on it, which I don't think is a good argument for not doing it. In fact, I think there's plenty of examples in pathology conclusions that we provide aspects that don't immediately result in an action from the clinical part, but we still do it. I think it's our task as pathologists to provide the entity, the disease entity that the patient is having. And right now, we have taken this to the level of molecular classification. I think it is not, it's almost at the point that I think a patient deserves to get the correct disease entity by us as pathologists. Now, I appreciate the money issue, and that's a different issue that we can discuss. But I think to say clinicians don't know what to do, they're not changing their treatments, that's my argument for not doing it. I don't agree with that. Okay. And also, the world is diverse, and it's something that is evolving. And for example, the guidelines are emphasizing that. So this is a process. So we can go to the second. I mean, unless you have any questions, we can go to the second question, which is related to the first one. And I think that more or less Gianfranco answered that, but we will start with Gianfranco. And the second question is, should the molecular classification be applied to all endometrial carcinomas? Or should we maybe prioritize high-grade tumors? And whether it is, is it or not, cost-effective in early stage, low-grade tumors? And we will start if you agree with Gianfranco. My position is that, of course, I hope to do examines in every case, but in my institution, that is not possible. So we decided to perform the pool and mutation only in high-grade tumors, particularly G3 endometrioid, but also other cases. And we perform in immunochemistry, only P53, ER, PR, and the protein of mismatured retain. So I think that in a real world, that we have to perform the poly in every case. But if we can outdo it, we can selectionate the case in which we can do the exam. And from the pathological point of view, I think that high-grade tumor, G3s, serums, ambiguous tumors, mixed tumors, need poly mutation. And Russell, although you are presently not using the full molecular classification, which is your feeling? Should that be done in every endometrial carcinomas or you would prioritize some types? So I would prioritize some types and I have a few examples. So similar to what was just stated, we just had yesterday a very unusual high-grade endometrial carcinoma. Histology on the biopsy was fantastic for serous carcinoma. So no doubt about that. Then the hysterectomy, similar, a very good for serous carcinoma, but there's no myometrial invasion, no lymphatic vascular space invasion, which is odd. And there's little areas of squamous morials within, which is also odd. So it's kind of this mixed high-grade cancer type. So I absolutely think this one should have P53 testing and should have poly testing. What I'm very pessimistic about, however, is that I really don't think the oncologist would use that information for any kind of treatment strategies. But I do think those tests should be run on this. Then I'm gonna take an opposite perspective. I actually think the most good this testing can do is actually with the low-grade tumors. So poly sequencing, no, but P53 information, beta-catenin information, mismatched repair immunohistochemistry, all of that has been shown in multiple studies to be prognostic for the low-grade early stage tumors. Again, if the oncologist would use that information to treat those patients differently, I would do those tests routinely in the low-grade and early stage cancers because they are so common and because you can capture patients who are at risk for recurrence. Thanks a lot, Russell. And what do you think, Dalin? Well, you know, one perspective of all of this, I think it's important that the way I view it is it's not, these are not prognostic biomarkers. In my view, this is a classification system. So a classification system has to be performed on a disease entity. And then currently I would consider, for example, beta-catenin still in the category of prognostic biomarkers, at least within the NSMP group of tumors. Should we do it on all cancers? Well, like Gianfranco says, in the ideal world, yes. And I understand the cost effectiveness analysis need to be performed. However, the way it's being, the direction this is going, of course, is that we can reduce adjuvant treatment after a molecular classification by not giving adjuvant treatment to those patients that have a poly-mutated endometrial cancer and possibly also some subsets of the NSMP category of tumors. And that in itself would, of course, save a lot of money and toxicity. So I think we're in a transition phase where at least it's a very nice and good basis for new and exciting trials like the RAINBOW program, but also which we are running internationally in Europe, PORTEC4A. And when we include as many patients as possible in these trials, we will learn as quickly as possible the value of all of this in a prospective manner. So I think I can understand not doing it routinely right now I can understand clinicians aren't acting on it right now, but what I think we should express is please put these patients on trials where molecular classification is required so that we quickly get through this sort of bridging phase from the old classification to the new classification. And then I will introduce a new question because I think I know your answer, Talin, but I would like also know the answers of Russell and Gianfranco. So do you think there is sense for using part of the surrogate? You know, only for example, mismatch repair deficiency and P53 without doing poly or the cases should be managed with the full four surrogates. That's that for you, Talin. Oh, I'm sorry. I thought you were saying you already know my answer. No, I know. I know your answer, but I want you to experience that. I know. I mean, it's sort of like, you know, so we find it a little bit complex and cheap or expensive. So we rather not do poly. So we do half of the classification kind of. And I think in fact, in this transition phase where also pathologists need to learn and understand the molecular classification and the subtleties of the double classifier is super useful to do the full classification. So only for that, for the educational purposes is already very good. But the other aspect of course is that poly trumps everything. So ignoring poly in a P53 mutant tumor is, yeah, is a missed opportunity for patients to get very good news. So I would be a little bit reluctant or I would be against promoting doing only MMRD in P53, especially in cases where you consider chemotherapy in the adjuvant setting. Any comments, Russel and Gianfranco? A little comment about the use of immunochemistry. I think it's very useful to perform the proteins of mismatch repair because they give a lot of information other than the molecular classification. Because when I perform my immunochemistry for an MRI, I have some information such as possibility of lynch, for example, possibility to use in relapse, a very useful drug or immunotherapy. And finally, I can have also information about molecular classification. So if I can't do the complete molecular classification, I promote the use of immunochemistry for mismatch repair and also for P53, because P53 is also useful for the diagnosis. In some cases, I think is a low grade carcinoma, for example, G1. I perform P53 and I saw P53 completely full and I suspect a serous. And in some cases, P53 psyched me in this case of diagnosis. I have only one brief question for Talin about a beta-catenin. Because my experience with beta-catenin is very poor. First of all, do you use a molecular biology or immunochemistry? First question. Second question is that in my experience, beta-catenin is positive only when I see a monular or squamous metaplegia. But I didn't see impositivity in monochemistry for beta-catenin in our cases. All right. So I'm just gonna quickly respond, but I think to keep the focus on the discussion, we should probably stick to the molecular classification as it's already providing us a lot of challenges to discuss. But beta-catenin and indeed immunochemistry has been shown also by, I think, Russell, but definitely also Brooke Howitt, I remember a paper of showing that it's not a great marker. It's okayish. And it's like you said, it's often in more relay and squamous areas. We find it relatively frequent in the context of NSMP, but also about MMR deficient tumors. And a lot of Russell's work has been looking at prognosis and it seems to be this select, you seem to be able to select poor prognostic patients within the NSMP category. We sequence exon three of beta-catenin in the context of PRTEC4, for example. So there are a few questions from the audience. I think we have to address them. Talin, maybe you can answer these two questions together. Except poly, the other markers are easy doable. What percentage of tumors are poly-mutated? All right. And the second one is copy number high. Does it mean P53 mutated tumors? Okay. So they're both good questions. So number one, poly frequency. On the population base, it's about six, 7%, but you can increase that percentage if you start to select, for example, particularly grade three endometrioid. So if you would select on histology, the majority is in grade three endometrioid. I think in our grade three endometrioid study, stage one A and B were towards 15 to 20%. So one out of five, it's quite high of your grade three endometrioid. Endometrial cancers, low