Hello and welcome to the first Master Session of IGCS 2022. We are so happy to see you here in person and shout out to the delegates participating virtually. My name is Glauco Baiocchi and I'm the co-chair of the Uterine Cancer Master Session alongside with my amazing colleagues Dr. Ramesh Eskander from USA, Brasiela Dalmolin from Brazil, Jessica McAlpine from Canada and Mansur Mirza from Denmark. The title of today's Master Session is Management of Endometrial Cancer in the Molecular Era and I can confidentially say the session is filled with amazing education and research. I will now pass it over to Jessica McAlpine who will moderate this first panel. Thanks very much Dr. Baiocchi and we are excited in this first panel to talk about surgical controversies in early stage disease. We encourage people to come to the microphone with their questions and I encourage the speakers please of the first four sessions to come and sit after you're done your presentation. So Dr. Mario Luteo is going to start us off with the presentation. Should we avoid uterine manipulator in MIS for endometrial cancer? Thank you. All right. Thanks. Thank you Jessica and welcome. Good afternoon everybody. All right. So this is in my slides. All right. I don't know all of a sudden this has come up now. Uterine manipulator is an MIS for endometrial cancer. I guess the lack trials just devastated our whole MIS world for oncology. So here we are. These are my disclosures. I don't own any stock in any company that makes manipulators. So I don't really care if you use them or not. It's up to you. I always like to give any surgical talk with this sort of overall statement. You know bad technique is bad no matter what tools and what approach are used. As oncologic surgeons you always have to remember your basic oncologic principles of surgery. And if you cut those oncologic principles or curtail them then you're going to hurt people with what you're doing. So just as a reminder there was a large randomized trial endometrial cancer that showed that there was absolutely no difference in oncologic outcome comparing laparoscopy to open surgery. This is the cumulative recurrence curves for this trial with the curves are basically superimposed on each other. And the question from this and here's the survival curves that is two curves there. They're on top of each other. I would assume at least from when I was a fellow this is when this trial was ongoing at our institution. I was a fellow at the time. We use manipulators on every single one of our cases and we still do. It'd be interesting to know how many of these patients had the manipulators used at that time. I'm going to assume a lot of patients. This is a U.S. based trial. A lot of these patients had a manipulator used at the same time. But I can't know that for certain because I don't think no one really cared about tracking that bit of data. This is the LACE trial. This is in Australia New Zealand and Dr. Obermeier just walking in who led this trial. And again this is again a non-inferiority trial. A second large randomized trial showing that there's no compromise in oncologic outcome using or comparing laparoscopy to open for endometrial cancer. Now here I think, and you can ask him later, but I know that he's a fan of the McCartney tube. So this is a manipulator but it does not cross through the cervix or into the uterine cavity. But I don't know if he really tracked how many cases in the MIS arm actually used this manipulator or different types of manipulators. So if we have that data from these two large randomized trials maybe we'll have a slightly better answer to this whole question about the uterine manipulator and safety. Then comes this study. We're all using manipulators. I've used manipulators for 20 years and we still use them. It makes the surgery easier. It doesn't mean you can't do it without it. But I'm not a fan of struggling when I operate. But I also don't want to hurt patients of course. So this came out as a retrospective study, multicenter from Spain. And they had 1,000, 1,800 patients who had manipulator used and 900 who didn't have a manipulator used, all MIS. And what they noted was that there was a higher LVSI rate. And they also didn't mention that there was worse disease-free survival for FIGO 1 to 2. But I never understand these things. But for a higher stage case there was no difference. I always wondered what the biology might be. Or maybe it could be because the stage 3s had adjuvant therapy and it compensated for whatever was happening with the manipulator. So because of this now we are having a discussion about this. And overall survival, same message for the stage 1 and 2 in the Spanish trial. There was no difference statistically. But for the FIGO stage 3s there seemed to be. I mean, I'm sorry, backwards. For stage 1 to 2 there was a statistical difference, but not for stage 3s. And there's many theories as to why the manipulators might be bad. I think perforation I would agree. If you perforate and you start spilling tumor all over the place, just like with cervix, you contaminate the peritoneal cavity, you will have bad outcomes. You do this enough and your overall cohort will have a bad outcome. This whole thing about retrograde displacement of cancer, that's been looked at over and over, including our own series. And we look at positive washings and they have higher positive washing rates. But then that does not translate into a worse outcome. And it really correlates to the basic uterine features in terms of outcomes and not that there's positive washings. And then they talk about manipulation during insertion and copotomy. So you have gross tumor on a cervix, maybe don't put a manipulator in. And this whole thing about pressure and uterus leading to LVSI. I'm not sure how LVSI for 30 minutes or an hour, as long as it takes to do this, will translate to this immediate spread of cancer into the lymphatics and elsewhere. But these are the theories behind how a manipulator could be a horrible thing to use. The Italian Society of Gynecologic Endoscopy tried to tackle this question before that other one was there. And you can see here there's various types of uterine cancers there with different approaches. The recurrence rates, which may not be coming across very well, the recurrence rate was 13.5% in the group that had manipulators versus 11.6%. And those with no manipulator, and this was not significant. That's what is highlighted here with the arrow. And what they did notice is that even on multivariable analysis, the known usual factors associated with recurrence maintained their independent significance. But the use of a manipulator, which is here, was an odds ratio of exactly 1.0. It's not even a 95% included one. It was 1.0. Again, it's a retrospective study, but so was the Spanish one. And there it is, that 1.0 highlighted for you. And if you look at the Kaplan-Meier curves, the manipulator versus not, you can see here there's no difference in disease-free survival or disease-specific survival. The curves are on top of each other, whether you use a manipulator or not. Then there's been a meta-analysis on this topic, looking at manipulators and MIS. And look at this, and there's no LVSI, at least looking at the combination of analyzing the results from three prospective, 13 retrospective, two randomized. There's no difference in LVSI rates. There's no difference in positive cytology. Recurrence rate, again, there's no difference. The randomized trials that are mentioned are these. This is one that was published in actually 2013. The problem with this trial is that, yes, it's randomized, but the primary endpoint is not survival, it's just the rate of positive cytology. So, you know, they only randomized 55 in each arm, so you're never going to have an oncologic outcome that's reliable from a trial like this. But be it as it may, I'm going to show it to you because it just supports my point. Manipulator cytology positive, again, they said there was no difference statistically. That was the primary endpoint, but it's 7% versus 2%. Recurrence rates, again, statistically no difference, but it's 9% with the manipulator versus 2%. Again, some might look at this and say, oh, there might be a difference, of course, but again, not powered to answer this question. The other randomized trial was from Italy. It's the Romani trial. Again, the primary endpoint is not oncologic outcome. It's the rate of LVSI. You can see here that the number of patients randomized is 76 and 78, ultimately. And here they say that there is no LVSI concern, not even a trend like the other one I just showed you. And the problem with LVSI, it's very pathology dependent. The rates of LVSI in our series compared to that of our friends at the Mayo Clinic when we did our work together was like two to three times higher for the same cohort of basic uterine features. So there is quite a concern as to how you actually define and interpret the presence or absence of LVSI. But be it as it may, this randomized trial showed no difference. And they tried to attempt to look at survival outcomes. And again, the median follow-up here is a little short for a cohort that does very well. But overall, the curves don't seem to show any separation to maybe signal there might be a concern using a uterine manipulator. We use manipulators in all our cases. And we've looked at this. We are now updating this. This was presented at a prior SGO. And this is for our uterine serous carcinoma, some of the highest risk endometrial cancers. And we use a manipulator routinely on all our cases. So this is kind of a surrogate, although we never really tracked it. And the MIS curve is the green one, which is on top of the open arm here. So statistically, no difference between the two groups. And again, we use a manipulator on every case. Same thing for carcino-sarcoma, which we have published. And there was also no concern for any oncologic outcome we looked at in patients undergoing MIS versus open. And again, almost every single patient in our institution, we use a manipulator. NCDB, again, this is a high-grade endometrial cancer. These are two curves, one MIS versus open. And there seems to be no difference in outcome. We don't know how many have manipulators used. One can only assume that the majority have manipulators used because that's kind of a standard thing in the U.S. But I can't say for certain. Stage 2, when it involves the cervix, actually MIS is better here. The curve on top is for MIS. I can only assume that most of these cases also have manipulators, but one never knows. So the overall impression I have from all of this is that, as of right now, I do not see a reason that we have to be concerned about using a manipulator for minimally invasive surgery. What I think you have to remember is you have to adhere to basic oncologic principles. I mean, you have a tumor, an endometrial cancer, a gross tumor on a cervix. Don't chop it up. Don't mess with it. Don't be mushing up the tumor and then doing a copotomy and then lathering the peritoneum with tumor cells. If you have a thin myometrium, you want to be a little more cautious. You have an elderly lady who has a tumor filling the uterus, and the myometrium is paper thin. You know, you perforate. I'm going to guarantee you that if you perforate enough, you're going to have bad outcomes. That's just bad oncologic surgery. And if you have a very narrow vagina, that's going to increase your risk of perforation as you're trying to force a manipulator in there. So, you know, you just have to use some judgment based on oncologic surgical principles. There is a study underway, which is prospective, nonrandomized, planning to have 1,200 patients. It's called a promusae study, and we'll see what that shows when it's published. And I'm exactly on time, and I thank you all. Thanks very much, Dr. Mateo. So I'm going to invite up, thank you, I'm going to invite up Amirasi to speak on suspicious lymph nodes during sentinel lymph node biopsy. Is there a role for systemic lymphadenectomy? Thank you very much. Here are my disclosures, none of which are relevant for today's talk. So before delving into the real question of should we complete a lymphadenectomy, just a few pearls to cover at the beginning of the talk and to remember throughout. Surgery with the exception of hysterectomy, surgery for endometrial cancer is largely a diagnostic technique, particularly when we're talking about sentinel lymph node biopsy or lymphadenectomy. It helps tell us if the cancer is confined to the uterus or metastatic and therefore helps us define our adjuvant therapies. There's never been shown a therapeutic advantage for removing clinically normal lymph nodes regardless of whether they contain metastatic disease or not. And another pearl to remember is if a patient has a clinically suspicious lymph node, regardless or not of whether it stains with a tracer, that is the sentinel lymph node that has provided you with that diagnostic information. So what does a suspicious lymph node look like here in the right presacral space? We've uncovered one. What makes it suspicious is it's slightly enlarged, rubbery, bulbous. It's lost its ovoid shapes, more spherical, prominent vascular attachments to adjacent structures. Firm, you can see, doesn't manipulate normally. And this node did, in fact, contain metastatic disease. So how do we find these nodes? We can find them preoperatively on imaging. Some forms of imaging, such as PET, are more optimal to find these, but none are particularly sensitive, better at ruling in than ruling out metastatic disease, and expensive. And given that most patients with endometrial cancer do not have metastatic disease, not really feasible to perform on all patients. And so most of these suspicious nodes are actually found during our surgery. Once again, we know that any node that appears suspicious is, in fact, the sentinel node and should be removed, regardless of whether the tracer carries to that node. And in fact, we do know that failed mapping is more likely to occur in grossly positive sentinel nodes. So how do you confirm that this node actually has the metastatic disease? Well, you can either wait for final pathology or proceed within surgery with a frozen section. There's a pretty high degree of accuracy with frozen section for macrometastatic disease, and that makes sense. And if this is a node that's obviously enlarged, it probably has macrometastatic disease