Hello, everybody, and welcome to the master session on uterine cancer. I'm Dr. Pernilla Jensen, and I will be moderating this session with Dr. Andrea Mariani and Dr. Matt Powell. These master sessions are a new type of programming for the IDCS, and the goal is to hear from leading experts in the field on the most current and important research in uterine cancer. So without further delay, let's hear from our first speaker, Dr. Edward Tanner from Northwestern University in the U.S. Dr. Tanner, please proceed. Good morning. All right. Thanks for having me here today, and glad to be having the chance to kick things off. I want to thank the IGCS and the session organizers. I'm really looking forward to this session and hearing how everyone else's perspectives are on these important topics. So these are my disclosures, none of which are relevant to my talk today. So really, our question here is, should I perform frozen section evaluation of central nodes at the time of hysterectomy for endometrial cancer, and whether I should be doing that to guide whether I'm going to perform a completion lymphadenectomy in these patients. So we're going to review the accuracy of frozen section of central nodes, the rate of non-central node metastases in patients who have positive central nodes, and whether finding non-central node metastases can be used and be beneficial for guiding post-operative therapy decisions. So why would I perform frozen section of central nodes? So maybe I think that removing additional nodes that have metastatic disease improves survival, or that removing additional positive nodes will help me better guide post-op therapy. Maybe I just feel like I'd like to have that information in the OR. It's not going to cause any harm, so why not? Before we actually go into that topic, I just want to briefly review central node mapping algorithm for endometrial cancer, because I think this is important when we think about what the role of frozen section might be and what we're talking about and what we're not talking about. So at the start of a central node evaluation, we always want to evaluate peritoneal and retroperitoneal surfaces and remove suspicious lymph nodes, regardless of the success of our central node mapping. So what we're really talking about with frozen section are patients that have successful mapping, not patients who fail mapping. Patients who fail mapping should undergo a side-specific pelvic lymph node dissection and perhaps a periodic node dissection. So that's really the most important thing, is to follow the algorithm in terms of managing and identifying disease. And by doing this, we have excellent detection rates and our negative predictive value of central node mapping is very good. So that already puts us in a difficult spot in terms of what the added value of a frozen section would be. So how accurate is it? There's not a lot of great data on this topic, but we have a few recent studies, including one published in the last couple of months, looking at patients who undergo central node mapping with frozen section of central nodes and then completion lymphadenectomy if they have a central node metastasis identified in some cases and then others where patients actually just underwent a completion lymphadenectomy. So the false negative rate is actually fairly significant for frozen section, especially when it's done with conventional H&E. The smaller the central node metastasis, the more likely you are to miss the central node met. There does seem to be some added value of imprint cytology. In a recent study, patients who had negative central nodes on conventional H&E had, on imprint cytology, had additional metastases identified and actually improves the detection rate. So that may be one way to improve your detection rate with frozen section. However, the bigger issue is what is the chance you're actually going to find additional non-central nodes when you perform a completion lymphadenectomy? So we have a fairly robust amount of data about this. So about 40% of patients who have central node metastases will have additional non-central node metastases. And it makes sense the larger the metastasis in the central node, the higher the risk of a non-central metastasis. So patients who have macromets, more than half of them will have additional non-central node metastases and micromets and ITCs, that rate is significantly lower. But beyond that, does this really make any difference? It does seem that patients who have additional positive lymph nodes have inferior survival outcomes. So performing a completion lymphadenectomy will provide at least perhaps some prognostic significance for patients. So if you have more than one lymph node metastasis, survival is inferior. Now, of course, a lot of this data is in registry studies. And so we don't know how many of these patients have grossly visible nodal mets. And so that's a little bit potentially a confounder in these kinds of studies. But certainly the more nodal metastases you have, perhaps the worst survival that patients will have. And the larger the metastasis, the more likely patients are to have inferior survival. Perhaps related to having more nodal disease. So does this impact survival? So we have great data looking at this question in patients with apparent early stage disease from multiple randomized trials. Patients undergo lymphadenectomy do not appear to benefit from removal of normal appearing lymph nodes. And the combination Aztec trial showed that most patients, as we've seen in the other data I've already shown, have only one nodal metastasis. But some patients do have additional nodal metastasis. In patients with apparent early stage disease, the number that have more than two is actually quite low, though. So really, it doesn't seem that removing additional normal appearing lymph nodes that are microscopically positive affects survival by itself. So why is that the case? Well, of course, with GOG258, we know that tumor-directed radiation does not seem to provide an advantage for patients with nodal metastasis. So chemotherapy is the driving factor for survival in these patients. Nodal disease certainly does impact survival, but it's the administration of systemic chemotherapy that's the most important aspect in terms of survival. And there are no subgroups of patients in this study that seemed to have any benefit from the addition of radiation. Now, to be fair, and I spoke to Dr. Mattei about this because I was trying to look at this in the study, the number of positive lymph nodes was not a subgroup that was evaluated in the study. So I can't say with complete certainty that patients with more nodal disease would have had a greater benefit from the addition of radiation, but no other factors