stage, have a poly mutation. So I don't think that's a low percentage for an actionable target. You say immunochemistry is doable, but the poly is not, I think. We should also not underestimate the interpretation of immunochemistry. I just want to highlight that for one minute because the focus is always on the complexity of poly testing. But I think a good interpretation of immunochemistry is actually something we need to educate because not always P53 and MMR staining interpretation is easy. So I agree it's doable from a, let's say, money perspective, but definitely also requires somebody who knows what he's looking at. Poly mutational testing, by the way, is getting cheaper. There's at least three initiatives I know of that are going to bring down the price for poly testing a lot. So I think it might be doable very quickly when it comes to the price problem. The other question, copy number high being P53, yes. The surrogate for the copy number high group as described by the TCGA is mutant type expression of P53. And we've referred to it as P53 abnormal in order to broadcast, send out, and communicate that we only did immunochemistry to show that. Now, there are a few cases in the TCGA. I think it's about 5%, if I recall, that did not have a P53 mutation, or at least it was not reported in the copy number high group. So there's a little bit of room there that we can still study and see what other surrogate markers might be able to highlight those cases. And Russell, I think there is one question for you. Dr. Russell, we have had recurrences in the so-called low-risk stratified endometrial cancer patients who were not subjected to any adjuvant therapy following a staging laparotomy and put only on surveillance. Will molecular classification prevent this? You know, that's a great question. And I think the answer is we don't know, right? I mean, so all of the prognostic data to date, with the exception of the PORTEC trials, has been retrospective data. So I would love for the oncology community to start organizing these prospective trials on a more organized basis. And we could start seeing if these markers are truly prognostic and if they could be used for that. If they could be used to help guide adjuvant treatment. So do you think that... That's a question for the three of you. Do you think obviously that, you know, there is room for improvement? Just Talin mentioned that there is a subset, a small subset of high copy number tumors that are P53 wild type. Someone asks for additional markers and we have mentioned beta-catenin and someone has asked about L1-CAM. Do you want to comment on that, Russell, Gianfranco, Talin? I would, if an oncologist asked me about those markers and said that knowing that information might help to inform their treatment approach, I would be happy to perform those in that. I think there's plenty of evidence in the literature to support that those could be helpful in helping to guide a treatment. Most of that data is retrospective for sure. But if this is like one piece of evidence that could help tip an oncologist one way or the other, I think it's worth doing. It's very inexpensive testing. Maybe in the low copy number known as specific molecular profiles. Correct. So of course, I think it's great that we have this structure for molecular subgroups, but really there are three. So there are three distinct groups, polyMMRD and P53 and all the others are mixed back and we call it no specific molecular profile and it's heterogeneous, right? So, and in that group, there's a real possibility for refinement and some of the low hanging fruits, candidate biomarkers have already been discussed. So those are obviously hormone receptor negativity, L1 chem overexpression and beta-catenin status. And those, the work we are doing right now and that I'm sure will be coming out the coming years will be definitely focused at refining this classification even further. And I think it is fair to say that we're likely going to be able to dissect out some of the poor prognostic NSMPs by some of these biomarkers. And since we are almost running out of time, I would like you, the three of you answering one question because the audience is composed by a significant number of clinicians. So in the era of the molecular classification of endometrial cancer, which is the place for traditional pathological analysis for myometal invasion, for histological typing, histological grading, lymphovascular space invasion. Any of you or the three of you. In my opinion, there is no difference between molecular classification and histological classification. There is, we have only one classification, the diagnosis. And the diagnosis comprehends histological features and molecular features. So in that case, I consider that histological features such as lymphovascular spaces, way to infiltrate the myometion, for example, melt pattern is an important point that only histologically we can assess because we know that melt means great possibility to have lymphonoidal metastasis, also low volume, but it is an important point for the surgeon and for the gynecologist. And in this case, melt is only histological features. There is no way to assess the melt system. Also other particular histologies such as mesonephric type, for example, is not completely assessing molecular classification, but histologically, the diagnosis is really important. So in my point of view, histological and molecular are not in a position, but molecular is an integration of histological. So histological is a base, molecular is the real integration that can have a lot of clinical information. But clinicians has a lot of information also by histological diagnosis. So thanks, Gianfranco. And I think that Russell, Talin and myself agree with that, that this is an integrate diagnosis. And as you said beautifully, the molecular classification is part of it, very important part, but should be integrated in the pathological report. So we are running out of time. Thanks a lot, the three of you for participating, for providing us with your expertise. Thanks a lot, Talin. Thanks a lot, Russell and Gianfranco. And it's a pleasure for me to hand over to Domenica Aloruso, who will follow with the second panel discussion. Thank you, Xavier. Thank you all of you for this really great, lively discussion, very helpful. I give voice to all the attendees and all the panelists. So let's move to the second part of the session, which is dedicated to the adjuvant treatment of endometrial cancer, which is the state of the art now, what are the perspectives? And I take the occasion to remember to our colleagues to please answer your question through the Q&A polling questions. Hi guys, it's Brian. Did we lose Keta? Do we have someone from the Canes group? I believe we lost Keta, yes. So why don't we do this? This happened to me yesterday. Let me just share my slides. Let me share my slides. I'll give my talk. First session and Keta can come next. Yeah, that would be great. So for the panelists for my session, please stand by. And then for the AV folks, why don't you just keep me ahead of time? Oh, Keta is back. Brian, I'm sorry, I had a problem with the connection. If you agree, I can continue. Yes, please proceed. Thank you. Thank you so much. Okay. So what about the adjuvant treatment of endometrial cancer? As Xavier, oh, these are my disclosures. So as Xavier and the group of pathologists very well reported, probably endometrial cancer is the disease among the gynecological malignancies who've made the great step forward in the molecular knowledge of the disease. Since a few years ago, we believe that endometrial cancer were two tumor, the endometroid and then the smaller group of non-endometroid tumor, but the TGCA classification reported that we are in front of at least four different tumor with the different prognosis, as you can see in the slide, but also different molecular characteristics. The great effort as already said in the previous session was to try to integrate this molecular information together with the clinical information in order to better stratify patient according to risk factor. These are the European guidelines which were published a few years ago, represented in my opinion, a great step forward in this issue. And we reclassified according to the molecular classification but also taking in consideration clinical characteristic our endometrial cancer patient. And we try to define adjuvant treatment according to these characteristics. So very briefly, when we move in the different risk group, the low-risk patient are classified as the stage 1A low-grade endometrioid tumor without or with the focal lift of vascular space invasion. But when the molecular certification is no, in the low-risk group, we put also the poly-mute stage 1 and 2 tumors and the stage 1A MMRD and SNP tumors with the same clinical characteristic. As you can see, for stage 3-4 poly-mute tumor, the panel suggested that we have no enough data to classify this tumor as any risk group. So we concluded that for this population, stage 3-4 poly, a prospective registry are needed and recommended in order to better define the class risk. What adjuvant treatment for this patient? I think that we all can agree that for low-risk patients, no adjuvant treatment after surgery is recommended. Why? Because all the reports, all the meta-analyses suggest that when we try to treat this patient with radiation treatment, we were not able to increase prognosis of this patient, but possibly we worsen the prognosis due to the incidence of secondary