within it. But the problem with frozen section, and the problem with performing frozen section routinely on all sentinel nodes, is that it distorts the node and prevents the pathologist being able to perform ultrastaging to look for micrometastatic disease. And Dr. Mariani will talk to us about that in a moment. Whereas when we wait for definitive pathology, we lose the opportunity to perform our additional surgical procedures if we feel these are important. So you've done your frozen section and it's positive. What should you do at that point in time? Your options are either to leave it with just the hysterectomy alone and rely on adjuvant therapies, chemotherapy, or other cytotoxic chemotherapies and immunotherapies, et cetera, to treat the disease, plus or minus radiotherapy. Or should you complete the lymphadenectomy? And in order to answer that question, you need to have some idea as to what's the probability that the non-sentinel lymph nodes contain metastatic disease. In studies in which sentinel nodes were removed alongside non-sentinel nodes, about 60% of the time, the non-sentinel lymph nodes also contain metastatic disease when the sentinel node was positive. But that's only true if it's macrometastatic disease, which, once again, is likely to be the case in this particular patient who has a clinically suspicious node. So most of the time, the non-sentinel nodes will have metastatic disease. However, in most cases, this is non-clinical, non-bulky disease. So what is the virtue of lymphadenectomy for stage 3C disease? Prognostication. We know the number of lymph nodes relates to prognosis. However, that's not really a patient-centered outcome and not really a primary reason to complete a lymphadenectomy for a patient. Cytoreduction. Well, that's only relevant if there's truly bulky disease to cytoreduce, right? Not relevant for microscopic disease. But certainly, we've observed in endometrial cancer in retrospective studies that there is improved survival or appears to be improved survival when complete resection of bulky advanced endometrial cancer is able to be resected. Why? Possibly to make those adjuvant therapies like radiation, chemotherapy more effective. Somewhat local control, although metastatic disease to the lymph nodes arguably isn't terribly local in its disease distribution. And then finally, an argument has been postulated towards treatment planning, helping the radiation oncologists understand which fields they need to focus on with their treatment. As I mentioned before, debulking for endometrial cancer, the virtues of this are predominantly based on retrospective series. We lack level one evidence to support debulking endometrial cancer in the same way that we do ovarian cancer. What these retrospective series tell us is that there may be populations who benefit from this primary debulking approach the most, particularly patients with endometrioid cell types and a disease distribution that's more nodal rather than carcinomatosis. What we've come to learn more recently is that molecular markers are also really important in determining the likelihood of nodal metastases. We know that P53 mutations are strongly predictive of a high likelihood of nodal metastases, more so than just relying on histiotype or grade. And so therefore, clearly this would seem to be a potential role for incorporating preoperative molecular classification to help us with our surgical algorithms intraoperatively to decide which patients may benefit more from our either surgical debulking or completion staging. And we're going to learn a little bit more about that later this afternoon. With respect to radiation for node positive endometrial cancer, once again, not itself associated with improved survival, but does somewhat shift the disease distribution at the time of recurrence. In GOG258, when patients were either treated with chemotherapy alone or chemotherapy with radiation, the combined adjuvant therapy experience decreased nodal recurrences or less recurrences within the nodal basins. And this population was about three quarters stage 3C disease. So that's this population that we're talking about. But didn't change the overall recurrence risk. And so once again, what we need to better understand is, is this driven in particular by certain molecular subtypes. From PORTEC3, we understand the virtues of chemotherapy or cytotoxic chemotherapy may be greatest in P53 mutant cell types, whereas mismatch repair deficient patients may derive benefit from other adjuvant therapies, and that might impact our surgical decision making and the added virtue of surgery in those patients. So in practice, what I would recommend is considering preoperative imaging for patients who are at highest risk for having what you'll find to be a suspicious node. And those are patients who have P53 mutations, high grade lesions, or clinical stage 2 disease. And for those patients, it's critically important that intraoperatively you search for those suspicious nodes that you found on imaging. Look for the unstained bulky lymph node because it too needs to be evaluated and consider frozen section, but really only on these clinically suspicious nodes. And then I would consider completing the lymphadenectomy, but only of bulky lymph nodes, right? Only as a debulking or cytoreductive procedure. Once again, no known or measured or observed benefit for removing or cytoreducing clinically normal lymph nodes. It's important we balance the risks of what we're doing, though. Consider increasing risks of lymphedema, intraoperative vascular or nerve injury, and understand that lymphatics are contiguous beyond the aortic basin. We're really only removing part of this patient's lymphatics and by no means sterilizing her. It really isn't truly an R0 resection if the lymph nodes are involved. Once again, understanding that no level 1 evidence has established a survival benefit in the primary resection of metastatic endometrial cancer, but certainly not when the disease is clinically microscopic. And we need to better understand, and we'll understand that a little bit more in a moment, how preoperative molecular subclassification should be incorporated within surgical algorithms. And all surgical studies moving forward in endometrial cancer need to include molecular biomarkers as part of the study design. So in practice, should we complete the lymphadenectomy for a clinically suspicious sentinel node? Yes, if there are other bulky nodes. And yes, if this is going to change and improve upon the outcomes of the adjuvant therapy you'll prescribe. Thank you. Thanks so much, Dr. Rusty, that's a really practical and helpful synopsis of something that's a challenge and there isn't an abundance of data on. So great pleasure to invite up Dr. Mariani, who's going to speak to us about another challenge. Should all ITC and micrometastases receive adjuvant treatment? Yes, thank you. Thank you for inviting me here and I have nothing to disclose. I'm grateful to be here with friends and colleagues. Thank you Dr. Biocchi and McAlpine for inviting me here. As you know the definition of low volume metastasis is based on the diameter of the metastasis. And here you know that ITC is a relatively common way of spreading grade one endometrial cancer. Grade one, 8% positive node, 73% lymph node metastasis are ITC. Grade two and three, 12 to 16% positive nodes, 50% of metastasis are ITC. And cirrus, 20% of positive nodes and only 24% of metastasis are ITC. So ITC is a relatively common way of spread for invasive grade one endometrial cancer. But which is the clinical significance of low volume metastasis in the sentinel nodes? Here are two papers from Memorial and from Canada, early papers on this topic. Similar survival curves. Many of these low volume metastasis receive adjuvant therapy. We observed that oncologic outcomes are improved in low volume metastasis when compared to macro metastasis. Low volume metastasis we can say do reasonably well when they receive adjuvant therapy. Another paper from Memorial, 207 patients with positive nodes, decent follow-up. And you can see that 17% recurrence rate in patients with ITC, 17%. But most of the recurrence are high grade in cirrus histology. Cirrus is the strongest predictor of recurrence. So in patients with ITC, there are recurrences, but mostly in high grade in cirrus. Unfortunately, in this study, most patients have been treated with adjuvant therapy. And we have no good information on who can avoid treatment. And this is a large multi-centric study, only ITC endometrioid, 175 patient early stage endometrioid ITC, 43% had no adjuvant therapy or vaginal brachytherapy only. And they observed only 5% of recurrences. They say that adjuvant therapy is not an independent predictor of recurrence. And they conclude that adjuvant therapy should be based on uterine and molecular factors and not ITC only. The editorial that came with that paper, they say isolated tumor cell utility or futility. So perhaps they don't matter. And this is a great paper, a fantastic paper. I believe it's the best that there is on ITC so far, but there are some limitations. Limited follow-up, high risk patients are more likely to receive adjuvant therapy. There is no comparison with a lymph node negative patient with similar risk factor and adjuvant therapy, and 57% of these patients receive adjuvant therapy. It's a kind of over-treated when compared with a similar group of node negative patients. So here is a paper from Japan, not sent in a node. They did ultrastaging retrospectively in patients with negative nodes, lymph nodes, after lymphadenectomy. And some patients were found with low volume metastasis and ITC after ultrastaging. And look at this. The shape of the curve for low volume metastasis is flat until 40 months, and then it drops. So patients with ITC may be at risk for late recurrences. And this is a multi-centric study, Mayo Clinic led this study. And Dr. Biocchi is part of that as well. We published about one year ago some initial data, 247 patients with low volume metastasis, half of them are ITC, and one quarter had no therapy, adjuvant therapy, or vaginal brachytherapy only. And grade 3 non-endometrioid histology, lymphovascular invasion, and uterine serosal involvement were the strongest risk factor for recurrence. We have seen this before, so we confirm that. But is there a low-risk subgroup of patients with low volume metastasis? We look at 51 grade 1 patients with ITC only, 25 of them had no adjuvant therapy. We eliminated a few patients with lymphovascular invasion, which was a very strong risk factor for recurrence, and we ended up with 18 low-risk patients with no adjuvant therapy. And you can see, certainly, a low recurrence rate. But again, it's evident, yes, this may be a low-risk group, but again, still limited numbers and short follow-up. And also, look at the shape of the curve in our paper, again, for grade 1. So there is a possibility for late recurrences in grade 1 patients. And grouping together the two major studies, the one that I've showed, and looking for low-risk patients, we identify 77 ITC patients with grade 1 and no adjuvant therapy or vaginal brachytherapy only. And overall, they have only 8% of recurrence, certainly. But still, they have some recurrences. However, there is a hint, even if I don't have all the data for the study that we didn't participate, but there is a hint that lymphovascular invasion may be a risk factor, even in this low-risk group, for recurrence. This is the best available data that we have so far, but still, you can see small numbers and limited follow-up. So in conclusion, should all ITC patients receive adjuvant treatment, at this point, I think it's appropriate to treat them based on uterine risk factor. Certainly, it is very appropriate. Endometrioid grade 1 with low lymphovascular invasion may do well without adjuvant therapy, but again, small numbers and limited follow-up, what we have so far. And as approximately, think about this, approximately two-thirds of ITC patients are endometrioid grade 1 tumor. We need to study this low-risk subgroup better. We need more patients, more follow-up, especially for those who didn't receive adjuvant therapy. We need a registry. We need more data on the role of lymphovascular invasion. Is this enough to treat them? And we need to identify other risk factors that may help those patients that may recur. Thank you. Thanks very much, Dr. Mariani. Another challenging topic. And so now on to our final presentation before the panel discussion, Dr. Amy Jamieson. OK. Thank you. So I'm going to be speaking about, can lymph node staging and other surgical decisions be tailored in the context of molecular subtype? I have nothing to disclose. So for this talk, I'm going to start with a brief recap about the prognostic and predictive implications of molecular classification and how this can be performed on endometrial biopsy so we can have this information now before surgery. And then in terms of how it can impact surgical decisions, I will discuss this in relation to lymph node assessment, omatectomy, and fertility-sparing treatment. So as we know, following the discovery of the four molecular subtypes of endometrial cancer, two research groups used surrogate markers to develop and validate a clinically relevant endometrial cancer classification tool. And since this time, the prognostic value of molecular classification in endometrial cancer has been demonstrated repeatedly. We've seen this in unselected population-based series, but even in narrowly defined series as well, such as age and histotype-restricted subsets. But perhaps the most promising has been the predictive implications of molecular subtype assignment that has been recently demonstrated, such as these two studies that have shown that adjuvant chemotherapy significantly improves outcomes in patients with P53 abnormal endometrial cancer, but provided no additional benefit to radiation alone in patients with mismatched repair-deficient endometrial cancer. And the excellent outcomes observed in patients with polymutant endometrial cancer, even amongst patients with high-grade disease who did not receive any adjuvant therapy. So molecular classification was endorsed by WHO in 2020. And since then, we have seen societal guidelines changing to incorporate molecular classification into both risk stratification and treatment guidelines. Importantly, several studies have shown that molecular