impacted it. So I think that sometimes it's helpful to actually create a hypothetical scenario to better clarify why frozen section really doesn't provide any benefit. So let's imagine we have a patient who has, let's say, a grade three endometrioid tumor. They undergo successful central node mapping and don't undergo a completion lymphadenectomy, don't undergo frozen section, and then nodal met is found on final pathology. So this patient would likely receive systemic chemotherapy and based on GOG258, maybe they would get radiation primarily for uterine factors, not other factors. So that's how I would treat this patient. I think many of us would treat this patient in that way. So let's now imagine that the patient had the same exact patient, but they had a frozen section and a nodal met was found on frozen section. So you would then perform a lymph node dissection, and let's assume it's negative. The patient would get systemic chemotherapy for their one positive node and maybe pelvic RT based on 258, just as they would have done before. If they have a positive lymph node, then they would get systemic chemotherapy, maybe pelvic RT. There would be no difference. The only question is, what if you have a non-central node metastasis in some other region? So let's say it's a pelvic node and you perform a lymphadenectomy and they have a positive non-central periodic node. What's the chance of that happening? So from FIRE's trial data, because I think we really need to look at central node data, not patients who just undergo a full lymphadenectomy, because many patients will have periodic central lymph nodes identified and have nodal mets identified this way. So in FIRE's trial, 80% of patients who had positive central nodes had them in the pelvis and there were no positive PA non-central nodes. So even if you thought pelvic radiation was important in this setting, it wouldn't be altering your radiation fields. 20% of patients had positive PA nodes in central nodes and the pelvic pelvis was negative. So again, it's not going to necessarily alter your radiation fields. So there were no patients that had positive pelvic centrals and a non-central PA node. So it's not to say that that's not possible, but the likelihood of that occurring is very low. And we can't include patients who have failed mapping in this. There was a patient in the trial who had a non-central, who had a failed mapping and a positive PA node, but that would be picked up with a completion lymphadenectomy. So the chance of this impacting treatment is very low. So what would be some other benefits from frozen section? I do think that there's one thing that frozen section could help with, and that's the issue of empty central node packets. So there's been a few studies looking at this over the last couple of years, and Dr. Plante has published one of those, and we had looked at one of these when I was at Hopkins. And about 5% to 10% of central node packets will be empty without any nodal tissue. So either performing a rapid gross or frozen section of central node will potentially identify empty packets. And this is really a problem in terms of postoperative therapy. If you have a patient who has a high-risk tumor and then you find out on post-op evaluation that you didn't get an accurate mapping, then you don't have the information you need to guide therapy. So I think it can be helpful in that sense, but not necessarily for identifying nodal metastases that benefit from further lymphadenectomy, only if you fail to identify nodal tissue. So just to wrap up, I don't think that there's any clear evidence that performing frozen section leads to a procedure that improves survival for patients, assuming you identify nodal metastases. And it would be very unlikely that a completion lymphadenectomy, a patient who has a successful mapping, would receive different radiation fields, although that's at least theoretically possible. But it's not clear that radiation improves survival anyway, so I don't think that there's any value in that regard. The only real area where there's a benefit with this is potentially to identify empty nodal packets, which is a concern. I think that's just not really clear that every case needs to be done with the frozen section. I think if you are suspicious that you've missed a nodal met, then I think it makes sense to do so. So thank you very much. I think we're going to go on to Dr. Rossi and then take some questions after her talk. Thank you. So thank you, Dr. Tanner. Next up is Dr. Emma Rossi from the University of North Carolina in the US. Emma, please proceed. Thank you very much. So today I'll be addressing if sentinel lymph node biopsy is valuable for high-risk, high-grade histologies. Is there sufficient evidence in this high-risk group? And what about the periodic nodes? I have nothing to disclose. When I'm addressing this, I'm really talking about evaluation of lymph nodes that are clinically normal. So I'm not talking about today debulking clinically suspicious nodes in the periodic region, but rather clearing a normal appearing periodic region. And the controversy really exists surrounding is this technique of sentinel node biopsy accurate in high-risk histologies? And is it safe? Are we losing some therapeutic virtue by routinely removing periodic nodes in these high-risk cancers? So why is this controversy present? Well, sentinel lymph node biopsy is predominantly a technique to sample pelvic lymph nodes, as we've talked about early with Dr. Tanner. With cervical injection techniques, less than 1% of sentinel nodes identified are in the periodic region, or at least isolated in the periodic region. And yet we do know that the uterine fundus, particularly the deep myometrium of the uterine fundus, has the possibility to drain directly to the infrarenal periodic nodes following the ovarian vasculature and lymphatic pathways. But how frequently does this really happen? Well, among all comers with endometrial cancer, only about 1% of patients have isolated periodic metastases. But in a subgroup of deeply invasive high-grade tumors, that risk goes up substantially to closer to 16%. So our concern is that we may be missing these isolated periodic metastases with a pelvic-only sentinel node sampling. And with that, do we lose some diagnostic virtue of recognizing who has stage 3C disease? And do we lose some therapeutic advantage of resecting that microscopic disease? So do patients with high-risk cancer actually have more isolated periodic nodal disease? Well, we know that these patients have less predictable patterns of spread. We can't rely on uterine factors such as the size of the tumor or the depth of myometrial invasion to predict if they have extra uterine disease or if they're