tumor and toxicity. What about the intermediate-risk patient? In the intermediate-risk group jumped the 1b endometrioid low-grade lymphovascular space invasion negative tumor, the 1a endometrioid high-grade lymphovascular space invasion negative tumor, but also the 1a non-endometrioid tumors, I mean serious, clear cell, carcinosarcoma, without myometrial invasion. Very interesting, when the molecular classification is known, in this category jumped the MMRD NSMP tumor with the same clinical characteristic, but also the 1a p53 mute endometrioid and non-endometrioid tumor without myometrial invasion. What we can offer to this patient? According to our guidelines, this patient can be treated in the adjuvant setting with brachytherapy, which is recommended in order to decrease vaginal recurrence, but also, as you can see, the omission of any adjuvant therapy can be considered, particularly in patients younger than 60 years. Why? Because the PORTEC3 trial comparing external radiotherapy with the brachytherapy in this setting of patients reported that the two treatments were quite superimposable in terms of local control of disease, but in patients with the lymphovascular space invasion, it was reported a higher incidence of regional recurrence. And this data confirmed another GOG trial suggesting that in patients with lymphovascular space involvement, substantial lymphovascular space involvement, brachytherapy is not enough because it's not able to prevent most of regional recurrence. In fact, patients with substantial lymphovascular space invasion are upgraded in terms of risk in the I-intermediate group and represent, together with the stage I endometrioid lymphovascular space involvement, regardless of any grade of invasion, and 1B high-grade endometrioid in stage II represent the I-intermediate risk patient. When molecular classification is known, the same clinical characteristics with MMRD and SMMP tumor jump to this category. What kind of adjuvant treatment? The choice of adjuvant treatment in this patient, actually, is mainly based on the knowledge of lymphonodal status. When lymphadenectomy or sentinel lymphonode has been performed, and we are sure this patient has negative lymphonodes, in this situation, we can suggest several strategies for our patient. You will see how many options we have in this category. Adjuvant brachytherapy to decrease vaginal recurrence, external radiation treatment, particularly in patients with substantial lymphovascular space invasion or stage II, adjuvant chemotherapy, particularly for high-grade patients and patients with substantial lymphovascular space invasion. But also, you can see with the lower level of evidence, for sure, also the omission of any adjuvant treatment as an option. We will discuss during the panel discussion all these opportunities we have for our patients. But when the lymphonodular status is not known, and we really do not know if that patient is a real high-intermediate stage I tumor, the risk is higher, and the panel suggested that external beam radiotherapy is recommended, particularly when substantial lymphovascular space invasion is present or the patient is stage II. But also, the option of adjuvant chemotherapy can be considered, particularly for high-grade tumors and tumors with substantial LVSI. And adjuvant brachytherapy alone can be reserved and considered for high-grade tumors or stage II, grade I endometrioid carcinoma. What are the evidence for suggesting a so large panel of opportunities for our patients? The first attempt that chemotherapy can have a role in this setting came from these two randomized trials, the MAGI and the SUSUMO trial, comparing radiotherapy versus three or five cycles of platinum-based chemotherapy in this population. The trials were superiority trials, which did not report superiority of chemo with respect to radiation treatment, but the two strategies appear quite superimposable in terms of outcome with a substantial difference. It seems that chemotherapy was more able to prevent distant recurrence, while radiation treatment was more prone to prevent local-regional recurrence. So, the logical conclusion was that possibly these two strategies should be combined. And in this combined analysis of two trials comparing radiotherapy alone versus chemo plus radiation treatment, it seems that the combined treatment performed well in terms of PFS, but also cancer-related overall survival. And it seems it's very interesting to underline that PFS, depending on the possibility that patient had to complete or not chemotherapy. More recently, another interesting GEOG249 trial compared radiotherapy alone versus the combination of brachytherapy plus the three cycles of carboplatin-paclitaxel chemotherapy in this setting of disease. And the trial confirmed that the two strategies are very similar in terms of two-year recurrent pre-survivor with the arm of chemo with a little bit more toxicity. What about the last group of patients, patients with high-risk disease that in our classification are represented by stage 3 and 4a without residual disease, but also by stage 1, 4a, non-endometriotic tumor. And when the molecular classification is known, all P53 mute tumor with myometrial invasion are classified as high-risk. What we can offer to this patient? Also, in this case, we will discuss what is the best option because the options are several. Concurrent chemoradiation followed by chemotherapy or chemotherapy alone has the same level of evidence in this moment. We remember that carcinosarcoma should be considered high-risk carcinoma and all P53 mute tumor with myometrial invasion should be considered high-risk. What are the evidence for this option? The PORTEC-3 trial compared external radiation treatment and multi-therapy versus chemoradiation followed by chemotherapy in high-risk endometrial cancer population, and the trial reported at an update follow-up a significant increase of five years overall survival, but also five-year failure-free survival. For sure, the subgroup analysis reported that the benefit of the combined treatment was higher in stage 3 patients and in patients with the serious tumor, while the benefit in stage 2 was quite limited, only a 2% increase in overall survival and 5% increase in failure-free survival, suggesting from my point of view that this strategy should be discussed with the patient in the light of the risk-benefit ratio, because for sure, the combined treatment increased the toxicity. But we have another level 1 evidence, which is represented by the GOG258 trial comparing concurrent chemoradiation followed by chemo versus chemotherapy alone in high-risk disease, and the trial confirmed that the two strategies are quite similar in terms of overall and progression-free survival, with a point that needs to be underlined. It was a surprise to report that distant recurrences were more common in the chemoradiotherapy arm, because chemotherapy was given after radiation treatment, thus suggesting that when we decide to combine the two strategies, probably chemotherapy needs to be given before. This is the state-of-the-art now, but what is the future of adjuvant treatment in endometrial cancer? The application of the TGCA analysis to the PORTEC3 trial not only identified and confirmed the different prognostic categories, but suggests that polytumor has a very good prognosis regardless of any kind of adjuvant treatment, and possibly this patient does not need any kind of adjuvant treatment. On the contrary, P53 abnormal tumor presents the worst prognosis, and this patient gained major benefit by the combination of chemo plus radiation. HMMRD tumor seems not to gain benefit from chemo, and possibly in this patient, radiation or new treatment strategy are the best option, and the nonspecifical and molecular profile tumor gained limited benefit by the addition of chemo to radiation treatment. Actually, we know that these four categories present different molecular features that can be used in the future to guide adjuvant and advanced metastatic treatment. For instance, polytumor but also HMMRD tumor present an elevated genomic instability and tumor infiltrated lymphocyte, so possibly this patient may have benefit from immunotherapy, and all the trials using checkpoint inhibitor in patients selected for biomarker and MSI reported outstanding results in terms of response rate up to 50%. And for patients to present not MSI tumor, we have an alternative. During this IGCS Congress, but we're already presented the results of this combination, TKI inhibitor pembrolizumab plus checkpoint inhibitor pembrolizumab in comparison to chemotherapy in second and third line endometrial cancer setting reported an increase in progression free and also overall survival in this population. All this information now will be validated in ongoing clinical trials. We are trying to explore if the combination of immunotherapy plus chemotherapy is able to increase progression-free survival with respect to chemotherapy in advanced disease in first-line metastatic setting, but we are also exploring if the combination of immunotherapy and PARP inhibitor may increase outcome in comparison to chemotherapy. And further, we are exploring if we can substitute chemotherapy with the combination of pembrolimbatinib in advanced disease. But very interesting to me, Tallin mentioned it during previous discussion, the RAINBOW program. This program is probably one of the most interesting studies in endometrial cancer in this moment. This program enrolls patients with early stage disease