classification is highly concordant on diagnostic endometrial biopsy and hysterectomy specimens, therefore providing earlier information for patients and physicians. So we can now get this important information prior to surgery. So can lymph node staging and other surgical decisions be tailored in the context of molecular subtypes? I'm going to propose that, yes, it can. The data I'm about to share is retrospective data, and I do acknowledge that there's no prospective data looking specifically at this question. However, I think in this new molecular era, it's important to be raising these questions and having these discussions. So let's first start with lymph node assessment. We know from two randomized control trials that lymph node assessment in endometrial cancer is not therapeutic. But we do know it's prognostic, and lymph node status has been one of the most important prognostic factors used to determine adjuvant therapy in endometrial cancer. With this additional surgical procedure, there is an increased risk of surgical morbidity. We know there's a lot of good data supporting sentinel lymph node biopsy in endometrial cancer, and this is now preferred in centers where this is available. So I'm not going to talk about sentinel lymph node biopsy versus full lymph node dissection in this talk. But what I am going to discuss is, in this new molecular era, can we limit lymph node staging to certain molecular subtypes? And I'm talking about in patients with apparent clinically stage 1 disease, so patients with clinically negative nodes, because as Dr. Rossi has already mentioned, there is no survival advantage of removing microscopic nodal disease in endometrial cancer. We recently assessed the association between molecular subtype and the presence of lymph node metastases, and found that molecular classification was significantly associated with lymph node metastases. And molecular subtype was a stronger predictor of lymph node metastases compared to preoperative grade and histotype, a multivariate analysis. And as we know, preoperative grade and histotype is what's commonly used in many centers currently to determine who should have a lymph node dissection or not. So let's consider each molecular subtype in a bit more detail, starting with polymutant endometrial cancer. Patients with polymutant endometrial cancer have exceptionally favorable outcomes, independent of adjuvant treatment. And these patients now have the option of de-escalation of therapy, either through clinical trials, or as now recommended by the 2020 ESGO ESRO ESP guidelines. So one could argue, what is the point of doing a lymph node assessment in this molecular subtype if we are not going to be treating these patients with adjuvant therapy? Obviously a concern with taking this approach is missing node positive disease. And we recently found that lymph node metastases were detected in 14% of patients with polymutant endometrial cancer, which was higher than the rate of lymph node metastases reported in a poly meta-analysis. But not all patients included in this meta-analysis had had lymph node staging performed. But despite this higher rate of lymph node metastases, you can see in this Kappa-Myopot, the patients with polymutant endometrial cancer in blue had excellent outcomes with no recurrence or disease-specific death events occurring during this follow-up period. How about P53 abnormal endometrial cancer? The 2020 ESGO guidelines recommends that all patients with P53 abnormal endometrial cancer regardless of the grade, histotype, or stage should be considered high-risk and all should be treated with adjuvant therapy. So again, one could argue, what is the point of doing lymph node assessment in this molecular subtype in patients with clinically negative nodes when everyone is now recommended to get adjuvant therapy regardless? But there are some controversies that have come up since this guideline was published. So the first is patients with stage 1 disease. Do they really all need to be treated? Leon Costello and colleagues recently showed amongst patients staged by lymphadenectomy, so therefore confirmed to have stage 1 disease. Patients with P53 abnormal endometrial cancer still had high recurrence rates and poor overall survival. And therefore, the poor outcomes of patients with P53 abnormal endometrial cancer appears to be independent of stage. What about patients with stage 1A disease with no myometrial invasion? There's currently insufficient evidence to guide treatment in this subset of patients. We recently assessed the risk of recurrence in 218 patients with stage 1A P53 abnormal endometrial cancer. And in those patients who did not receive adjuvant therapy, the rates of disease recurrence were the same regardless of whether there was myometrial invasion or not at around 17% in both groups. And these recurrence rates should prompt consideration of adjuvant therapy. And what about patients with low-grade P53 abnormal endometrial cancer? There's evidence set up to approximately 5% of low-grade, so grade 1 or 2, and low-stage endometrial cancers of P53 abnormal. And we've pulled cases from each respective cohorts in the PORTEC 1 and 2 clinical trials and found that these patients who have low-grade P53 abnormal endometrial cancer have a substantial risk of disease recurrence, even in patients with stage 1 disease, with a five-year recurrence rate of 29.5%, again, supporting the use of adjuvant therapy, even in these patients with low-grade disease. In contrast, nodal status is very impactful for directing treatment with an MMRD and an SNP endometrial cancer. So should we restrict lymph node assessment to these two molecular subtypes, where nodal status would change adjuvant treatment recommendations? And again, just to recap, patients with polymutant endometrial cancer have excellent outcomes, now with the option of de-escalation of therapy. Patients with P53 abnormal endometrial cancers, these are aggressive cancers with guidelines now recommending that all P53 abnormal endometrial cancers, regardless of the grade, histotype, and stage, should be considered high-risk and treated with adjuvant therapy. And as I've already mentioned, you could therefore argue that nodal assessment would not change management in these molecular subtypes. So how about other surgical decisions, such as omentectomy? This appears to be especially important in patients with P53 abnormal endometrial cancer. We know previous studies have shown that up to 25% of patients who have a grossly normal appearing omentum at the time of surgery for uterine serous carcinoma, of which we know almost all are P53 abnormal, were found to have metastatic disease. And two other recent studies have shown up to 24% of patients with P53 abnormal endometrial cancer were found to have metastatic omental or peritoneal disease. And this was seen across all P53 abnormal histotypes, including serous carcinomas, clear cell carcinomas, and endometrioid carcinomas. And unlike nodal staging, a positive omental biopsy, and therefore upstaging to phagostage 4B disease, could alter the recommended adjuvant therapy, such as using chemotherapy alone. And how about young women who may wish to delay surgical menopause and or preserve fertility? So this study assessed the molecular subtypes in over 250 patients with endometrial cancer who were less than 50 years old. And as you can see from these Kaplan-Meier plots, molecular classification was prognostic in this cohort of young women with endometrial cancer. And this information could be used to guide who's suitable for a child of conservative hormonal management versus those patients who should be encouraged to have a hysterectomy. For example, you can see the patients who had P53 abnormal endometrial cancer in red in these Kaplan-Meier curves, they had poor outcomes, and you would not want to try conservative management in this scenario. So in conclusion, molecular classification can be accurately performed on biopsies, providing early prognostic and predictive information. This information could be used to guide surgical decision making, such as limiting lymph node assessment to molecular subtypes, where it will make a difference in management. It's performing omentectomy in all P53 abnormal endometrial cancers, not just serous carcinomas. And it could be used to guide treatment in young women who may wish to delay surgery and preserve fertility. But again, prospective data is needed, and that's why molecular-directed clinical trials should be encouraged. And I'd like to thank all our collaborators who helped contribute to this data. Thank you. So thank you. Thank you to the speakers for staying on time, because we actually have time for discussion. I think we've heard a very common sense, don't mess around with tumor cancer rules that make a lot of sense from brush of the tail, and then we have three talks that are talking about surgical interventions that context is really important. Is it going to make a difference in treatment, or could that information from a given thing, such as obtaining data on ITCs, be gleaned from other parameters, be they uterine or molecular? I encourage people to come to the microphone, and I'm going to start with one of the questions that's come from our online colleagues for Dr. Mariani. For ITCs with uterine factors, I guess, in other words, if you're driven to treat someone, they're asking you radiation versus chemoradiation, not a surgical question, really, but about that, it's a good question. Thank you. No, frankly, for high-risk patients, so like a serous patient, I would treat them if they have ITC and they have high risk, like if they are patients with positive notes. So this is how I would approach that. So ideally, so especially for the high-risk with chemoradiation. But at the same time, I acknowledge that there is also a group of patient of let's call them intermediate risk in which we don't have the answer to this question. So again, this is my best guess, but this is why it's important that we collect the data we get together really to answer this question even better. But thank you for the question. We'll take it from the back of the room, thanks. Hi, thank you. This is, I'm Amanda Fader from Baltimore. Wonderful opening session. Dr. Jamieson, that was a great talk. I have a question though about your provocative suggestion about omitting lymphadenectomy with our current clinical trial paradigms where stage is important in the upfront setting and in terms of existing design of trials. Omitting staging may be problematic in that regard in terms of eligibility for trials that are being done to move the field forward. Would you suggest that we solely focus on molecular characterization in future trial designs and eliminate stage in those paradigms? Yeah, it's a good question. I guess it depends on what the clinical trial is trying to answer. If it was, for example, should P53 abnormal endometrial cancers just be treated with chemotherapy or should those patients be treated with chemotherapy and radiation? I think if we were to design that trial, nodal status would be important because that would potentially help answer that question of is there additional benefit in radiation on top of chemotherapy, especially if someone has positive pelvic nodes, would you radiate the pelvis, also give a paralytic nodal boost? So I think it depends on the type of trial, but you're right, staging is an important trial eligibility. So I think moving forward, ideally, all clinical trials have a component of molecular classification in their eligibility criteria. So I would favor clinical trials rather than foregoing staging. Thank you. Dr. Obermeyer? Thank you very much, Amy. I also got intrigued by this thing about saying, if I understand you correctly, that 14% of patients with positive nodes had polymutations and they did all well. Did I understand this correctly? Yes. So that could mean a number of different things. That could mean, for example, assuming that a lot of patients had adjuvant treatment, that poly patients are extremely sensitive to chemoradiotherapy, which would be quite different to all other endometrial cancers. It could also mean that we may not need to surgically stage patients with polymutations. Would the panel be happy to say there is an element of unknown? I know for surgeons this is hard to say, that something is unknown. We don't like to admit that. But I think in advance to further the science on this, it would be nice to hear statements. What do we feel is known about this? But more importantly, to say what is unknown about this and what is unknown in surgically staging in fact of the data that you shared with us today? Thank you. Yes. It's a good question. It's a good point. And the rainbow blue arm, looking at management of de-escalation and poly mutant endometrial cancers, does have the option to include stage 3 patients with certain node positive patients with the option of de-escalation. So that trial will be really important for telling us the outcomes of those patients that do have de-escalation of therapy, even with no positive disease. I mean, I might add to that, too, I mean, that's a small number of patients in this series, right, that were lymph node positive within that. If the large meta-analysis, it's around five, another series around five or seven. But we know that those series were markedly under-staged and lymph nodes weren't done in them. And again, it just goes back to, in the meta-analysis, who recurred? They weren't just the advanced stage cases. Those are small anyway. And what is your justification for treatment? Huge resource implications of when nodes are done. So I think it should be something that's questioned or addressed. Oh, yes, go ahead. I think we're all way enthusiastic about this molecular stuff and it's great, but I don't see that we are ready to switch completely, eliminate what we know is already prognostic and useful in caring for these patients just with a completely new molecular profiling, which those of you who actually do this on a regular basis realize that a lot of these can't actually be accurately classified sometimes and there's all mumbo-jumbo on the results sometimes. They're not so clean. So I think what we need to do is continue to do what we know is prognostic, such as stage and histology, and see how these molecular findings augment our knowledge of these cancers as opposed to completely flipping over to just molecular. And