going to relapse and where they're going to relapse. We do know that they're more at risk for having deep myometrial invasion. And as I mentioned before, that's the group in whom likely there's most access to these ovarian channels that drain into the periodic region. In order to overcome this, some have explored myometrial injection for patients with high-risk disease with the hope that they will better target or identify the periodic region. And certainly they do here. The photograph is where a hysteroscopic injection of the myometrium has taken place with ICG. The fundus is glowing green. And you can see a little channel on the left that's traveling in the ovarian vessels up towards the periodic region. With this technique, about 50% to 60% of patients will have a sentinel node identified in the periodic region. But only 5% of them have an isolated sentinel lymph node identification in the periodic, meaning no pelvic sentinel nodes identified. What this tells you is that even the deep myometrium still predominantly drains to the pelvis. Ultimately, to address the question of is sentinel node accurate for high-grade cancer, what needs to be done is a study in which patients with high-grade cancer are subjected to both the traditional gold standard approach of complete pelvic and periodic lymphadenectomy and the novel diagnostic technique of a sentinel node biopsy. And fortunately, that trial has been done and has been presented early this year at the SGO and earlier in this meeting here with Dr. Ferguson from Toronto, the lead PI. The SENTOR trial enrolled a total of 176 patients. It included patients with grade two and grade three histologies, including non-endometrioid high-risk histologies, all received a pelvic lymph node dissection. And 80% of those with grade three endometrial cancer received a periodic node dissection. What was important about this study design and what was good about it was that it was powered based on the total number of node-positive patients, not the total number of patients enrolled. And they designed this using a Fleming two-stage design, which is the ideal method in which to study a diagnostic test. In doing so, they set the lower limit of acceptable sensitivity at 80% and ensured that they would not stop until they had enrolled enough patients with node-positive disease to confirm that the technique was truly at least above 80% sensitivity. In this study, you can see the patients enrolled predominantly had grade three disease. And so 80% had grade three disease. And of those, most of them actually had non-endometrioid, those highest risk histologies. And the two-by-two table from the SENTOR trial looks both reassuring and familiar. Reassuring because you can see very high rates of sensitivity in detecting metastatic disease. The sensitivity of the technique was 96%, with that lower limit of the confidence interval above 80%. False negative rate of 4%. There was only one patient who had missed 3C disease with this technique. And a negative predictive value of 99%. It's familiar data because this looks almost identical to the two-by-two table from the FIRES trial. And why might that be the case? Well, the truth is the Sentinel node technique is actually agnostic to grade. It doesn't really matter if it's a grade three metastasis or a grade one metastasis. The question is, is this technique going to find a metastasis in the lymph nodes if one exists? And this study essentially validates the findings of the FIRES trial in which only about a quarter of the patients have high grade cancers and shows that, yes, in a concentrated high grade population, this technique is accurate at finding metastatic disease or stage 3C disease when it exists. And this is consistent with historical data, both in prospective studies, such as Dr. Solomon's study, in the subgroup of the FIRES study, and other large retrospective series that have looked at the sensitivity of Sentinel node biopsy for high grade cancers. Once again, largely in populations where high rates of pyritic lymph node completion were performed and found that consistently in these higher count studies, the ones that are highlighted in red, sensitivities were greater than 95% for finding metastatic disease. So is it accurate? Is Sentinel node biopsy accurate in finding metastatic disease in high grade cancer? The answer is yes. But even if it were not, one could argue that lymph node status for high grade cancers likely influences therapy a lot less than it does for low risk cancers, because many of these patients go on to receive chemotherapy regardless of their nodal status. An exception might be the endometrioid histologies. I'll talk about that in a moment. There's an important caveat to these results. It's important that surgeons and clinicians follow the algorithm. These patients in the Sentinel trial had clinical stage one disease. And it's important that your patients also have clinical stage one disease. And this can be challenging in morbidly obese patients. What do I mean by that? Well, the pyritic nodes can be difficult to clinically assess using minimally invasive surgical techniques in obese patients, because they're frequently shrouded in an obese mesentery. And so it's important to obtain preoperative imaging for these patients with either CT scans, PET scans, MRI, something that can evaluate particularly those pyritic nodal basins to ensure you're not missing gross bulky disease that's isolated in this particular chain. So it's accurate, but is it safe? Are we losing any therapeutic value by not resecting the periodic nodes? Well, as Dr. Tanner discussed, lymphadenectomy in and of itself is not therapeutic for endometrial cancer, at least among all comets, including the low-risk population. We know that from randomized control trials. But retrospective series like the C-POL study showed that among patients with high-grade cancers, there was a survival benefit with a complete periodic lymphadenectomy added to pelvic lymphadenectomy. So this data is retrospective. And the challenge with retrospective data analyzing this question is it becomes very difficult to tease out if you're seeing a benefit that's derived from increased diagnostics or from the better direction of adjuvant therapies by those improved diagnostics of taking more nodal tissue. What we do know is that the periodic nodes do not represent the limit of metastatic potential, meaning that a high-grade endometrial cancers that spread to the periodic region are also spreading to other regions too. And so we're not removing all microscopic disease when we're removing microscopic disease in the periodic nodes. Additionally, for these particularly high-grade histologies like serous cancer and carcino-sarcoma, even when they