or with no residual tumor who require adjuvant treatment. All these patients receive a molecular profiling and according to the molecular classification are treated in four different parallel trials. If patient is p53 mute, this patient will receive chemoradiation followed by PARP in the experimental arm versus chemoradiation alone. If patient is MMRD, this patient will be treated with radiation treatment versus the combination of radiation followed by checkpoint inhibitors. If patient present a non-molecular-specific profile, will receive radiation treatment as a standard of care versus radiation followed by hormonal treatment. And if patient is poly, all stage poly, this patient will not receive any kind of adjuvant treatment. So, in conclusion, I think that it is a very interesting moment for endometrial cancer treatment. Endometrial cancer is not a single disease, but at least the four different tumor with the different prognosis and the different treatment implications. Molecular driven treatment are the new strategy in the adjuvant, but also metastatic endometrial cancer treatment. P53 mute tumor require chemotherapy, but probably in the future we will discover this tumor need also PARP inhibitor. Polymute tumor probably do not need any kind of adjuvant treatment whichever the stage of disease. MMRD tumor will benefit more and more in the future by checkpoint inhibitor and the ongoing trial will explore what is the best adjuvant treatment according to the molecular profiling. Thank you so much for your attention. And now we will start the discussion. I have a very, very good panel of discussion, great colleagues from Europe and from US. Before starting the discussion, I just want to remember to the colleagues who are attending to pull the question in the Q&A session, but also to answer to a very quick question that we will discuss during the next few minutes. And in particular, the question is for our colleagues, but also for the panelists. Do you believe we have enough evidence now to suggest adjuvant treatment according to the molecular classification or we need more information before implementing it? So, while the colleagues answer, it is my pleasure to introduce the panelists for the second topic discussion. Mansoor Mirza, welcome Mansoor. Hi, thank you. Thanks for inviting me. Daniela Matei. Hello, thank you for inviting me. Hi Daniela and Karin Kreitzfeld. Hi, it's a pleasure to be here. The panel is very interesting because we have the European point of view, split the inefficient, more prone to give chemotherapy and one other more prone to give radiation treatment. And also the US point of view, which is represented by Daniela. So, I'm very happy to have a so interesting panel discussion. So, I will start while waiting for the question of our colleagues. I will start asking you the same question I ask to people with attending. Do you believe we are prone to use molecular classification to guide adjuvant treatment according to the subgroup analysis of the PORTEC-3? I don't know to whom you are asking this. I'll just start and the others can give their opinion. I think we were happy at first when we completed PORTEC-3 that we thought, okay, state three and serious cancers, they will benefit from chemo. And the others, you have to discuss the pros and cons with the toxicity and benefit ratio. But then we were really amazed. It was much stronger than we had expected. The differences, not only in prognosis with the four molecular groups, but also in the difference between the two treatment arms. And that's why I think just also respond to an earlier question of the audience that they said the best benefit to get from POR-E determination is in low risk. I think that in high grade, apparently high risk tumors, that then the consequences of detecting a POR-E mutation are largest because otherwise this patient might get chemo and radiation, but otherwise with POR-E mutants, you could really discuss if they would need any adjuvant treatment. Having said so, there are people saying that in PORTEC-3, of course, all patients with high risk tumors who had a POR-E mutation received at least radiation. So in the rainbow blue, we will for the more advanced stage also allow some adjuvant treatment to just learn from it. Thank you, Karin. Mansoor, your point. Yes, thank you. And thanks for inviting me to this session. It's great and great talk, Keita. First, I want to, you know, really emphasize the work has been done by the Dutch group for so long and so, you know, systematically answering one question from and the other. And this is really helping us today to discuss what we are discussing today. But when said that, I would say that we are there, that we have received quite a lot of information about the risk factors. And we have the retrospective analysis from the prospective trials telling us, guiding us that probably we have to treat this way or the other. What we are missing now is the level one evidence. And I believe that we are ready to plan. And already you mentioned the last, the trial, which is already ongoing and there are other trials ongoing. We are ready to plan wiser trials on the basis of PORTEC-3 wonderful molecular information to find out if this holds in the future trials. And I think this is what is ongoing. Partially, we are ready, probably. Partially, when it comes to the MSI, high or MSS, I believe that we are getting ready and I believe that we will not be giving any chemotherapy to the MSI high patients in future. Probably it would be enough to give a PD-L1 as adjuvant therapy. I say, I believe we have to prove it and trials are ongoing. So that would be my cautious way to say that we are in a great era, that we have so much great information available and we have to really implement that in smart clinical trials. Daniela, we show you our European guidelines. Do you use, or are you guided by molecular information in choosing a treatment for your patient in US? Yeah, endometrial cancer is a fascinating disease in that, you know, generally it has a good prognosis but then you have a subgroup of patients who relapse and die from this disease. And what's fascinating, I think, about uterine cancer is the diversity, the histological diversity that so many subgroups kind of, I think, difficult for the general oncologist that doesn't think about endometrial cancer all the time. It's difficult to kind of, you know, follow. And now we are finding out that we have also a lot of diversity in molecular pathways. So now we have even more complicated, it's hard for me as an expert in endometrial cancer to, you know, to keep all these different factors in mind. I think in the US, especially given our payers, you know, policies, we are guided by level one evidence as Mansoor mentioned. But I think that we are now at a great point, you know, in historic, in the history or evolution of treatment to plan smart trials. We have to think about these patients that, right, we can cure them. Sometimes we can just cure them by surgery alone and they'll live a long life. And we want to make sure that they don't live a long life with a lot of toxicity. So, you know, although we are very excited about radiation, at least in Europe, the evidence for the stage three patients does not support that chemo radiation is in fact superior to chemotherapy alone, but it has a more toxicity. So that's another angle. But I think- How would you then explain that you had in both arms survive here, relapsed free survival of 85% while it was the same in our radiation alone arm? All of the trials point to the same, that the extra benefit of the chemo, if it's there, should be to select a patient because it's small if you look at a whole bag of tumors together. Let me just finish about the molecular points. So I wanted to say that I think, you know, with the recent proven evidence that immunotherapy is highly active in metastatic disease, I think we're going to see this coming into the adjuvant setting for the lower risk patients. And that will be certainly guided by molecular classification. So I think we are, you know, at the transition point, we can have aspirations that we will use the molecular classification more in the future, but I don't think that we are doing that today in standard of care practice. We are doing it in clinical trials. And, you know, it's difficult to plan this trial that are not going to be a mixed bag of tumors, but more selected patients for each individual subgroup. So your point is that probably we need further evidence, the level one that Mansur mentioned. Based on trials. Rainbow is just the start of this way to work. And thanks again, Karin, for starting that idea. So I think Rainbow is just the start. And that's exactly what we should do now. We should try to, we have been doing dinosaurs. I have been doing dinosaur trials. I call them dinosaur trials because everybody get treatment A or treatment B. And there was no subgroups. And now we are understanding, we are becoming wiser about the molecular classification. And we really need to plan. It's us who has to plan these trials. It's us has to run these trials and get the level one evidence. Completely agree with Daniela. Daniela mentioned the heterogeneity of endometrial cancer. And one of our colleagues who is attending ask a question. If we believe, he reported that he experienced recurrence in so-called the low risk patients according to the clinical characteristic. And he has, in your opinion, in our opinion, the implementation of molecular classification to better stratify the