who knows in 20 years from now, it's going to be a whole different molecular profile that we come up with. We should continue to do our research. We should not just automatically start replacing, because like it's mentioned, you don't always know if these patients were treated or not, if this is prognostic versus predictive of therapy. Those are all questions that are important to be asked, but I don't think we're ready to just completely forego surgical staging with an SLM mapping that takes 10 to 15 minutes with relatively little morbidity and actually less cost than molecular profiling. I'm going to go to our next speaker, but I will respectfully disagree and remind people no, please, I'd love to hear your question. Please come to ask it, but I was just going to say that not everyone has access in this audience or internationally to the resources for sentinel lymph node dissection and not everyone does nodes routinely. So I think we can't always wait for prospective clinical trials to come, and I don't think a new molecular wave is going to come. I think your last comment has modified my question, so I just have a small suggestion that when ITC is there, but there is also LVSI, then I would treat ITC simply as extension of LVSI and treat as if it was extensive LVSI. But if there is no LVSI and you see ITC, not only ITC, but if you have a positive node and there is no LVSI, then even the positive nodes, they do extremely well. So I would not treat if there was ITC but no LVSI, then I'll ignore that ITC from the adjuvant treatment perspective. And I would, that's good. I think we're on time and we can shift, but remember that clinical pathologic factors and other molecular features are not prognostic within POLI. So I think the message, I think, of what all these talks are coming at is that, again, it's context. Certain parameters matter more and will be essential to make a treatment decision in certain molecular subtypes, and they may not matter so much in the others, and we should continue to question. This session is meant to be provocative, so it should push some buttons about thinking of the next steps of where we want to go. Do you think it can, your question can go to the next session or do you, is it? For the, Dr. James, very, very, very quick, if you can. Thank you. You mentioned 5% of the low-grade endometrioid cancers, P53 overexpressed to abnormal. Was it done up front? Is anything different of those from other P53 abnormals? Is it fair, is it okay if I direct them to a poster on that exact topic in this session? Last name, Jameson. It's a great question of whether it's real, but they're low-grade endometrioids. But it's great, my great pleasure. I will invite our panel to step away. Thank you so much, all of you. I'm going to pass off to Dr. Del Moline, who will take it from here. You'll be lonely for a minute, but everybody will come join you. Thank you very much, Dr. McCartman, and thank you IGCES Scientific Committee to be here. I think this will be keeping here this amazing discussion, especially for international conference. We will have Navina Singh to discuss, how can I get molecular classification and subtyping for patients, considerations for both low and high resource settings. And I'm talking from a middle-income country, I'm from Brazil, and with the last comments, we know that the world is not the same. So we need to discuss this. Thank you. Thank you. I'm really grateful to be invited here to speak on molecular testing in different resource settings. These are my disclosures. I think I skipped my disclosures, never mind, there they were. So I'm going to go over a couple of things by way of background, and then briefly cover the barriers, and then come to the solutions, some that are already in place and some that are more futuristic. So by way of background, we've heard endlessly that the Cancer Genome Atlas, the four molecular groups classified by TCGA, offers a more accurate estimate of prognosis than the conventional parameters that we have been using all these years. And not only that, it appears to be predictive, not only for conventional treatment, but also to targeted treatment. So the question is now how to incorporate this in clinical practice, because across the world, there is variation in the resources, obviously. And so categorization has been put forward, dividing up our patients into low to high risk based on knowledge of the molecular classification, as well as in the absence of that knowledge. And where the molecular classification is able to be carried out, there the big differences are in the two polar prognostic groups, obviously. So that where a cancer case is P53 abnormal, then with the small exception of those cases that are stage 1a without myometrial invasion, these classify as high risk, regardless of histotype, grade, and the presence or absence of vascular invasion or stage, while at the other end of the spectrum, a stage 1 or stage 2 poorly mutated endometrial carcinoma classifies as low risk, again, regardless of the presence of LVSI and the histotype, the stage. And in fact, as you heard just now, even nodal status does not appear to make a difference in that group. So before we go to how we can apply molecular classification, let's see how we can not do it. We can not start with histotype. And as you can see in this diagram, all the four molecular groups have a mixture of all the different histotypes that pathologists diagnose down the microscope. And most significantly, as was mentioned just in the last session, P53 abnormal endometrial cancers, whether you look at all comers, as shown in the upper panel, or you look at just the high risk cases, as in the lower panel, they include a number of cancers that pathologists diagnose as grade 1 or 2 endometrioid. And so if you started with saying, let's just do this for the high grade cancers or for the high risk cancers, you would already be putting a subset of patients at a disadvantage. You can't start with histotype. You can't do what the TCGA did, because they used a complex multi-platform analysis. And you know in some countries how long you have to wait for a histology result. You certainly can't be doing all those fancy tests on it. But the PROMIS algorithm has worked that out for us and has been validated multiply over the last few years. We know that we can translate this into a routine clinical practice just using immunohistochemistry and sequencing for POLE. So one more thing to cover, though, is that although the four molecular classes are essentially non-overlapping, the three tests, unfortunately, are not mutually exclusive, meaning you can have an overlap. And in an extreme example, you can have a single cancer showing both a POLE mutation and a TP53 mutation. How are you going to handle that one? It's estimated that this occurs in about 3% of cases, but in truth, it may be a little higher than that, because that depends on our immunohistochemistry assessment. And the reason for that is very simple. It's because both POLE mutation and MMR defect as underlying causes for cancer result in high numbers of mutations in those tumors, and part and parcel of those mutations can be a mutation in TP53. So in an individual case, you do need the results of all three tests in order to classify it, and these tests need to be interpreted in a very particular algorithm. And this is what PROMIS has put forward, which is now incorporated in the WHO Blue Book, that you first consider the POLE status, you secondly consider the MMR status, and it's only after you've excluded both of those that you take TP53 or the P53 immunohistochemical result to interpret the remainder. So what are the barriers? Well, the first barrier is obviously cost, because next-generation sequencing, POLE does not still have an immunohistochemical surrogate. We've already seen that we cannot predict the molecular outcome by histology. Immunohistochemistry is cheap and standardized and quality-assured and available everywhere, but the access to next-generation sequencing is not really there at the moment. A second barrier, possibly, if I can go back to this algorithm, is the way that this algorithm is set out, that it puts POLE up at the top so that people think that, oh, if I can't do POLE, I can't do anything. And that in itself is possibly a barrier, but this is not all or none. There is a lot that we can do in the absence of, or at least limit the amount of tests that need sequencing. And then there are, as we've heard, a lot of clinical issues that need to be sorted out before we feel this is ready for primetime, but I think you know that better than me. So what are the solutions? So with the existing algorithm, we can do one of two things. We can either diminish the number of cases that require next-generation sequencing, and those are what we've done in the two algorithms that I'll show you that are already in place in different parts of the world. We can look for cheaper alternatives for POLE testing, cheaper than next-generation sequencing. And then there are a few future things to show you right at the end, if time permits. So this is the first algorithm. This is what we've incorporated in the United Kingdom, something we're very proud of. Of course, it's much easier to do that in the U.K. because we have a single publicly funded healthcare system and a single national genomics service, so all genomics tests are done in a few hubs across the country, which means that we have economies of scale, which means that we have all the quality assurance aspects worked out. But I'll walk you through this algorithm, if you allow, just one at a time. So up at the top, we ask for MMR, P53, and ER immunohistochemistry on every case. And out of this comes a group that is either MMR abnormal or P53 abnormal, and on these we recommend for POLE testing to be done on the biopsy itself. The reason for this is to pull out those multiple classifiers and enable the surgeons to know which cases are truly P53 abnormal, because high-risk cases should, you know, that should be known at the outset before any treatment is given. In the U.K., these cases are operated in different centers. If they are MMR proficient and P53 is normal, then they proceed to surgical staging. Because it is only after surgical staging that we have all the other parameters known. We know the histotype, we know the grade, we know the final stage, and we know whether or not there is substantial LVSI. And that pulls out our second group, the group which is very, very low-risk, that are low-grade, they are endometrioid, they are ER positive, they are stage 1A, and they do not have LVSI. And really, when we looked at this retrospectively in advance for asking for the funding, what we found was that that group that is shown on the right-hand side panel, for both disease-specific and progression-free survival, you would see that that fifth survival curve that appears above the four molecular groups consists of the best prognosis, NSMP and POLE, because we've removed the other two groups already, and they do exceptionally well, even better than POLE mutated. And here, you do not need to waste money doing next-generation sequencing, because knowing their POLE status is completely irrelevant. And then we come to the big group where this testing is needed. This is our group of stage 1 or 2 non-endometrioid cancers. So these are the ones who show any risk factor, whatever. They're non-endometrioid, or they're grade 3 endometrioid, or they have high-stage disease 1B or stage 2, or they have substantial LVSI. And the only other parameter here to explain is the ER status. And this is because of new data that are coming out, both from TransPortec and from Vancouver, showing the same thing, that if there is a way to subcategorize NSMP, that largest group that consists of 50% of our patients, it appears to be ER status. So ER-negative cases do exceptionally poorly compared to ER-positive. And in the Canadian study, what they have demonstrated is that this holds true even for stage 1 cases there, that the outcomes of ER-negative high-grade cases is substantially worse than the others. And so this group 2 requires knowledge of POLE status, because this is the group that could have cases that sit anywhere from low risk to high risk. And these are the ones where you do need to know POLE status, and also to say why ER is in our algorithm, because ER-positive NSMP constitutes a low-risk group. And if you combine low-grade with ER-positivity, that's the group you're looking at that has outcomes which are comparable to a POLE-mutated endometrial cancer. And then we come to the leftovers, which are the high-stage cases, stage 3 or 4. And here we recommend not to test for POLE unless the oncologist is going to change their treatment, because the management algorithms for this remain unresolved. In British Columbia, we came up with an algorithm that's slightly different for funding and logistical reasons, that all testing is done following hysterectomy, with the exception of MMR and P53 immuno, which we recommend on all cases, but it's not invariably done. But certainly the next generation sequencing is done only after we have surgical staging and knowledge of the final histotype grade and LVSI. And it is done on all stage one and two cases, except for those very low risk cases as defined in the previous slide. So finally, in my last couple minutes, come to the cheaper, the other solutions. You can use cheaper assays, actually. I'm gonna go over this very quickly. We've all known forever, you can use Sanger sequencing. You can use an RT-PCR based targeted method, which is cheaper in terms of reagents. But all of these still require a functioning molecular laboratory and they come with their own problems with sample quality and the interpretation and so forth. So I don't think they are really cheaper solutions. Much more exciting is what's coming in the future. The graph that I've shown up there shows how the cost of next generation sequencing has changed over the last decade. And you've heard this morning about PROMIS-II. If we can come to a one-step NGS, and NGS becomes cheaper than in the future, we might be able to do this as a single test on biopsy material. But very exciting, and in the future, in the near future, are AI histopathology algorithms. The genomics of any cancer are reflected in the morphology. The morphology, the response of the tumor microenvironment and so forth. And if you fit thousands of images of the different molecular groups into a computer, you are able to come up with AI algorithms that can replicate the, I'm not sure why my two graphs have disappeared, but I would have shown you a fantastic graph. This is bad luck to transport it, but where the AI categorization or prediction of molecular classes has very, very close to that which is offered by NGS. I'll show you what Vancouver has, very similar results, but showing that in those cases where there is a discrepancy between AI and the molecular result, it is the AI that seems to predict the outcome better than the molecular result. So it seems to be picking out bad actors within all of the subgroups. So very exciting, very exciting for everyone. Possibly not so exciting for pathologists. But in conclusion, molecular classification can be delivered with judicious use of immunohistochemistry and NGS. And this is the best way to deliver personalized treatment for our patients. I will go on and on. Thank you. Dr. Singh, thank you very much. And now we'll have a great debate. And in the end, we'll have time for questions. I would like to invite you to be here with us. So we'll now start a debate with a critical situation and we will start with what is the best approach for endometrial grade three with small volume long-term relapsed disease. We have all the type of treatments and we start with pro for surgery for Dr. Nadine Brewston. Thank you. Thank you and thanks to the program committee for the opportunity to present. These are my disclosures. So FIGO grade three endometrioid carcinoma, this pathologic entity is really a collection of at least four distinct disease types. And that's very important as we talk about this process. This is an eye-opening paper led by Jalink Bosi that included multiple institutions from Europe and the Americas, all done by expert gynecologic pathologists who confirmed by looking at biopsies that these are called FIGO grade three endometrioid endometrial cancers, 381 patients. However, this same group is actually more than one disease. 