are comprehensively staged and determined to be surgical stage one, they still have extremely high rates of recurrence, 30% to 40%. And those recurrences are just as likely to be distant as they are local. And for this reason, the general recommendation is to consider adding adjuvant chemotherapy, adjuvant systemic therapy for patients with these highest-grade and highest-risk histologies. And therefore, if we remember back to Dr. Tanna's slide where he was talking about the results of GOG258 and how that influences our therapy, we have determined that the results of GOG258 have said that the standard of care treatment for patients with stage 3c disease is chemotherapy. And now I'm telling you that the recommended treatment for patients with stage 1 disease of these high-risk histologies is chemotherapy. The question then is, what added value is there to removing nodes to confirm that a patient has stage 3c disease versus surgical stage 1 disease? The group at Memorial Sloan Kettering, who have been practicing sentinel node biopsy for high-risk histologies for more than a decade, have looked at the survival retrospectively in these populations. And they've noted that for patients with sarcoma, as well as serous and clear cell cancers, that survival was preserved among their patients who had received sentinel lymph node staging, as opposed to complete lymphadenectomy staging. But what about high-grade endometrioid tumors? That makes up about 20% of patients with grade 3 disease. Well, unfortunately, we do not have good level 1 evidence that suggests that patients with endometrioid histologies benefit, who have stage 1 disease, benefit from the addition of systemic therapy. GOG249, which included about 20% of patients with grade 3 endometrioid cancer, showed no benefit of the addition of chemotherapy to radiation in stage 1 disease. And most of those patients had received comprehensive staging. So this is a group in whom there may be a potential diagnostic and therefore subsequent therapeutic benefit in detecting if they have isolated periodic disease, which then would then trigger them to receive chemotherapy that they might not otherwise receive, and from that receive a survival advantage. But ultimately, we're going to be able to better characterize that subset of patients using the information that we've gleaned from studies like the TCGA, where we know that there is a fairly significant subset of these patients who have serous-like tumors, and probably we can predict that they will benefit from systemic therapy. And we're going to talk a lot more about this later today. So the future of staging of high-grade endometrial cancer is really molecular, not surgical. I foresee a decreased emphasis on surgical staging for these patients and an increased emphasis on systemic over local therapies. We can't rely on our surgical staging results to predict which of these patients are going to relapse and where they're going to relapse. And so likely, we're going to see a future in which adjuvant systemic therapy is administered for most of these patients, if not all, and that will be determined based on molecular markers and ideally targeted to those markers. So what's the role of routine periodic lymph node dissection in high-grade cancers? Well, for now, the question really is, how do you treat patients with stage 3C disease? And Dr. Tanner discussed about what some of the options are. If you still treat stage 3C disease with both chemotherapy and external beam radiation, and if you think that that knowledge about the periodic region containing additional positive lymph nodes is important in planning radiation fields, then there may be some added benefit in these patients of understanding the extent of their nodal disease to plan those fields. However, if you reserve external beam radiation for salvage of those patients who we know are at increased risk for nodal basin recurrence if they receive chemotherapy alone, if you reserve it for those patients and you treat with chemotherapy alone in the upfront adjuvant setting, then there's probably less benefit to clearing the periodic region with a routine lymphadenectomy. But there is one subgroup of patients, those with a deeply invasive grade 3 endometrio cell type tumor who have up to a 16% risk for isolated periodic node metastases in whom detecting that disease is going to change your adjuvant therapy significantly. That may be a subgroup in whom there may be the greatest benefit for a routine PA node dissection. But I predict certainly in the future, probably none of our patients will be having a routine periodic sampling. Thank you very much for your time. Thank you. Am I on? I'm on again. So thank you, Dr. Rossi and Dr. Tanner. I think we have two minutes just for a few questions from the external panel. There's a question that in sentinel positive cases, should we perform completion lymphadenectomy? I think you pretty much covered it, but this is a question for you both, I think. I don't think that there's added benefit. We know that therapeutically there's not added benefit to a completion lymphadenectomy and it's not going to change the plan to prescribe chemotherapy. So it's not my practice to complete that. No. So maybe I could add, is there any reason for doing any kind of a lymphadenectomy if even sentinel node, it may be a little provoking, but is there any reason to do it if you want to, if you give chemotherapy to everybody with high-risk histology? I think that's a great, great question. I mean, certainly patients with high grade disease that we are going to likely give chemotherapy to anyway, it becomes harder to make a justification for that. I do think that there are points about having information about prognosis that is potentially a value for patients and the sentinel node evaluation certainly seems to have limited morbidity, although that's a question, still an open question that we need to answer with the prospective data. But I think that that is a real question. I think that Dr. Rossi's point about low grade disease being more problematic where we would not give systemic therapy for patients who are lymph node negative is more of an issue than in high grade disease. But of course the rate of node positivity is much lower in that setting. So I think that's, I think we are at some point like nibbling around the edges of very low risk situations. There were some comments in the Q and A about periordic nodal metastases. And I had shared some data about the FIRES trial and the risk of periodic nodal METs. There certainly are other studies that suggest that there are patients that have PA nodal METs. The real issue is just those patients just, they benefit from chemo. They have systemic disease, you