so-called low risk clinical patient in order to prevent some of this recurrence. But that's what we hope. And that's what the hint is from the oldest, all the data, which is there. Going back to protect three and the subgroups, seven said that, I think again, we have to validate our new classification with clinical trials. That's me, but I also think that the molecular classification will not only help to prevent recurrences and otherwise low risk cancers because you might find an undetected P53 mutation or you might find L1 chem. I would think that the molecular classification strongest when integrated with the strongest factors such as LVSI, L1 chem. And also the molecular classification will also help to deescalate treatment, not only for POE, but also for other, and not only PORTEC4A, but also the Canadadian taper trial. I think that the U.S. is also going to participate in the trial if you can also add treatment deescalation based on such factors. Unfortunately, the time is running, but before leaving the stage to Brian, the last question with a quick answer. One colleague asked if, in your opinion, the molecular classification in the future will guide also the surgical treatment in terms of what patients should be staged or not, what patients should receive lymphadenectomy or not. What is your opinion? It took an effort to do the ECLAT trial. It never moved. It was such a pity. And it is difficult. I think the session we just had, the presidential session where we discussed how difficult it is to do the surgical trials. And of course, it would probably, it will guide. I'm not a gynecologist, I'm the medical oncologist, but I believe that we have some great achievements in surgery. And I believe that this alone is moving our survival to a next level. And the same is for the radiation oncology and for medical oncology, but surgery has really, really improved. And we, I think, both Karin and I being not surgeon, would give that credit to our surgical guys. Lovely. I'm not a surgeon either. Or Daniella, yes. So thank you so much. I want sincerely thank this great group of panelists, Mansoor, Karin, and Daniella. Thank you so much for being here. And Brian, the stage is yours for the third part of the meeting. Great. What a great session. That was really nice and formative. And it's always nice to present with such a great, really, group of investigators. I want to thank Rob, Anna, and Matt for allowing me to participate in this great session. Obviously to Cat and Xavier for working with you. It's always a great opportunity. And Mansoor, it's really been great being a partner with you, especially with our NGOT-GOG liaison work. So I want to thank everyone for being here over the next 15 minutes. I want to go through the treatment of advanced and recurrent endometrial cancer and sort of continuing the conversation that we're having. Is chemotherapy, you know, when is going to be the end of chemotherapy? And I do think as Mansoor was briefly saying, I do think that we're going to get there soon. So I'm excited about this talk and I'm really excited about the conversation and the panel discussion that we'll have afterwards. Here are my disclosures. Real briefly, when we're talking about getting rid of chemotherapy, we need to know where we are today. Here's the NCCN guidelines. And I know in such a great international conversation like this, every country has their own guidelines, but we're sort of aligned with what's going on internationally. In our first line regimens for, in the NCCN, carboplatin and paclitaxel, I'll talk about some of the alternatives there, particularly with the great work done by Amanda Nichols-Fader. And continuing, the NCCN appropriately still lists the progestin guidelines and some of the other biomarker treatment related options as well. Really not going to spend a lot of time on this slide because we know this, but our current standard of care for patients with advanced or recurrent measurable disease is carboplatin and paclitaxel. And this is based on Dave Miller's work in GOG 209, showing the equivalency to the three drug regimen with a decreased toxicity. And earlier this morning, if you missed it, Amanda gave a great review from Johns Hopkins. She gave a great review of uterine serous carcinomas. And what she highlighted in those patients with HER2 elevation, whether plus three by IHC or whether they were amplified in the IHC2 setting, those patients that were treated with carboplatin and paclitaxel with Herceptin of trastuzumab did better. The benefit was particularly striking when given in the upfront setting and for stage three or four patients, the median overall survival was 25.4 with chemotherapy versus not reached in those patients treated with trastuzumab as well. And in all comers, it was 24.4 versus 29.6 months, which was clinically significant. You know, this, and as seen in the NCCM guideline, this was a tremendous advantage for those patients with HER2 positive disease. Again, an older slide, I just want to highlight that hormones are still a good option for these patients with advanced or metastatic disease. The two most active regimens are the progestins with tamoxifen. Truthfully, oftentimes we're still using the progestins alone. I want to highlight here, and I like to go bantering a little bit with Mansour that letrozole is not one of the most active agents. And when we talk about paleo, we'll see if it was the right control arm, but either way, I think, you know, this gives us an option for our patients, particularly those with the ER positivity and low grade may be a surrogate of that, that hormonal therapy still has some responders. And we've talked about this slide really all morning and for a lot of the conference when we're talking about endometrial cancer. So I'm not going to go into it in depth. However, just to highlight these subgroups don't just classify hot tumors that will respond to IO versus cold tumors, but it also gives us a sense in each group which of the mutations that we should go through. And I think Keta highlighted that in one of her slides as well. How, you know, picking when we're talking about biomarker driven therapy, which groups can be treated with certain inhibitors, not necessarily in the immunotherapy group. As many of you know, the GOG did the study, GOG-3007, where we did a randomized phase two trial of Everolimus letrozole versus the active hormonal therapy, the progestin and tamoxifen. In this study, we, the objective response rates were similar, which I think it's interesting. And, you know, we may see that more and more as we're doing these biomarker driven mTORs or CDK4-6, we may see similar response rates. However, in the Everolimus letrozole treated group, the PFS was 6.3, OS not reached, compared to 3.8 and 16.6. Compelling from this study, and this is something that we need to take into account, especially as IO moves further and further into the frontline and maybe in the adjuvant setting, that in chemo-naive patients, this is looking at chemo-naive patients, the response rate to Everolimus letrozole was 53% with a PFS of 21.6 months. We always say we can't do cross trial comparisons and we're not, but when you look at, when you, sorry, when you look at that compared to carboplatinopaclitaxel, the 21.6 months was greater than the 14 months seen in the GOG209. Moving ahead in the Paleo study, which I alluded to earlier, Mansour did a really nice study presenting this at ESMO, comparing the CDK4-6 inhibitor pavlocyclob with letrozole versus letrozole alone. Again, my only consideration of this trial is if letrozole is the best control group knowing that the progestins probably are a little bit more active than letrozole alone. But that being said, the primary endpoint was PFS and the hazard ratio is 0.56, three versus 8.3 months, suggesting activity of CDK4-6 inhibitors in combination with aromatase inhibitors in patients with advanced or metastatic disease. Secondary endpoint was disease control rate and we could see that there was also a benefit in those patients treated with the CDK4-6 inhibitor, 63.6 versus 37.8. We talked about this a little bit earlier, but when we talk about iotherapy in a non-biomarker-selected patients, really two conclusions here. One, it's not that active. And secondly, it's pretty much a class effect across all the different checkpoint inhibitors. For a while, when GARNET data was first presented, we thought it may be a little bit higher, but on reevaluation, it's somewhere in the single digits to 13%, not that robust in knowing that in that population of patients, we really need to add something to it in order to get a better response in the IOs. However, obviously in the biomarker-selected patients, and we know there's at least two FDA indications based on this, PEMBRO and the Starlomab, in those patients with DMMR or MSI-high, there is good activity. And again, it's probably a class effect. We don't do any head-to-head comparisons, but in the mid-40s to 50s, percentiles in response rates we're seeing obviously suggest that this is a good agent and we should move forward on IO, particularly in those patients with these subgroups. And I don't want to be repetitive of what we've seen. Vicky Maker led this really game-changing study in all comers, particularly in the proficient MMR patients, a combination of Wenbatin and PEMBRO versus dealer's choice chemotherapy, the doxorubicin with a weekly pack of Paxil, did better. All comers in the PFS, 7.2 versus 3.8 months, in the PMMR, 6.6 versus 3.8 months, and similarly in overall