13% of them have poly mutations with a five-year overall survival of almost 90%. 36% of them are MSI high with a five-year survival of 75%. 30% are with no specific molecular profile and a five-year survival of 69%. And finally, 21% have the serous type P53 aberrant and have a five-year survival of 55%. So this is one group of patients that we have historically called grade three endometrioid. And in that same cohort on a pathology report, you have patients who will have a 90% survival and patients who will have 55% survival. So clearly we have to use the added value of molecular profiling to histotyping when we're talking about this disease. So surgery in endometrial cancer really is the cornerstone, is the main treatment modality for primary disease. For recurrent disease, the data on surgery is much more limited and multimodality approaches are commonly used and likely associated with better outcomes. Selection of treatment for recurrent grade three endometrioid cancer is usually based on patient's overall medical condition or symptoms, and of course, the patient preferences. Location of the recurrence, the presence of single versus multiple lesions, disease-free interval, and again, is complete resection of macroscopic disease feasible with an acceptable morbidity to the procedure? Very importantly, the initial treatment, including any adjuvant therapy, particularly external beam radiation and vaginal brachytherapy are important selection criteria. And again, the availability of resources to take care of these patients. So what should be the best approach for an endometrioid grade three with small volume, long-term relapsed disease? Again, small volume, long-term relapse could be a nodal recurrence, could be a vaginal recurrence, could be pelvic non-vaginal, abdominal or mental peritoneal. It can be pulmonary. It could be other, like a bony metastasis. The NCCN has looked at this, and again, you can see that for local regional recurrence, if patients have had prior radiation, there are options for surgical exploration, whether it was EBRT or vaginal brachytherapy. Similarly, ASCO, ASTRO, and ESP guidelines for the management of patients with endometrial cancer. Speaking about the oligometastatic recurrences, meaning one to five lesions, they do consider patients with oligometastatic disease should be considered for radical local therapy, which includes surgery, also includes radiation with either the possibility of stereotactic radiotherapy or other local ablative techniques. So just to illustrate a case, this is a 70-year-old patient who originally had a stage Ia grade III endometrioid carcinoma, initially had superficial myoinvasion, no LVI, negative staging, negative washings. Her germline testing was negative. Her original tumor was P53 wild type. She was ERPR positive. Immunohistochemistry was abnormal for MLH1, PMS2 protein expression, and her TMB was 14 mutations per megabase. So she was originally classified as an MSI high patient. Four years later, after a TLHBSO and staging, she also did receive vaginal brachytherapy. She was being surveilled by a CT scan for a pancreas lesion, a pancreas cyst, and noted an approximately 3-centimeter left common iliac lymph node that was FNA-ed and showed malignancy. This is her original molecular diagnostic profile from the original grade III endometrioid. You can see all the mutations in this tumor. And again, now four years later, she has this isolated nodal recurrence common iliac area confirmed by CT and PET. And she can undergo a resection, so she can be rendered disease-free with two hours of surgery, same day, complete response to remove this area. You also have the added value of inspecting the peritoneal cavity, making sure that it's a true isolated lesion. And based on the resection results, decide on any additional treatment that can be made, whether it's adjuvant chemotherapy or radiation. And of course, you can make the argument that because she was initially MSI high with a high TMB, she would be a good candidate for chemotherapy or radiation or both. When we look at recurrent endometrial cancer, the best treatment, systemic review of the literature, our colleagues from Italy did a really nice review here, and basically in all four scenarios, whether it's vaginal, central pelvic, single local regional, or abdominal, there is some selection where patients can be treated by surgery. I think patient selection is paramount here. Jenny Mueller and Lia Mokarzel from our group looked at 376 patients with recurrent endometrial cancer. The recurrences happened at a median of 14.3 months. These were all treated for their recurrence. And again, if they had surgery, it was non-exenterative, so this is not a pelvic exenteration group. You can see we only selected 16% to undergo surgery. They were usually younger, with a median age of 62. The range is from 39 to 83. There was endometrioid histology, and 61% of the patients selected to surgery, and about half of them were grade three endometrioid. A large percentage were stage one at initial diagnosis, 57% of those selected to go to surgery. Again, no residual disease after the primary surgery was in all patients selected to surgery. They had a longer time to recurrence, with a median of 19.4 months. And again, 69% have received initially some type of adjuvant radiation after their primary surgery, but 25% had multi-site recurrences, so not everybody that went to surgery was single-site recurrence. And you can see from these 16% of patients who underwent surgery as initial treatment for recurrence, not everybody had a complete gross resection. 75% had complete gross resection. However, there were no grade four or five severe post-operative complications. 88% received adjuvant therapy, including either chemotherapy, radiation therapy, or hormone therapy. And again, for those selected patients that were chosen to go to surgery, they had the longest overall survival of 57.6 months. The post-recurrence median survival for the whole cohort was 29 months. So, on multivariate analysis, selection to surgery was an independent predictor of improved survival. From this data, our group was able to suggest a higher consideration for selection to surgery in the following patients. A younger age of 70 or less, a longer progression-free survival of 19 months or more, lower grade. However, the clear cell histology also panned out as a favorable for surgical management. Early stage one to two would be favorable. No residual disease at primary surgery. And again, having received upfront adjuvant radiation was a selection criteria and preferably a single-site of recurrence. So, from this data, Leah and Jenny were able to come up with a nice MSK criteria that we use currently, really based on what we would consider a suggested criteria for consideration of secondary cytoreduction. Of course, overall medical management or radiation management was also very important in this disease. But these are the criteria that we are using now to select patients to surgery. Thank you very much. Thank you very much for your great presentation. And we'll keep going this debate now with Pro for SPRT with Dr. Anuha Hingram. Thank you. Good afternoon and thank you for allowing me to talk. So, I'm gonna talk about something completely different than what we've been talking about throughout this afternoon. So, we're gonna talk about radiation therapy. So, I have no disclosures except that I don't listen to instructions and therefore the format of my slides are definitely different than everybody else's. So, I apologize ahead of time. Sorry. Okay, stereotactic radiation therapy. What is stereotactic radiation therapy? So, I know most of you guys are gynecologic oncologists out here or surgeons. So, stereotactic radiation therapy is very conformal radiation therapy that is given at a high dose, which is an ablative dose. The fraction is usually from one to five and it can be given in multiple ways. It can be given by a linear accelerator, CyberKnife and MRI Linac or GammaKnife. Now, GammaKnife is usually used for brains but everything else can be used throughout the body. Let's see if we can get this to work. So, this is just an example of stereotactic radiation therapy in two different sites. The first site shows you a lung and you can see how conformal it is. It really just treats that lesion without treating the rest of the lung, the heart or the ribs or anything else. The other one's an adrenal lesion that actually of a patient of mine and you can see again, very conformal, doesn't give any dose to the cord or the kidney. So, this is what stereotactic radiation therapy is. It's a very conformal dose that is ablative. It's a cure to dose but given between one and between three and five fractions. So, why stereotactic? So, why are we talking about stereotactic? Well, we're talking about stereotactic because of this data that came out. These are four different phase two prospective randomized studies that looked at stereotactic radiation therapy versus other treatments. So, two of them are on lung and both of those, in those two studies, they all had metastatic disease and they were randomized to stereotactic radiation therapy to those lesions versus other treatments and the patients who got stereotactic radiation therapy had better overall survival. Another study in prostate also showed the same thing. The big study, which was the SABR comment, which also had GYN patients, 90 patients, and they were randomized two to one to radiation therapy or palliative treatments. The patients who got stereotactic radiation therapy had an overall survival benefit compared to the rest of the patients. Now, the toxicity was higher but there was definitely an improvement in survival with the addition of stereotactic radiation therapy for metastatic disease. So, the summary is that based on phase three data on metastatic disease, if you treat the primary, there's a better overall survival. And based on these phase two studies that I just showed you, there's actually a progression-free survival and an overall survival benefit with the addition of stereotactic radiation therapy in recurrent and advanced cancers. So, how about GYN? So, this is actually, and I'm trying to keep to my time limit, so we're gonna talk about a systemic review that was published in Gen Oncology. 17 studies, 667 patients treated, 100,071 lesions were treated. 