know, they, they, they're high risk of distant failure. So chemo is the thing that really guides and determines their outcome. Yeah. Thank you. I think we'll have to stop now. Thank you for your participation. Next up is Dr. Andrea Mariani from the Mayo Clinic in the U.S. Dr. Mariani, please go ahead and then take over the moderator responsibilities. Thank you. Thank you. And thank you, Dr. Jensen for this. And I would just add that in endometrial cancer, the battle is lost at distance as our speakers were saying. And so surgery is a local treatment. In our comparison with Memorial, we saw that we can potentially decrease the risk of paraortic recurrence, for example, but it's difficult to demonstrate the survival advanced with a local therapy like paraortic lymphadenectomy. So I think this is important. This has been well described both by Dr. Rossi and Dr. Tanner. So thank you both for your great presentation. I will moderate the second part of the, of the session to the audience. Please remember that you can ask questions electronically. I take the opportunity to thank my friend, Dr. Mario Leitao from Memorial Sloan Kettering, who is helping us from behind the scenes in selecting questions. The second part of the session is a review on the significance of low volume metastasis, in particular, isolated tumor cells in the sentinel nodes of patients with endometrial cancer. The title is what to do with ITC and micrometastasis in the sentinel lymph nodes. No need for adjuvant treatment or send to chemotherapy and radiation, or the truth is in the middle. This is a very controversial topic and data in the literature are lacking. Mainly we have a limited patients in the literature with ITC who did not receive any adjuvant therapy and a relatively short follow-up. We have asked the two world experts of this topic to speak about that. Dr. Marie Plante and Dr. Flor Beckes. Dr. Marie Plante is from Laval University in Quebec, Canada. Dr. Plante completed her OB-GYN residency at McGill University and a fellowship in gynecologic oncology at Memorial Sloan Kettering. She's a full professor in the department of OB-GYN at Laval University. She's currently vice president of IGCS and chair of the cervical cancer research network. She's one of the major experts of fertility sparing surgery and sentinel lymph nodes, both in endometrial and cervical cancer. She's one of the authors who have published most on the topic called low volume metastasis in endometrial cancer. I greatly admire her for all the major contribution she has given in our field. Dr. Flor Beckes is from the Ohio State University and James Cancer Hospital in the US. Dr. Beckes did medical school from the University of Groningen in the Netherlands and completed the OB-GYN residency in gynecologic oncology fellowship at the Ohio State University. Dr. Beckes has been working on a multi-institutional extensive registry, collecting patients with low volume metastasis in endometrial cancer. Thank you. Thank you, Flor, for all the great work that you have done. Dr. Beckes, please begin your presentation. Thank you. Thank you for that very nice introduction as I prepare here to share my slides. So, Dr. Mariani, we added some last minute data on his data too, because also he has been putting some major effort in to figure out what to do with these patients with isolated tumor cells or micrometastasis found in the sentinel lymph nodes. So, really a topic of great interest to us. And so, on behalf of Dr. Pons and myself, thank you for allowing us to discuss this topic and hopefully give you a little bit insight and background. So, here are my disclosures. None are relevant to this talk. And here are Dr. Pons' disclosures. So, as mentioned before, sentinel lymph node mapping has been around for quite some time. And in 2012, Barland published a sentinel lymph node algorithm that is shown here on the right. In 2014, the NCCN adapted the sentinel lymph node algorithm in endometrial cancer. And in 2017, SGO published consensus recommendations regarding sentinel lymph node mapping. Just this past year, there was an SGO survey. And so, in this survey, over 1,000 members were approached and 17% responded, so a relatively low response rate. However, of those who responded, 70% performed sentinel lymph node mapping and 77% reported that micrometastatic disease should be treated. In addition, 21% reported that isolated tumor cells should also be treated as node positive. And so, we'll go and talk a little bit more about that. So, for this talk, our objectives are to discuss some factors that determine the decision for adjuvant therapy. And some considerations when we make these decisions are risk of positive non-sentinel lymph nodes, the risk of recurrence with and without adjuvant treatment, recurrence patterns, local versus distant. And so, we'll go do a little bit of literature review, recommendations, and of course, some words of cautions as well. So, to make sure we're all on the same page, the AJCC, the College of American Pathologists, and the NCCN defined macrometastasis as metastasis greater than two millimeters, micrometastasis greater than 0.2 millimeters but less than two millimeters, and isolated tumor cells as small clusters of cells not greater than 0.2 millimeters. These could also be single tumor cells, clusters of 200 or less cells, and it has to be in a single histologic cross-section. So, it's really important that there's been serial sectioning or also called ultra-staging to make sure there's no additional clusters in the adjacent slides. And this can be detected by routine hematoxylin and eosin or by immunohistochemistry. And so, one of the first things that we consider is, well, should we treat these patients? Well, there could be a risk of positive non-sentinel lymph nodes that we're leaving behind. But when we really look at the data in a little bit more detail, there are several studies now that have shown, yes, the risk of positive non-sentinel lymph nodes is somewhere between 30 and 50, maybe as high as 60 percent or so. But when we look at the size of the sentinel lymph node metastasis, this really seems to matter. So, Tahami showed that if there's micrometastasis or isolated tumor cells, so low-volume metastasis, the risk of a positive non-sentinel lymph node is down to 5 percent. In the FIERS trial also, that decreased with micrometastasis, and really the risk is the smallest with isolated tumor cells from personal communication with Dr. Rossi. And in the SALVO and PLAN studies, those patients who either had isolated tumor cells detected with IHC only or had low-volume metastasis, none of those have positive non-sentinel lymph nodes. So, overall, pretty low risk that if you have low-volume metastasis that you have any risk