survival that we saw an advantage. You know, game-changing type of study. And we saw the updated data here at this meeting, really great work that really does great for our patients. I want to spend now time on, you know, where are we going? I think a lot of the earlier talks talked about this, but I really want to go a little bit, dive deeper into the current trials that we're looking at and how they may change the landscape moving forward, how they may predict the future. I've separated this into categories. The first is adjuvant trials that we have. And a lot of this, as I alluded to earlier, but a lot of this we can't do by ourselves. And through the GOG-NGOT relationship, we've really come together and are doing some really nice trials that really will hopefully globally affect our patients in a positive way. Adjuvant trials, we haven't had a large treatment adjuvant trial in a long time. It was always difficult to put one together. The first trial here is an NGOT trial, EM11-GOG3053. I'll go through this slide in a little bit that's currently active and recruiting. For all this, I am very careful about this. All of these trials are in the public domain and their clinicaltrials.gov numbers are listed there. In addition, I'll show you the schema of fluorobaccus's GY020 study that we're actively accruing in the adjuvant setting. KETA did a nice job really defining what we consider high-risk early-stage disease. And this is the criteria for this population, for this study, GOG3053 or Keynote B21. Patients with surgical stage one or two with myometrial invasion of non-endometrioid type. And related to the first conversation, which was really great and Russell brought us as a friend, the P53 expression not only could help with diagnosis, but we're using it here as an eligibility criteria for stage one endometrioid patients to put on this trial, knowing that those patients do worse. So it is really coming into play. And I do think personally that all patients with early-stage disease should have a P53 stating as well in their initial workup. But basically chemotherapy plus minus pembrolizumab in stage one, followed by pembrolizumab maintenance in those patients who got pembro versus placebo maintenance. One of the reasons why we never got an adjuvant trial going up until now is because we've always had great debates with our phenomenal radiation oncologists on as far as whether or not radiation should be included. This study solves that. It allows for radiation at the clinician discretion. So it'll be one of the stratification factors, but this will really help accrual and has helped accrual, allowing for radiation again, if the clinicians want to include that. I mentioned also another adjuvant trial that is being done through NRG, stratification by radiation. Arm one is vaginal brachy alone with pelvic radiation versus the same with or without pembrolizumab. And that's ongoing and accruing. First line metastatic. I'll show slides on a lot of these. We're really come together and work nicely. The first two trials are looking at chemo plus minus checkpoints. And both of them now also are looking about the impact of PARP inhibitors in this setting. The third trial is also a study that being done by Vicky Maker, looking at a maintenance strategy with a nuclear export protein inhibitor, Salinexer. And three other trials. You know, a moment of pause here. I'm talking about six ongoing trials in the first line metastatic and recurrent setting for not ovarian cancer, but for endometrial cancer. We've never been in a situation like this before. We have so many active trials and we're gonna get a lot of great data and a lot of great information on best ways to treat our patients. Leave 001. I have slide on, it's a game-changing type trial depending on the results. Attend an NRG018. Similarly, chemo plus minus IO to see the effect. Here's the schema of RUBY. GOG3031, Mansour is leading this trial. This is actually part one where we wanted to see singularly the effect of IO with or without chemotherapy. And this accrued actually rapidly to 470 patients. And this will read out shortly. It's nice that we've recently opened up part two where similar to the next trial I'll talk about GEOE, part two is also looking at the impact of PARP inhibitors. So this one's Dostarlimab and Norepirib versus chemo and placebo in the maintenance setting for these patients. As we do know, and as has been mentioned, there may be a role of PARP inhibition in this population. A similar trial, but I definitely want to show it. This is GEOE led by the GOG on this one. Shannon Weston's doing a really phenomenal job with Katie Moore, leading this and partnering with NGOT and Dr. Burgotte and colleagues. Three-arm trial, chemo versus chemo and DERVA maintenance with Olaparib in two arms with DERVA maintenance and one arm with the quadruplet carbotaxel-paclitaxel followed by Olaparib and DERVA maintenance. Again, this is going to help determine what their future landscape is for the treatment of this disease. Finally, another study is the maintenance trial I mentioned, a nuclear X-point inhibitor, the Selinexer versus placebo after partial response or complete response in the frontline setting. And this trial, and I want to just highlight here, this may be a game changer. This is the first line trial of getting rid of chemotherapy in the first line. Pemberlin-Vatnib based on the extremely positive data that we've seen in the second line setting versus carboplatin-paclitaxel. This study has accrued, but it hasn't read out yet. And if this is a positive study, this will obviously be a game changer as well. So I want to congratulate the team who's working on that. Second line trials, these are all a listing of the second line trials that we have ongoing. We have a GOG303 that we're doing with NGOT, GOG3039, which is the U.S.'s way of doing the CDK46 inhibitor trial, which will be interesting, and Endomap that we're doing, a combination with the Alliance Foundation here and with Genentech. 3038 is shown here. This is a, the nice thing about this trial is two of the arms, it's an IO trial, first two arms, primary endpoint, looking at sort of a me-too trial, checkpoint inhibitors in MSI-high or DMMR patients, monotherapy. But arm C and D, this is going to be the first data that we have looking at checkpoint after checkpoint. Arm C and D allow for prior checkpoint inhibition. Arm C is a biomarker negative group getting breathed out in the lab with epicatastat, their IDO inhibitor, and arm D is for FGF mutation patients, tumors receiving the pemigatinib with their checkpoint inhibitor. This study is ongoing and accruing, and again, international collaboration. And finally, the last study that I'll present is AFT50, which is an endomap checkpoint naive, so these patients can't receive checkpoint biomarker driven. Right now it's three arms, but it's written to add additional arms, biomarker negative, atezolizumab, bevacizumab. If they have the AKT signature, atezo with ipihavastatin, and if there's less of heterozygous, similar to like a serous ovarian cancer, they're getting a PARP inhibitor that we're partnering with Pfizer on. So let's just briefly talk about what are we going to do to predict the future based on these results? How will this change things? Well, let's say that the rubies, the DOEs, the ATENs are positive and the LEAP trial is positive. This would likely push IO into the first-line therapy. It will eventually need head-to-head trial to determine which IOs are maybe more effective, or if the chemo IO is better or worse than the LEAP arm, the Pembrolin-Batinib. You may need to have a crossover-type trial to determine best sequence. We have to consider patient-reported outcomes in these type of trials. We always talk about the potential toxicity of chemo, and likewise, we talk about the potential toxicity of Pembrolin-Batinib. We need to include those in these type of trials. Obviously, in the MSI-high patients, we need to determine the contribution of Lin-Batinib. The multiple ongoing trials will determine if all checkpoints have similar results, and if these are positive, it'll change a second and third-line landscape. What if the chemo IO is positive, but the Lin-Batinib-Pembrolin is negative? Again, it would push IO into the first-line setting. We need to then determine the efficacy of Pembrolin-Batinib after IO, if IO after IO works. We'll need to evaluate the contribution of PARPS in the Ruby and DOE trial. Subgroup analyses of the LEAP MSI-DMR patients, and we need to do that separately. Obviously, we're going to have to determine if the checkpoints are the same. Scenario 3, chemo IO is negative, but LEAP positive. Again, there we'll need to determine the efficacy of chemo after IO. Again, we'll have to evaluate if PARPS work in the second-line setting, or if that stops in the first-line setting. And again, the subgroup analyses of the DMMR patients will be crucial. Moving along, what if both trials are negative? Then what do we do? I don't think this is going to happen, but what if IO is negative in the first-line setting? It'll really maintain GOG209 as the standard of care. We do have the ongoing CANDOR trial, which may still give us a better option in the first-line setting. It'll maintain the current second and third-line options. Again, re-evaluate PARPS and subgroup analyses will be necessary. Finally, what if the adjuvant trial is positive? This will really confuse the picture. What if B21 or GY020 are positive in the adjuvant setting? What do we do? Is there IO