65% had only one site of disease, the rest of them had multiple sites of disease. The most common site of recurrences was in the abdomen or pelvis. As you can see, the primaries, now, granted, it's a uterine talk, but we're gonna talk about GYN because I couldn't find just uterine, but the primaries were ovarian, majority of them, but cervical was 27%, uterine was 11%, and other, which includes vulva and vagina, was 4%. And what they found was with stereotactic radiation therapy, there was actually an excellent complete response rate or a partial response rate. So the complete response rate ranged from 49 to 97%. In majority of the cases, the response rate was really high, above 80%. Two-year local recurrence rate was 71% to 100%, which is excellent. So radiation therapy does have great local control. So how about progression-free survival and overall survival? So one thing that we did find in all of these studies was the patients did reoccur, but they recurred outside our field. So it didn't recur in the field, as you can see in the first graph, they recurred outside the field. Progression-free survival was 33, I'm sorry, 3.3 to 21.7 months. Two-year progression-free survival rate was 15% to 48%. Not bad. I mean, 50's not bad, right? Median overall survival, 20 to 60 months. Two-year overall survival rate was 57 to 85%. Again, really pretty decent for metastatic and advanced disease. Predictors for local control was nodal versus non-nodal. So patients who had nodal recurrences actually did better, smaller lesions, and the radiation dose. Predictor for overall survival was response rate. So if you had a complete response or partial response, you actually did better than stable disease. So what are the pros for stereotactic radiation therapy? One, it can be delivered safely. There was no grade three or higher toxicities in those 17 studies. It's quick. It's three to five fractions, no invasive procedures, less patient time, very convenient to patients. You can treat multiple lesions at the same time, and it can be given with other therapies. The cons are there is definitely a high recurrence rate out of the field, and the key is we don't know what the status of other disease or microscopic disease may be. So what are the future directions with stereotactic radiation therapy? I said we had great local control, right? But we still failed outside the field. But what we also know is what we're doing right now for our advanced and recurrent disease isn't working as well. As we know, five-year survival rate is 29% for ovarian cancer, 17% for cervix, and 16% for uterine cancer. So how can we improve with immunotherapy? But we also know despite combined immunotherapy, survival is not great. So can we improve on that? So what we do know, SBRT does promote tumor antigen release and stimulates antigen-presenting cells. SBRT may work with DC40 or toll-like receptors to help work with immuno-checkpoint inhibitors. We also know that SBRT may work with DNA damage response inhibitors, so may combine better with PARP or single-cell signaling modulators. And in fact, there are actually several studies that are combining stereotactic radiation therapy with other treatments, especially immunotherapy. And this is just an example of several studies looking at stereotactic radiation therapy with immunotherapy presently ongoing. Sorry about this. So in conclusion, stereotactic radiation therapy is safe and quick. It gives us excellent local control, less patient time and discomfort. Key is we need to find the recurrences early so we can treat them early, especially so that they're smaller and that radiation can control it. But the future direction with stereotactic radiation therapy is to combine it with novel therapies so we can improve both progression-free survival and overall survival. Thank you. That was great. And to finish the last part of our debate, we'll discuss now the pro for systematic treatment with Dr. Domenico LaRusso. Thank you very much. Thank you for having me. It was a great pleasure to be here. Can I have my slide, please? I have to start my presentation doing a public outing, how you choose surgery for this patient. If the risk of surgery is very high, how you choose a local regional treatment as stereotactic. But there are some good reasons also for supporting systemic treatment in this patient. Yeah. Thank you. My disclosure. For several years, we have considered endometrial cancer as benign tumor, easy to treat and easy to manage. But unfortunately, this is true for most of our patients. But unfortunately, when the disease presents some risk factor and when they recur, the survival rate is only 17% at five years. And until recently, in terms of systemic treatment, we only have carboplatin-paclitaxel, which provide a median PFS of 13 months and the median OS of 37 months. And when patients recur after platinum and paclitaxel, we have no standard second line therapy because whichever drug you use in terms of chemotherapy, hormone therapy, TKI or placebo, the response rate was between 10 and 15% and the median PFS around three months. In this scenario, the TGCA project clearly reported that endometrial cancer is not a single disease and probably neither two diseases, we believe, for several years. But there are at least four different tumors with different prognosis, different natural history of disease, and different possibility to respond to systemic treatment. And we know that polytumor are very good profile and good prognosis tumor and probably this tumor do not require any treatment. On the opposite, p53 mu tumor are really aggressive and this tumor will require chemotherapy and probably in the future also PARP inhibitor. NSMP tumor are a very miscellaneous of tumor, probably particularly enriched of estrogen receptor positive tumor and this tumor may require hormonal treatment. And the MMRD tumor are the tumor that better responds to immunotherapy and not to chemo probably. I fully agree with Dr. Aburuston when he say endometrioid grade three actually does not mean nothing. We need to better understand what are the molecular characteristic of this tumor in order to offer the best treatment. If this tumor present hormone receptor positive, in our guidelines we reported that even in first line, low-grade tumor should be treated with immunotherapy, sorry, with hormonal therapy. But probably hormonal therapy alone is not enough because the Paleo trial clearly reported that if we combine immunotherapy with the CDK46 inhibitor, we increase progression-free survival and also overall response rate in our patient. And two randomized trial are ready to start to confirm these results in a larger population and we will change our standard of care in this patient. If patient present HER2 overexpression and this is a characteristic for up to 30% of endometrial cancer which increase to 65% of serious cancer, this patient should be treated with trastuzumab or more in general HER2 inhibitor. After the publication of this randomized phase two trial suggesting an increase in progression-free but also overall survival when this patient are treated with trastuzumab and the benefit was greater in chemo-naive patient exactly as the patient we are talking today. If the patient present microsatellite instability, we have no doubt that this patient can benefit from immunotherapy single agent and it's a clear message that the number of prior line of therapy impact of the efficacy of these drugs. So patient who have received in the K0158, patient who have received only one prior line of therapy experienced 53% of overall response rate with respect to 44% in patient who have received at least two prior line. And we have the same suggestion from the GARNET trial endostarlimab and very, very important when this patient responds, the duration of response is very long. 84% of patient are the probability to remain in response at two years. So we are talking about extraordinary drug which now are being approved for patient failing one prior line of chemo but two randomized trial are trying to demonstrate that these drugs are better than chemo in chemo-naive patient if patient have MSI high. What about the MSS tumor? Immunotherapy alone provide scanty response in MSS tumor but we are trying to improve and there is a strong rationale in combining immunotherapy with TK high inhibitor because of cross-talk between immunotherapy and VGS vasculature. And these are the results of K0775 which in second and third line reported a strong advantage in terms of PFS for the combination of pembrolimbatinib with respect to chemotherapy. Chemotherapy at physician choice between antracycline and weekly paclitaxel. For the first time in the last 20 years, an overall survival advantage, a clear benefit in terms of overall survival was reported for this patient. But coming back to our patient, when we look at the efficacy of the combo pembrolimbatinib according to histotype, endometrioid grade 3 patient experienced great benefit with a significant increase in median progression free survival from 4 to 7.6 months and more interesting, a significant increase in overall survival which was not reached in this population treated with pembrolimbatin. And again, the forest plot suggests that the earlier the better. Patients who have received only one prior line of therapy experience higher advantage from this combination. For sure, we need to manage the toxicity. A local regional treatment has a better toxicity profile than a systemic treatment. And we need to manage the toxicity of this drug in terms of hypertension, hypothyroidism, diarrhea. But luckily, this toxicity, if we are good in managing, does not impact in quality of life of our patient. And we can manage by reducing the dose. And we are lucky because the evidence we have is that also when we reduce the dose, the drug continues to be active. And the future of immunotherapy and the future of systemic treatment of endometrial cancer will change again and again in the coming years. And we are exploring the possibility to combine immunotherapy plus chemotherapy since the beginning and in this scenario, we have at least three randomized trials combining immunotherapy to carboplatin-paclitaxel in the first line setting. And we have one trial combining immunotherapy to carboplatin-paclitaxel in the adjuvant setting before the patient recur. But there is also a strong rationale in combining immunotherapy plus PARP inhibitor. And in the coming years, a lot of data will arrive, including the results of these two trials which are combining immunotherapy plus carboplatin-paclitaxel plus PARP inhibitor in the first line setting of advanced disease. So should this patient be treated with systemic therapy? This patient has a very peculiar history with the singulation after a long time. So probably systemic therapy is not what I would think since the beginning. But in all the other situations, the answer is definitively yes. Because actually, chemotherapy is a very potent weapon in our treatment algorithm and in our strategies for this patient. This patient should receive a molecular profiling analysis and should be treated accordingly. Thank you for your attention. Thank you very much, Dr. LaRusso. And to finish this important discussion about molecular classification, I would like to invite Dr. Shannon Weston. And she will discuss, are we ready to incorporate molecular classification into clinical practice and treatment planning? Thank you, Dr. Weston. Thank you so much. Thank you for having me. This has been such a great session. And we'll round it off talking a little bit about something we already kind of hinted at. Those of you that were at the earlier plenary session will remember some of what I already had to say. But I hope we can get into a little bit more detail about the prospective clinical trials that are going to inform this. Because we've been hearing over and over again the need for prospective analysis. These are still my disclosures. So how are we doing with adjuvant treatment? I think you've heard over and over again, we have a need to do better with our risk stratification. Histology grade are poorly reproducible. You've heard over and over again from my colleagues that the molecular profile matters. This inconsistent categorization has impacted the results of our clinical trials for years now. And I think we're finally getting to a point where we're doing the right thing. Hopefully, we'll get the right results. I know you haven't seen this at all today. So I'm going to spend a lot of time on it. But in all seriousness, we have some wonderful ways to pragmatically classify endometrial cancer with this new molecular stratification. And we've seen over and over again today the PROMIS guidelines and the PROMIS testing algorithm using that poly sequencing, using the two markers of IHT to identify the microsatellite unstable patients, and then assessing P53 in some way, whether that be with sequencing or IHC. And again, this has been demonstrated to recapitulate the TCGA findings where we do the much more extensive molecular test to identify these four classifiers. I mentioned this a little bit earlier, but I'll spend just an extra minute on it. And we heard our pathologist talk about this as well, Dr. Singh. We do have a need to understand what to do with the patients that aren't binned into simply one group that test positive for multiple of these classifications. It does seem that the best classification wins. We still need more data to understand that. But what do I mean by that? So if we've got a patient that tests positive for MMRD but also has an aberrant P53, it would seem that patient would do as well as other MMRD patients. And conversely, if we look at poly, so either poly with P53 or even poly with microsatellite instable, again, it seems that poly would drive that. So the best acting molecular profile does seem to be dominant, but we still need more data to confirm that. So how can we use these molecular classifications to guide our adjuvant therapy? Let's start with the early stage kind of intermediate high-risk patient population. We've seen from the PORTEC-1 and 2 data that when we break the patients that were, again, randomized in PORTEC-1 either to pelvic radiotherapy versus surveillance or in PORTEC-2 to pelvic radiotherapy versus vaginal cuff brachytherapy, that the prognosis is there based on those molecular classifiers. So can we use that to direct our therapy? Well, certainly you can anticipate the better prognosis may need less therapy, but we really need to prove that in our prospective studies. And so we're really excited about what we'll see with the results of a couple of studies in this space. So first is the PORTEC-4A study, which is a randomized trial that is basically utilizing molecular profile-based treatment versus standard recommendations outside of knowing that molecular profile. So what does that mean? I'm going to go to a little bit more detail here. So on the left, you can see that there are patients with stage I endometrial cancer that are thought to be higher in a minute risk and that are going to be randomly assigned two to one to either the experimental arm, which is using the molecular profile to guide therapy versus the standard arm, which everyone will get cuff brachytherapy. So they're broken into risk groups, favorable, intermediate, and unfavorable. And the way they do that is POLE is favorable. If they're MMRD and they are beta-catenin wild type, that's also considered favorable. MMRD with beta-catenin mutation or, I'm sorry, non-MMRD with beta-catenin mutation is considered intermediate and MMRD is considered intermediate. And then, of course, the worst actors are those with a p53 mutation. And so we will see if truly we can start either de-escalating or escalating care based on those findings. Now, the taper study is also very interesting. This is trying to take out patients that are stage I and kind of the best favorable group. So either POLE or the nonspecific molecular profile p53 wild type group. And again, based on this testing, they either get de-escalation of care or escalation of care. And so you can see that in the group with POLE mutation, that's the blue, everyone gets observed, no matter their histologic factors, no matter anything pathologic. The patient population that's p53 wild type or no specific molecular profile gets separated out again by beta-catenin mutations, which are found to be detrimental. And then based on some of the other either