for leaving positive non-sentinel lymph nodes behind. But here's one of the first studies that kind of broached this topic of what do we do regarding treatment or not. So, this was a retrospective study of patients with endometrial cancer who had undergone staging. They identified six to three patients with intermediate risk, stage one or two, and they defined intermediate risk as those with deep myometrial invasion, grade three or non-endometrial testology, cervical involvement, lymphovascular space invasion, or positive peritoneal cytology. And so, they did remote ultra-staging on almost 2,500 lymph nodes of these 61 patients. They found nine patients with occult lymph node metastasis, six were isolated tumor cells, and three were micrometastasis. They found also that if you had this, there was a higher number of patients with lymphovascular space invasion and deep myometrial invasion, which other authors also have confirmed. The majority of these patients, even without knowing that these occult metastasis were present, received adjuvant therapy, the majority received chemotherapy, and some also received radiation. They then found that the recurrence rates were higher, almost 50% if you had low-volume metastasis, so both isolated tumor cells or micrometastasis, versus 15% if you had negative lymph nodes. With an eight-year recurrence-free survival of 56% versus 84%. And while this looks to be a pretty large difference, this difference was non-significant in their analysis. But something else to note is that these recurrences appear to happen later, as opposed to earlier. But when we look a little bit more in detail about those patients that had low-volume metastasis, as highlighted, for example, in this lower box, the last patient, patient nine, had serous cancer with deep invasion and all other risk factors and received chemotherapy. Patient eight had deep invasion, grade three cancer, received radiation. So these patients are not just recurring, but also they have these high risk factors that maybe this low-volume metastasis principle doesn't really apply to these patients as they are going to do poorly regardless of treatments. And so when we look at some other studies also, here's one that identified 14 low-volume metastasis out of 230 patients. Eight were micrometastasis and six were isolated tumor cells. About a third received no adjuvant treatment or brachytherapy only. A third received external beam radiation, and 43% received chemotherapy plus or minus radiation. The five-year progression pre-survival was slightly lower with low-volume metastasis versus those who were lymph node negative, but this was a non-significant difference. And as you can see in the graph also, it's really those with macrometastasis, as depicted with the yellow line, that do the worst. And furthermore, if we look at these patients here, above the blue line are those with isolated tumor cells, and below the blue line are those with micrometastasis. A lot of these patients receive adjuvant treatment, and despite adjuvant treatment, they still recur. So they concluded that patients with low-volume metastasis have significantly better survival than those with macrometastasis. So there still may be some part of a prognostic factor here, but low-volume metastasis has not been shown to be a worse prognostic factor than no negative patients. A worse prognostic progression pre-survival was observed, but with non-significant differences. Going to another retrospective multi-institutional study, this is a large number of patients, and what they did is they had these patients with negative lymph nodes, and then identified 126 who had mycometastasis. Those with, the 95 with mycometastasis received adjuvant treatment, chemotherapy or radiation, and then they also had 31 patients who received no adjuvant treatment, but did have mycometastasis. And so this was not a controlled study or propensity score matched or anything like that, but when they looked then at those patients who had, were node negative as seen here in the graph on the left in the upper line, those patients had a much better recurrent disease-free survival than those who were, had mycometastasis and did not receive adjuvant treatment. But then when you look on the right, when we compare those curves for those who had mycometastasis who did receive adjuvant treatment, now those curves are almost similar. And so this would argue that mycometastasis should receive adjuvant treatment to bring them back up to the progression-free and disease-free survival, more equal to those with negative nodes. Another small study, and as I mentioned before, a lot of these studies are quite small and all of these are retrospective. So in this study, they identified endometrioid grade one and two stage one patients. They had 11 patients who had isolated tumor cells and 12 with mycometastasis, and these were retrospectively matched to a lymph node negative group. Most patients received adjuvant treatment, 70% received chemotherapy and 90% received radiation. None of the patients with ITCs recurred and two with mycometastasis recurred. So they concluded that with adjuvant treatment, low volume metastasis and otherwise well-staged and well-differentiated endometrial cancer have similar outcomes to the matched lymph node negative patients. And with that, I will let Dr. Plant continue this talk. Good afternoon, good morning, good evening, wherever you are in the world. Thanks for joining. I'm gonna present now with different types of studies and hopefully the data presented will help you figure out what you think is best for ITC patients in terms of adjuvant treatment. I'll begin with the Sloan-Kettering series. It's a large cohort of 844 patients and all histologies were included. And you can see the 23 patients, that's just 2.7% of the cohort at ITC and the majority of the patients have received adjuvant treatment. So they went ahead and looked at the data more specifically for the endometrial histology and that's 724 patients, 19 of which had ITC. And as you can see 87% received chemo, 9% radiation therapy and only one patient in fact did not receive any adjuvant treatment. So the recurrence-free survival for the ITC cohort and the node negative patients was essentially identical, but remember that the 95% of patients got treatment. So that doesn't really help us determine which patient truly need adjuvant treatment and which patient could perhaps avoid the toxicity of chemotherapy. So we went ahead and looked at our own data, 519 patients and identified 31 patients with ITC. As you can see in the pie chart, the green color, approximately a third of our patients have not received adjuvant treatment therapy or just devolved brachytherapy. And none of the 28 