after IO? Will this move biomarker hormonal therapy to the first or second line? What about the DMMR patients in the adjuvant setting? Do we really need chemo? Or as Mansur alluded to, is checkpoint alone going to be enough? And finally, on the second line, how will that change the landscape? As I mentioned, Podium will evaluate the role of IO after IO. If that's positive, that could be beneficial for our patients. Endomap is looking at those IO-naive patients in doublets, and we need to continue to do our work in the CDK46 arena. That's what I have, and thank you very much for your attention. Let me just stop sharing. So, I have a quick polling question while we're getting ready for our next group of panelists. If you could go, and the question is, do you think patients with metastatic or recurrent endometrial cancer, who had MSI DMMR, should be treated with single-agent checkpoint or checkpoint with Linvatinib? And while you're answering that, I'd like to introduce you to my esteemed panel of colleagues, Nicoletta Colombo. She's actually the lead of the ATTEND trial, one of the IO chemo trials that we briefly referred to. Anna Okun, Rana Shapira, and David Tan. Thank you all for being here, and I look forward to our discussion. Let me, do we have the answers yet? Good. Well, Nicoletta Colombo, good. Nicoletta, let me start off with you. What do you think, I mean, you're a lead of one of these important trials. What is your opinion? If this is a positive trial, how is that gonna change the landscape? Do you think we still need to do something differently to the DMMR patients as far as getting rid of chemo? What is your take on this, and how do you think we're gonna move forward? Yeah. Well, I hope we'll be positive, of course. I don't know if we will be positive, but I hope. I think this will be a great step forward for sure for our patients. And of course, the question remains about DMMR if you really need chemotherapy or not. I think this will be probably one of the most important next question. In all these trials actually included all patients, all comers. They are stratified for mismatch repair deficiency, but of course, all patients are included because we think that the combination with chemo may overcome the problems of not having a deficiency in mismatch repair. So if this trial are positive, this will change the standard of care. And as I said, probably we need to establish whether for the mismatch repair deficiency, chemo is needed or not. I think this will be probably the most important question that we have. No, thank you for that. And right now in our polling, just to give folks, right now we're about, what is it? 61% would be CPI alone. Anna, you're a leader in this area. And what should we do? We're talking about first line. What if it is positive in the adjuvant trials? What if we're giving checkpoints right up front? I mean, what are your thoughts about checkpoint after checkpoint? What are your thoughts about sequencing? Should we save? If the results in the adjuvant trials aren't robust, should we save that until they recur in measurable disease? Please share your thoughts. I mean, this is a very good question, a very interesting one that we don't have the right response yet until we see the data from the first line therapy. What is clear is that we have some data in melanoma that when those patients who respond to IO in adjuvant therapy, they are able to respond once again at the recurrence. So it's something I need to explore. The point that I had been raised by Nicoletta is we need to see what is the real benefit in the MMR, namely in those patients who are the MMR and receive chemotherapy plus IO, those patients who receive limbotomy plus pembrolizumab. So I think we need to have a lot of answer in order to explore the next or the future landscape for the patient with the MMR. What is sure for me in those patients should receive IO earlier in the patient journey as we can. No, that's, there's a lot more to learn. Ronnie, let me hear from you. The toxis, you know, I alluded to this. Pembrolin-Vatnav has some toxicities associated to it and carboplatin and paclitaxel has some toxicities associated to it. If we had a crystal ball and we were to predict and, you know, if LEAP is positive and if these other chemo trials are positive, where are we going to go? Which direction will we go in? Will we give the chemo still or are we going to switch over to Pembrolin-Vatnav? So we have for the second line data of quality of life that chemotherapy was equal to Pembrolin-Vatnav. But of course, if we are facing the unique group of deficient MMR, it seems quite reasonable to expect they may benefit from monotherapy and they can be a reserve of the toxicity of the combination. I think it's, we just learned from the 775 trial that this arm must be included in all design studies. So DMMR patients must have a single arm monotherapy of the new IO as an option as well, at least in the studies to compare that to the combination of TKI and IO. And even looking at these patients, we might have from the collection of tumor biopsies from the studies, maybe we can learn who are these patient DMMR that needs the combination. Maybe these are just clinically signals like high burden disease, or maybe there are any other signals, biomarkers by the tissue that can signal the reason to give combination. Of course, it might be that in these patients who are DMMR and have high burden disease, maybe we need to choose the combination. We have to learn that, of course, from the studies and then quit the TKI and keep on with the IO as a single arm. If I may, Brian. So I think it's quite difficult to show a greater response rate with the IO plus chemotherapy in the DMMR. So when you look at the data of the paclitaxel carboplatin, the overall response rate is around 50%. And when we see the overall response rate for IO immunotherapy is around 50%. So for me, it's quite difficult to be able to raise the bar and to see a greater number of response rate in the combination of IO plus chemotherapy in this group. What I want to say is that although the patient have a high volume of the disease, I don't expect that the combination of chemo plus the IO in the DMMR provide a greater response rate. Yeah, no, I think that's a great comment. I mean, we've seen in the colorectal setting, the DMMR patients versus the PEMBRO versus chemo that the PEMBRO won out there. So I think we definitely need to do that trial in our arena. You know, one of my passions is again, to get rid of chemotherapy for these patients if they don't need it in a non-toxic setting. However, I don't think response rate should be our target. But when we talk about IO, I don't think response rate is really our target. I think we have to look for particularly overall survival and we know that this may be the case. So it's a kind of surrogate which probably does not work so well for IO. So I will be cautious about talking about response rate. Yeah, thank you, Nicolette. I made the comment because Ronnie was talking about those patients with high volume of the disease. I agree with you. I don't think that the overall response rate will be our target in terms of outcome for this group of patients. So I don't think that we should select our patient with DMMR based on the volume of disease. I wish to let the patient eligible for this therapy according to the outcome, long-term outcome that we will have in the coming trials. I agree with that. But I think that we still have about 40% of the patients that do not respond to IO despite being the DMMR profile, having the DMMR profile. So it's a very interesting question how we can identify these patients. I'm wondering if these are the patients who have higher burden of disease and maybe we can add not necessarily chemotherapy but maybe TKI to the first-line treatment and then omit the extra toxicity to keep them just on IO. So I agree with what Ronnie is saying then in the sense that perhaps the key is to select out the patients that do respond very well to single agent IO therapy. And then in those that don't respond, figure out exactly why they're not responding, right? It could be multifactorial. I mean, there are many factors that modify the microenvironment in a way that even with DMMR may not make you susceptible to IO monotherapy that's the microbiome as well as we're learning more and more. I mean, in the context of immunotherapy melanoma, for example, we're learning that patients that have not responded, if we tweak the microbiome a bit by doing a fecal transplant, they start responding. So perhaps those are the sort of more novel strategies that will have to be adapted in the future. And I think that the fact that we've seen such great responses and also don't forget from the keynote studies in 158, we saw very significant median progression free survivals that were prolonged even with single agent IO. So I do think that we're gonna see really good prolonged responses. And as you say, Ronnie, I think really it's understanding those that don't respond and then extrapolating that to possibly the PMMR group as well. Yeah, no, I think that's a great point. One question I wanna bring out from that's in the discussion group. Someone's asking about HER2 targeting given in the class of molecular classifications and why limit it to just the serious patients? Should we do HER2 testing in the non-serious patients? And there I would define non-serious as carcinosarcomas or in the grade three tumors. From my opinion, the answer is yes. I don't think that we should be