staging, the presence of LVSI, get vaginal brachytherapy or no de-escalation recommended. Now, what about the kind of higher risk group, our more advanced stage patients? So again, we can see the prognosis of the different molecular groups based on the study of PORTEC3, which you've seen multiple times today, where those four molecular profile groups really do divide out. But perhaps the most interesting thing that came from retrospective analysis of this prospective study was starting to understand who might benefit from more adjuvant therapy or different types of adjuvant therapy. And I do, I can't believe I'm saying this, but I do agree with Mario about the POLE mutated group, right? What we don't know for this group is, do they do better with any treatment? So they need to have something, or would they do better with no treatment at all? And I think we suspect that it's the latter, that they really don't need treatment. But I don't think we really know that yet. And so that's why some of the studies that are ongoing are really exciting. And then conversely, when we look at the mismatch repair deficient group, it seemed like they did the same no matter if they got radiation or radiation with chemo. So the question is, what's the best way to benefit that patient population? And then finally, that P53 aberrant group seemed to benefit the most from chemotherapy. So I think we're starting to see a teasing out a way that we can start directing therapy. And I know in our multidisciplinary clinic meetings, we often will say, oh, this patient is P53 aberrant. Should we do more in the absence of data? And then of course, we saw from the GOG86P study, now that's just as a quick reminder, that was a pick-the-winner study where we had a historical paclitaxel carboplatin control and then added either bevacizumab, temserolimus, or an arm with exabepillone and bevacizumab. And we saw potentially an improvement in overall survival for the patient population that was treated with chemo and bev. And then when they teased that group out, it did seem that that was more associated with the mutant P53 group. So again, indicating that more may be more for that population. So finally, how do we get to that next step? Well, this is the RAINBOW study. It's a really delightful study with kind of a more high-risk population that is being, again, directed by their molecular profile. So the P53 aberrant are getting randomized to either chemoradiation therapy with or without a DNA damaging agent, which you just heard from Dr. LaRusso's quite a bit of interest in this group. Mismatch repair group is getting PD-L1, so that's pretty exciting. And then again, that poly group getting de-escalated care. So interestingly, this is not a randomized arm. All the patients with poly are gonna be de-escalated. So we'll really be looking at survival in that group. And I'm not gonna spend too much time on this. I wanted to spend more time on our trials, especially since you've seen these wonderful guidelines over and over. But I just wanna highlight again that until we can safely and cost-effectively do this molecular testing across all resource settings, it is important to still have that histologic classification for groups that cannot do the more advanced molecular testing. And then, of course, the NCCN guidelines that simply provide a guideline of how to do the testing, but really no guidelines quite yet of what to do with that once we know. So I think the bottom line, we know those subgroups are prognostic. It seems they may be predictive, but we still need more data. But it's exciting to see these molecularly-driven adjuvant trials that are gonna help us answer these questions. The bottom line is we need to understand how to reduce costs, how to increase access, and how to time this testing to be effective and allow that if we're moving the needle forward for patients, we need to be moving the needle forward for patients across the world, not just in specific high-resource settings. And so I'll stop there, and thank you all for your attention. Thank you very much for this great talk. And to keep moving your session without delays. So unfortunately, we won't have time for questions now. And I would like to invite Dr. Ellen Mackey to keep here to moderate the last part of our session to discuss the metastatic setting. Thank you very much for all the presenters. So thank you, that was a terrific session. And I think the third and last but not least session, we've got some great speakers, and the topic will be new treatment options for advanced and metastatic disease. And we're gonna start with a discussion led by Dr. Anna Awaknant. Give me a minute, because I cannot find my presentation here. Well, I might read out the title then, cuz that was probably a good place to start. We already listened to that. Here we are. Okay, good afternoon, everyone. I would like to thank the scientific committee for inviting me to deliver this talk. Biomarker in clinical practice for advanced metastatic endometrial cancer. How can we improve our outcome? I'm very sorry, because you have seen some of my slides a few times during today. But I hope that I can make a little bit interesting the talk. So this is my disclosure. Endometrial cancer remains the only gynecological malignancy with rising incidence and mortality. And you know that until recently, treatment option for patients with recurrent metastatic disease remained limited. Therefore, a enhanced understanding of the tumor biomarker and molecular findings may guide our therapeutic option and will lead to an improvement in patient outcome. You know that based on genomic abnormalities, sorry, not passing. No? Now, you know and you have seen several times, based on genomic abnormality, TCGA segregating endometrial cancer in four molecular subgroups with different prognosis each. However, TCGA requires a high methodology. So a simplified classification was developed to be implemented in the daily practice. And this classification identified four molecular subgroup that are analogous but not identical to TCGA. Polymuta, DMMR, P53, the normal, and no specific molecular profile. And the initial prognostic value demonstrated for molecular classification was also confirmed for the PORTF3 trial and the GOG210. So in light of this result, the international guideline, mainly ESMO guideline and CCA, has incorporated the molecular characteristic in the endometrial cancer initial diagnosis to inform prognostics and mainly guide the adjuvant therapy. But the adjuvant therapy is not the focus of my talk. So I will try to elucidate if we can guide our treatment in the recovery and metastatic setting based on molecular feature and biomarker. So let's start with DMMR. You know that endometrial cancer is the solid tumor with the greatest percentage of MSI-high cases, around 31%. And this tumor has a particular microenvironment that make them ideal candidate for immunotherapy. And in addition, there's a large overlap between MSI-high and tumor mutation burden high that may indicate that DMMR as a useful biomarker to identify those patients who will benefit most from immunotherapy. In this slide, we have summarized the activity of the different anti-PD-1 and PD-1 agents in DMMR endometrial cancer patients who have failed after platinum therapy. As you can see, the 48% and 45% overall response rate for pembrolizumab and dostarlimab, respectively, are very compelling. And this activity make this agent the therapy of choice after platinum failure. However, half of the patient doesn't respond. And moreover, when we look at this Kaplan-Meier curve, half of the patient are only free of progression of 12 months. So the key point is, is DMMR an homogeneous biomarker? We know that DMMR endometrial cancer originates from different pathways. In a short manner, those with methylation of MLH1, they are considered sporadic. And though we generalize mutation in the mismatch repair protein, they are confirmed as Lynch syndrome. So the key point is whether mechanism underlying DMMR, MSI-high endometrial cancer, can alter responses to immunocheckpoint inhibitor. The data from these two small pembrolizumab studies show us both, PFS and overall survival are shorter in the methylated group. However, these data are hypothesis generated. And further research will be needed to determine whether the origin of MSI-high tumor will have therapeutic implications. So I invite all of you to stay for the plenary session too, and then you will learn more about the data in the Dostarlimab trial. So moving forward, can we consider that PMMR is a biomarker of no response to IOM monotherapy? When you look at this table, the overall response rate ranges from 3% to 50%. And it's not only 50% of the patients respond. It's that the median duration of response is 90 months. And the probability of remaining in response up to a year was 44%. What does this mean? It means that there's a subset of patients with PMMR tumor that are able to respond to IOM monotherapy. So we should investigate further what biomarker make this patient response to IOM monotherapy. And then this will avoid to expose these patients to unnecessary and potential more toxic combination therapy. So is then mandatory to analyze the tumor mutation burden as biomarker? From the keynote 158, we learned that those patients with tumor mutation burden high response better achieve a greater response compared with those with tumor mutation burden low. And very interesting from the Garnett trial, those patients who had tumor mutation burden high seems to respond better to Dostarlimab. But for me, the key point is when we look at the tumor mutation burden high, those patients with mismatch repair proficiency and mismatch repair deficiency tumor achieve almost the same overall response rate. So acknowledging the limitation of this post-hoc analysis, this provide further insight in tumor mutation burden as a reliable biomarker. So what else? What about the P53-anormal as biomarker? We know that the P53-anormal endometrial cancer is the group with the worst prognosis, and from this very interesting paper from the PORTUS-3 trial, they analyzed all the cases with a normal P53 expression, and then they reported the most frequent genetic alteration. And you can see in this slide, the most frequent genetic pathogenic mutation was P53, 95%, followed by PE3K, and then HER2 amplification. And very interesting, when we do look at the histology from this tumor, 50% of them had serous histology. So aligned with this data, in this recent publication, they report the genomic alteration in serous carcinoma compared with endometrial cardenocarcinoma. And you can see here, the P53 mutations are almost universal. And in addition, you can see how the serous tumor had a higher frequencies of beta-catenin mutation and Rb2 mutation compared with endometrioid. And in addition, very interesting, they reported a 22% of the tumor harboring homologous recombination deficiency. All these genomic alterations together provide us with the information to develop new target therapeutics for these tumors, such as anti-HER2 therapy, parainhibitors, and on top of that, try to identify if P53 may guide us in the systemic therapy. So indeed, in the GOG86 negative trial, as you can see in the old population, those with a mutation P53, so in the P53 mutation group, sorry, they have a worse overall survival. And in addition, we have learned from this trial that those patients who harbor a P53 mutation, it seem to get benefit of adding vebacizumab to a standard of Kerpaklitaxel carboplatin. So these data raise the question, if those patients with P53 mutation should be treated with vebacizumab plus Kerpaklitaxel carboplatin. Further information come from this study that was nightly presented by Dr. Marker this year in ASCO. As you know, the CNDOT trial is analyzing the role of the expo1 inhibitor selinexor as maintenance therapy. And we know that in 10 to 3 population, the trial was positive. And following that, a pre-specified exploratory analysis was developed to determine the results according to the P53 state. As you can see in this slide, only those patients with a P53 wild type obtain benefit of selinexor as maintenance therapy. So this result raise the question as P53 as biomarker to determine those patients who may benefit from selinexor. Moving forward, as we can see in the previous slide, to test HER2 protein should be mandatory in this group of patients with serous carcinoma. But I think that we need to take some characteristic into consideration. When we determine HER2 in serous carcinoma, we need to know that there is a significant heterogeneity, intratumoral heterogeneity. And in addition, that 75% of the HER2 positive tumor lacked apical membrane staining. And very important, there are discordant HER2 status between primary and metastatic tumor. Despite all this caveat, we have this important trial that have been already presented. And this trial show us adding trastuzumab for patient with a stage 3 or 4 newly diagnosed or recurring uterine cell with overexpression of HER2 provide a significant benefit in terms of PFS and overall survival. And very important, this benefit is greatest when the patient receive the combination of trastuzumab plus chemotherapy as newly diagnosed. Moving forward in the development of, sorry. Moving forward in the development of this combination, you know this importance trial NRGG1026 is analyzing in patient with serous and carcinosarcoma with HER2 overexpression, the combination of trastuzumab plus pertuzumab. And what's else beyond trastuzumab, we have the ADC, and in particular, trastuzumab derustecan. This ADC is under development in the destiny pan tumor 02, in solid tumor that harbor overexpression of HER2. And this trial include three gyne cohort. In waiting for this result, we have already learned the efficacy of trastuzumab in carcinosarcoma expressing HER2, as you can see. The overall response rate are really, really promising. 