patients with endometrioid histology recurred and none of the patients who have not received adjuvant treatment recurred. Our three-year progression-free survival for ITC patients and node negative patients was essentially comparable, but of course much better than patients with necrometastasis. So we had concluded back then that none of the ITC patients with low-risk endometrioid histology who received no adjuvant treatments have recurred. And we submitted that indications for adjuvant treatment should actually be tailored to uterine factors and histology and not just on the presence of ITCs in the sentinel node. So Dr. Mekesent Ol presented a very important data two years ago at SGO as she expanded the cohort by collecting data from multi-institutional several institutions. And she was able to collect 175 patients with ITC only and with endometrioid histology only. The majority were stage 1A, 1B and two-thirds had LVSI median follow-up of 31 months. What you can see in this pie chart, again in the green color, is up to 43% of the cohort of ITC patients, that 76 patients have received no adjuvant treatment or just a vault bracket therapy. As could be expected in that group of patients who received no adjuvant treatments, the majority were 1A, 1B, were more likely to be 1A, 1B grade one and twos, whereas patients with ITCs who received chemo and or radiation were more likely to have like stage two disease, grade threes and LVSI. The overall survival of the entire cohort is very good with 5% recurring in a three year recurrence free survival of 93%. But what is interesting is if you look at the survival of patients who received no adjuvant treatment or just vault bracket therapy, that PFS is actually excellent and similar to patients who've received chemotherapy. Now, of course, as I just said, patients who had chemotherapy were more likely to have higher risk of features, but nevertheless, that would suggest that the patients not receiving adjuvant treatments is not suffer from worse outcome. Another very interesting observation from that series is that the number of positive lymph nodes for ITC did not seem to be associated with higher risk of recurrence. So that's an interesting observation that we need to dig in a little further in. So the conclusion of Dr. Bakkes was that the risk of retroperitoneal or distant recurrence is low, under 5% if only ITCs are present in the sentinel node in that adjuvant treatment does not significantly affect recurrence free survival or the patterns of recurrence. But of course, longer follow-up time is needed and more patients are required. It's interesting if you look at these three now series and you look at the proportion of patients not receiving treatment, it's increasing. So we're starting to get better and bigger number. But so far, particularly for the last two series, it does not look like not receiving treatment impairs outcome. Now, Dr. Mariani presented a very interesting study yesterday, which is similar to what Dr. Bakkes presented. It was able also to collect internationally a large number of patients with low volume metastasis up to 247 patients, of which 132 patients had ITCs only. And of which 49 patients had ITCs who had not received adjuvant treatment or just low-brachytherapy. So the numbers are getting smaller and smaller. And what's interesting is that they reported seven recurrences in those 49 patients who got no adjuvant treatment, which is somewhat higher than would have been expected. But I would like to point out that many of those seven recurrences were patients who had other risk factors such as cervical stromal invasion, uterine serosal invasion, peritoneal cytology was positive. So it's hard to know if these patients actually recurred because of those four features or because of the presence of ITC only. We don't know for sure, but it's suspicious. They were not able to find significant predictors of recurrence, but the presence of LVSI in grade approached to significance. Now, what I found even more interesting is they further wrote down the data and they looked at very specific risk categories. And here, what we say is there were 25 patients with ITCs, grade one, endometrioid histology who received no adjuvant treatments. There were 25 patients like that and only one recurred, so that's 4%. So to me, that says that patients with ITCs and otherwise low-brachytherapy and otherwise low-risk endometrioid histology patients probably derive very little benefit from getting adjuvant treatment. But it's with data like the one presented by Dr. Mariani, we're breaking down the data into more specific risk categories. And by getting greater number of patients, that hopefully we will be in a position to further be able to define which patients truly benefit from getting adjuvant treatment and which patients could be spared the morbidity of treatment. And with that, I would certainly would like to congratulate Dr. Mariani and colleagues for this very excellent study and excellent data analysis as well. Now, I'm gonna move on to a completely different kind of a study. Again, that was presented and published by Dr. Backes. In their institution, they do robotic surgery for endometrial cancer, including sentinel mapping. They have a cohort of 204 patients. And what's interesting is that they performed the ultra staging of the sentinel node remote from surgery and blinded to the surgeon. What that means is that patient's decision to receive adjuvant treatment was based on the regular pathology of the uterus and the regular pathology of the lymph nodes. And then later on, after the treatment had been completed, they went back and did the ultra staging of those sentinel nodes. And they identified nine patients with ITC. Turns out that none of those nine ITC patients recurred and eight of them had not received adjuvant treatment, which again is an indirect evidence that not receiving adjuvant treatment was not detrimental to these patients. Another observation was that none of the ITCs patients had other non-positive sentinel node. I would like to continue now with another completely different design of a study. It's a case control study, which was actually presented by Dr. Castellano and group at the recent virtual 2020 SGU meeting. And I want to thank them for allowing me to present some of that data. It's a case control study. They looked at their own database and identified stage one and two endometrioid endometrial cancer. All patients had underwent staging hysterectomy with a complete lymph node dissection. They identified what they call the cases, which were the patients who recurred. Those were matched to what they call the controls, which would be the patients who did not recur. Now, all these patients were no negative