treating these patients based on histology alone. I think the molecular classifications, even HER2 overexpression can drive these tumors. I do believe that future studies in this arena will include all patients that have the HER2 overexpression. But any other thoughts on that as far as just limiting that to the serious, David? Yeah, hi, Brian. So yeah, I think in the context of HER2 it's important to sort of define the mechanism of activity against HER2 you're talking about. Because if you're talking about the monoclonal antibody approach with Herceptin, for example, then perhaps the data suggests that it's the sort of HER2 overexpressed three plus and fish positive tumors that sort of are oncogene addicted that may have the better responses with that sort of Herceptin plus chemo. Having said that, we have ADCs now that are sort of possibly even active in those lower expresses of HER2 that might actually be susceptible to that sort of approach as well. So across all endometrial cancers, I think we see levels of HER2 expression in even across the whole plethora of histological subtypes of ovarian cancer. I think as a group, we'll have to understand a bit more about whether or not the ADC approach may also be relevant to those low expresses of HER2 as well. But then again, what will be the sequence of HER2 targeting? Yes. I mean, if you look at the, well, the FADER data, it does suggest the stage three and fours, you know, with Herceptin, it does make a difference. The question is also how long do you use that for and how long do you carry on with that for these patients, right? Do you do sort of like the breast cancer strategy, do a year and then you stop, or do you just carry on? If they haven't received a complete response and they're still in partial response, do you just say, right, just carry on with Herceptin and how long do you do that for? So again, I think there's sort of questions that still need to be answered even with that strategy. Yeah. Yeah, I mean, thank you for bringing up this question. For me, my main concern is how we are selecting those patients for anti-HER2 therapy. So, because the determination of the expression of HER2 in endometrial cancer is far away from cancer and gastric cancer due to the heterogeneity of the tumor. So we don't know yet if 1+, 2+, or 3+, is the best cutoff to select this patient. In fact, you know, we are running now a trial with Trastuzumab, Daroxetam, and then we are selecting patients from 1+, 3+. So, I mean, we need to navigate further in the right selection of the patients. Otherwise, we'll be once again in a mess and we will not have the reliable biomarker. Mm-hmm. Yeah, such a great- I think, sorry, I think GOG is doing now a phase three, you know, or not? Or Carbotaxel plus Receptin, or in- It's in development. I think we're doing that with the GCIG as well, but it hasn't opened yet. I'm asking how would you select the patients in this trial? Because this is, you know, it's a large phase three. So it is important to understand how to select HER2 positive patients. So it's not ready yet, so you don't know. Yeah, but I think that's one of the priorities is to have consistent testing. You know, it's not, HER2 testing, it's not the same as breast cancer, right? And a lot of times we do that. For that matter, ER testing in endometrial cancer, that's already not, also not well-defined. When we try to do ER positive as an eligibility criteria, we don't have universally accepted ER guidelines. But speaking of this, now we're, it's probably safe to say that IO is going to move up into a first line, if not adjuvant setting. We as leaders need to be prepared for that world where IO after IO doesn't work, and what are our options then? You know, who would like to comment? And even Matt, sorry I know it's so on the line. CDK4-6, paleo was a positive study. Is that a future second line therapy? mTOR is something I was involved with. Where should we, or even chemotherapy, where should we go from there? Whoever wants to take it. I would say you also are not forgetting the EN5 trial. That is a pure maintenance trial after chemotherapy. So that could be an option. The Siendo. Yeah. You know, and I mentioned that briefly, but you're right, the nuclear exploit inhibitor, which is accruing nicely in both of our groups. That may be a great option there. But you know, what else? So we have another agents on the horizon. We have the gui inhibitor for those patients who are P53 of serocystology. I mean, they will be an excellent option after failure to IO, because maybe we are going to deliver IO plus chemotherapy in those patients that the majority of them are mismatched repair proficiency. So I think we should continue our, I mean, our analysing of these new agents. But for sure, I think that gui inhibitor are a promising agent for this group of patients, serous of P53 mutant. Yeah, I agree. I think, you know, if we move IO front line, then for second line, we have to go more personalised or more precise and look at different histotypes and different molecular profile. So for instance, for the P53 mutated, as Anna said, there is this ongoing trial with a divositive, which is a gui inhibitor. And this is a very interesting approach, but also path inhibitor in this population should be tested. And for the hormonal positive, we should expand the hormonal treatment, which remains a very effective treatment in patients with hormonal positive receptors. So, and the paleo is just one way to go, but maybe we can think also other combinations. And then in the mismatch repair deficiency, remember the radiotherapy seems to be very effective. So we should not forget about also radiotherapy in case of localised, of course, disease, because it seems at least for the PORTEC3 transport tech analysis, that radiotherapy may be effective in mismatch repair. So I think we should individualise, you know, in case of second line treatment with more precise approach for each different histology or molecular different tumours. I'll take Nicoletta's point as well. In fact, in the context of recurrent disease, it's really important also not to assume that the original tumours molecular profile is the same as the recurrent lesion as well. We've seen some patients with DMMR initially, then subsequently when they recur, when we profiled them, we find that they become PMMR. So, I mean, the point as well is if we're going to move into a sort of precision umbrella approach to how we manage these cancers, the ability to profile and really to understand the molecular features of each tumour at each point of recurrence is going to become more and more important as well. Yeah. Yeah. Thank you. I think the bottom line of that is that we need to have the molecular profile for every single patient with endometrial cancer, because it's the only way to move in the personalised medicine. Now we have therapy, again, HER2, we have therapy, we inhibit our PORTEC3. For, I mean, for sure, I've not mentioned the mismatch repair proficiency in a state but it's quite important to have the global picture for every single patient in order to determine what is the best therapy for each one. Yeah, no, these are all great points. I'm sorry, these are all great, great points. So go ahead. Okay, sorry. No, I was going to say these are great points. We're coming to the end of our session, but, you know, I just want to re-highlight, first, it's great work in this group. The future is bright for endometrial cancer. It will be a multidisciplinary effort, gynecologic oncology, medical oncology, radiation oncology, pathology. It'll be a worldwide effort. You know, we need to come together in our international forums like this to come together and share our knowledge so we could get the best response for our patients so they can live longer. So, you know, this is really exciting. This concludes our master session on uterine cancer. I think we covered a lot of great information. The panellists, you guys, everyone's been great. Be sure to explore the rest of the meeting portal when the programming is done for the day. There's a lot more to see. If you missed any part of the session, it will be available here until December 4th. As a final reminder, IGCS is running some contests on Twitter. So if you're a big tweeter, head out, check out Twitter, and you can hashtag IGCS 2021. That's IGCS 2021. The more chances you have to win the prize. If I wasn't a gynecologic oncologist, I was going to be a used car salesman. They're also doing a photo contest for those to take a picture of your experience online. Make sure it's an age-appropriate picture, but that could also be tweeted out. Two things. Next in the hallway, I want to remind you there's an ovarian cancer debate. Should all newly diagnosed ovarian cancer patients receive the PARP inhibitor as maintenance therapy? You don't want to miss that. And more importantly for me, Rob has selected myself and Audrey to lead the IGCS 2022 in New York City, the center of the world, the capital of the world. So it's, we'd love to see everyone there. And we look forward to that meeting and to have similar great discussions. Thanks everyone for your time. And I look forward to seeing you all soon. Bye. Thank you. Bye. Thank you. Bye-bye. Thanks everyone.

uterine cancer

molecular classification

endometrial cancer

treatment decisions

molecular subtypes

adjuvant treatment

radiation therapy

chemotherapy

brachytherapy

immunotherapy

PARP inhibitors

trials

checkpoint inhibitors

metastatic endometrial cancer

recurrent endometrial cancer