54% in HER2 high and 70% in HER2 low. So this bring me to the end of my talk that I wanna finalize with this slide. There is no doubt that the classification in the four molecular subgroup is really informative and is guiding the management of our patient newly diagnosed with endometrial cancer because it's guiding mainly the adjuvant therapy, but I think that we need further stratification within subtype. We need to know the methylation status in the mismatch repair deficiency. We need to know the ERPR status in no specific molecular profile. And we need to know for those patients who harbor P53, a normal tumor, the HRD status, the HER2 protein, the beta-catenin. With all this information, I'm sure that we will be able to tailor a better therapy for our patient. Thank you for your attention. Thank you. That was a really terrific talk. Thank you so much for that. And now finally we have Dr. Vicki Macker, who will be presenting on what is the concept of platinum resistant and platinum free intervals in endometrial cancer. Thank you. Okay. Just loading my slides. All right, great. Hi everyone. Thank you for the invitation. It's really a privilege to follow this esteemed group of speakers today. And I have the task of speaking about what is the concept of platinum resistance and platinum free interval in endometrial cancer. Here are my disclosures. All right, good. And just by way of background, we all know that the worldwide incidents and also disease-associated mortality of endometrial cancer are sharply arising. And while cancer survival has improved since the mid-1970s for the most common malignancies, endometrial cancer is clearly a notable exception. And I think that at least up until recently, as has been discussed by the speakers before me, there really has been a lack of treatments in advanced recurrent endometrial cancer. And with this malignancy in particular, we're clearly losing ground. In the US, for example, the two-fold higher risk of death from ovarian cancer compared to endometrial cancer that was seen in the early 1990s has been virtually eliminated. And now endometrial cancer mortality rates have caught up to those of ovarian cancer. And will soon surpass ovarian cancer mortality rates if the current alarming trends with regard to incidence and disease-related mortality in endometrial cancer continue. The other issue certainly is that among black women, this alarming crossover has already occurred. And the uterine cancer disparity has widened. And this mortality for black women is actually now two-fold greater compared to white women, despite a similar incidence. This slide has been presented numerous times, but the TCGA certainly challenged the historically dualistic view of endometrial cancer and moved it towards the current era of precision medicine. By identifying at least four subtypes that more accurately reflect underlying tumor biology and also clinical outcome in endometrial cancer. We know that the poly-ultramutated and microsatellite instability hypermutated subtypes are the hot or inflamed subtypes of endometrial cancer that are more likely to respond to immunotherapy. And then there are the cold or not inflamed endometrial cancers that are represented by the copy number low and copy number high subtypes. And importantly, each subtype has its own prognostic significance, with the pole E subtype bearing the best and the copy number high subtype displaying the poorest survival. Now, NCCN, SGO, ESGO, ESTRO, ECP guidelines all recommend using biomarker testing much more widely now that additional treatments are becoming available. However, further research is required to develop concise and comprehensive treatment guidelines as we're still attempting to understand and really more clearly attempting to define how to optimally treat patients in the advanced recurrent metastatic disease setting. And despite the advent of next generation sequencing and a much more robust understanding of endometrial cancer molecular subtypes, standard first line treatment for patients requiring chemotherapy, regardless of molecular phenotype, remains carboplatin and paclitaxel chemotherapy. However, the issue with chemotherapy, of course, is that response rates and activity are finite. And so we clearly need to develop better treatments. And I would argue that upon receiving prior platinum therapy, this disease really does become chemotherapy resistant. Now, the other issue, of course, is that endometrial cancer heterogeneity, I think, poses clinicians with many, many challenges. And it's really difficult to decide about the optimal course of treatment for their patients, especially those that have advanced or recurrent disease following first-line taxane or platinum chemotherapy. And of course, important factors that must be considered include tumor histology and molecular phenotype. And again, while molecular characterization is becoming more critical in directing treatment for advanced recurrent endometrial cancer, it is not yet universally available, which of course creates many challenges and may impact treatment decisions. And clearly, clinical practice in many instances is lagging behind advances in molecular characterization of endometrial cancer. Other factors that are important, of course, are patient factors. What is the patient's performance status? What are their comorbidities? And we know that endometrial cancer patients are often obese, have metabolic syndrome, and a myriad of other maladies that can make treatment of their disease quite challenging. We need to consider sites of metastatic foci, also the pace of the disease. Is it indolent? Is it fast-growing? Are they at risk for visceral crisis? And all of these are very important factors to consider. Prior therapy, surgery, radiotherapy, hormonal therapy, chemotherapy, and are there lingering toxicities from prior therapy? Clinicians also consider treatment-free interval, the time between initial and subsequent therapy. And this is also a factor that does bear importance. And of course, treatment goals. Is the intent of therapy curative, or is the intent of therapy palliative? Following first-line taxane-platinum chemotherapy, treatment goals generally evolve. And generally speaking, treatments are palliative for our patients following prior systemic therapy. Additionally, while there does appear to be consensus among the various guidelines around the first-line treatment of endometrial cancer, and of course, that's with platinum taxane-based doublet chemotherapy as the preferred option, second-line treatment guidance lacks the same consensus with various options that are suggested and with no globally accepted or endorsed standard of care in the second-line treatment of advanced recurrent endometrial cancer. And again, the struggle to achieve improved outcomes following prior systemic therapy with limited options available, at least until recently, physicians have adopted this idea of platinum doublet re-challenge based on concepts that have been taken from ovarian cancer. However, endometrial cancer differs greatly from ovarian cancer and warrants its own treatment approach and paradigm. In ovarian cancer, the terms platinum resistance and platinum sensitivity are based on the time between first-line platinum-based therapy and disease recurrence or progression. So PFI of less than six months, platinum resistant. PFI of six months or more, platinum sensitive. However, in endometrial cancer, there is no consensus regarding this terminology. In fact, in endometrial cancer, the concept of platinum sensitivity, optimal platinum-free interval, and efficacy of platinum doublet re-challenge has not been prospectively investigated, making it difficult to determine the utility of platinum-based doublet re-challenge in this malignancy. Given the recent approvals of immune checkpoint inhibitors and the combination of lenbatinib and pembrolizumab in previously treated advanced recurrent endometrial cancers, as well as other emerging promising data, for example, surrounding CDK4-6 inhibitors in combination with hormonal therapy for certain subtypes of endometrial cancer, I think it's critically important for us to reassess the role of platinum doublet re-challenge in endometrial cancers. Additionally, it's very important to remember that the evidence behind platinum doublet re-challenge in endometrial cancer does not originate from large prospective clinical trials. This table demonstrates the scale of evidence available, and it's mostly from small, certainly heterogeneous and only retrospective studies. The retrospective data that is available, though, does suggest that platinum doublet re-challenge achieves shorter survival than initial treatment, even in patients that have a long platinum-free interval. Longer platinum-free interval, which, again, is determined differently in various studies, however, does appear to be associated with a better median PFS and OS. So for example, platinum-free interval of less than 12 months, again, this is purely based on retrospective data, is associated with PFS of around 4 months and OS of around 14 months. PFI of greater than 14 months shows a PFS of around 8 months and OS of around 28 months. And endometrial cancer patients who have a platinum-free interval of less than 6 months, those are sort of deemed platinum-resistant, are unlikely to achieve satisfactory outcome or response when re-challenged with platinum therapy. Now platinum doublet chemotherapy re-challenge may be considered for some patients following prolonged treatment-free interval, and of course, that is reasonable. However, there is no consensus regarding how long that interval should be in endometrial cancer. And I think it's important to remember that as many of our patients with endometrial cancer may not go on to third or fourth line treatment, it really is important to utilize novel therapeutics that may be more robust in response and that patients may do better with in terms of efficacy when used in earlier lines as was presented earlier by Dr. LaRusso. So I think it's important to use novel therapies that are emerging earlier in the disease course in this particular malignancy. Next, I think physicians have also contended with the limited prospectively investigated treatment approaches for patients as they ponder second-line therapy for those that have had prior platinum taxane therapy. And the data that we do have really comes from small phase two studies that are thankfully there to help guide therapy after front-line chemo. But again, there is no globally accepted standard of care second-line chemotherapy regimen. Efficacy with single-agent chemo in the second-line setting is disappointing compared to initial therapy as demonstrated by the modest to poor response rates, PFS and OS, that we have seen. And retrospective analysis of endometrial cancer patients given non-platinum-based chemotherapy as their second-line treatment has showed that those with a shorter PFI are also less likely to achieve optimal outcomes compared to those with longer platinum-free interval. And this is a situation that is similar to what we have seen with platinum doublet rechallenge. And for patients with a platinum-free interval of less than or equal to six months, the median OS was around six months, and those with a PFI greater than six months, median OS is around 10 months. Again, this is based on retrospective analyses. I think it's also really important to remember that chemotherapy can adversely affect our patients' physical, social, and emotional well-being. And these considerations should be very carefully weighed when we consider subsequent treatments for our patients. And with the approval of pembrolizumab and dostarlimab and DMMR, MSI-high endometrial cancers, and lenvatinib pembrolizumab for advanced endometrial cancer following prior therapy, we have robust alternative options for therapeutics for our patients with recurrent disease. And we believe that such therapeutics, as well as clinical trial participation, of course, should be considered and should be encouraged earlier in the course of recurrent disease. And so, in summary, endometrial cancer is a difficult-to-treat malignancy beyond the first-line regimen of carboplatin and paclitaxel. Despite the lack of prospective data, platinum doublet rechallenge is used to treat our patients with recurrent disease due to limited options. And again, thankfully, the treatment landscape is rapidly changing, and we will have many more robust options for our patients. And following first-line use, prospectively assessed chemotherapeutics are associated with limited response. Certainly, diminishing returns are seen, and the disease, I would argue, largely becomes chemotherapy-resistant. And there is, of course, a very significant negative physical, social, and emotional impact that our patients sustain from chemotherapy. Further characterization of endometrial cancer has provided the rationale for I.O. and targeted therapy options. And again, such therapies really should be utilized earlier in the course of disease as standard therapies, when they are much more likely to have effect. And it's important to remember that our endometrial cancer patients are often more feeble than ovarian cancer patients and may not go on to third, fourth, fifth-line therapy. Molecular phenotypes should be considered to guide best treatment, as well as to guide clinical trial participation. Approvals of new treatments will alter the use of chemotherapy, though there will still be a place for chemotherapy. And I think with regards to platinum re-challenge, we must consider individual patient factors aside from platinum-free interval. Thank you very much. Appreciate your time. Thanks, Anna. Thanks, Vicky, for great talks. Unfortunately, we are more than five minutes over time, and we won't have time to discuss these two brilliant talks. Thank you. And you can catch both these ladies in the pause and ask the questions. Thank you. Thank you. And just so you guys know, this concludes the Uterine Cancer Master Session. Again, thank you to all the presenters who presented their work. It was an unbelievable session to kick off the first day of IGCS. I will just say repetition is a branding iron of knowledge, and if anyone leaves here without recognizing the importance of molecular testing, I want to speak to you in front of the room. The Tumor Board Molecular Profiling of Uterine Sarcoma's Current and Future Management will also take place, so please stand up, stretch your legs, get some air, and converse, and then we'll reconvene. Thank you again. Thank you, Anna. Appreciate your time.

algorithms

histopathological slides

molecular subtypes

endometrial cancer

molecular testing

low-resource settings

point-of-care devices

genetic mutations

molecular classification

treatment decisions

personalized treatment

molecular profiling

prognostic significance

biomarkers

DNA mismatch repair deficiency