based on regular pathology assessment. And they were recommended to receive adjuvant treatment according to usual histopathological risk factors. It's a grade, depth of myeloma to invasion, LVSI and so on. And then these patients were matched one to two according to the factors outlined to the staging grade and so on. Now, retrospectively, they went ahead and ultra-staged all the removed lymph nodes. So they had the pleasure of looking at over 2000 slides. So here's what we see. They identified 50 cases. That is 50 patients who recurred and 103 patients who did not recur. It's hard to see, gets a lot of data on the table, but they were very well matched in terms of the uterine and pathology characteristics. They were very, very comparable. And what they found is this. When they did the immunohistochemistry and ultra-staging, they identified ITCs in 18 patients. And you can see it in the table that the ITC patients were equally distributed amongst patients who recurred and patients who did not recur. And they were pretty well balanced in the sense of patients who were high risk according to GOG criteria. They did pretty sophisticated statistical analysis, but for the sake of time, I'm gonna just present the capital minor curves. But in essence, what they've concluded is that neither recurrence-free survival nor overall survival differed significantly according to ITC status, which is the green shadow on the slides that you can see. And so the authors concluded that the presence of micromet and ITCs was not associated with an increased odds of recurrent endometrial cancer, and that the presence of ITC was closely associated with the known clinical pathological risk factors in early stage endometrial cancer, such as the grade and myometrial invasion and LVSI. And they proposed that the presence of ITC may not warrant upstaging, but that information can be taken into consideration when deciding or guiding adjuvant treatment. So I will now turn the presentation back to Dr. Backus to finish and conclude. Thank you. So basically, in summary here, regarding the isolated tumor cells in endometrial cancer, the data is limited to retrospective studies. These are subjective to selection bias and short follow-up overall. There are a small number of cases, and so it's really good to see that there's collaborative efforts ongoing international and national. And many of these patients have received adjuvant treatments. And so it really seems to be pertaining to endometrioid histology, and I think that's a really important thing to keep in mind. Those patients with non-endometrioid histology, as we have seen from several of the data, as well as from Dr. Mariani's data, those patients, if they have ITCs or micromets, they're going to do poorly anyways, even when they receive chemotherapy and or radiation. So next slide. So we would suggest that the ITCs per se are considered to increase the risk of recurrence, and it doesn't justify stage migration to stage three. So we would recommend that the decision to offer adjuvant treatment should be based on uterine factors only, and not only on the presence of ITCs. But it is really important. We know that micrometastases certainly are a completely different thing, and that those patients do require chemotherapy. So we really need to make sure that these isolated tumor cells are isolated tumor cells only and nothing more, by making sure that those sentinel lymph nodes are ultra-staged to rule out those larger metastases. Large perspective trials with longer follow-up are needed, and we're really going to require those large number of cases to detect small differences. And one of those efforts also ongoing, which is listed on clinicaltrials.gov, is an observational study by Dr. Martinelli that's going to collect this data for ITCs in uterine and cervical cancers. Next slide. As far as micrometastases in endometrial cancer, the data is limited, small numbers, retrospective studies, same thing again. Most patients did receive adjuvant treatment, and currently these patients would be classified as stage 3C. While the level of evidence to support the benefit of adjuvant treatment is limited, we still would recommend to continue treating these patients with adjuvant treatment. And really where we may need to go is that rather than focusing on ITCs or micrometastases, should we really be focusing our efforts more on looking at different molecular profiles and what treatments can we match up for these particular profiles? And would that be more prognostic and also predictive of the response to treatment rather than these low volume metastases? Thank you so much for your attention. And with that, both of us would be happy to answer any questions. Thank you. Thank you both Marie and Flor for the great presentation. And again, it seems that you underline the fact that we need to look at the primary tumor and the risk factors for that. You already mentioned about molecular profiling. One of the questions that came out was about molecular profiling, but you mentioned about that. One thing that I would like you to answer is this. For example, when you presented the data on grade one untreated in our series, about 50% of those patients had less than two years follow-up. And so my personal concern was perhaps we are missing some late recurrences. So I would like both of you to comment about that and also to state as of today, how would you counsel a patient that is in front of you with grade one, no risk factors and ITC, both of you? I can start if you want. I think your point is valid and well taken. Longer follow-up is needed, and that's weaknesses of many of the series that I quoted. And to make sure, as you pointed out, that we're not seeing late recurrences in the future. So that's a valid point. As far as I am concerned, I personally feel comfortable in face of an endometrial cancer patients, endometrioid, low risk factors with the presence of ITC to observe and not get a matching treatment or vulvar IT factor when necessary, but withhold chemotherapy. I feel comfortable with that. Yeah, and I would add to that. We do the same here and don't treat those patients with systemic treatment. We counsel them and our surveillance is the same as what we would normally do based on their uterine factors. So whether that's every three months or every six months, but the majority from all the studies that we've done so far in these early stage patients before sentinel lymph nodes, when we weren't even looking at this detail, there should have been some patients also had ITCs who weren't detected at that time when we were just doing a single cut section. So from those studies, still the majority of the patients recur within the first three, most of them within two up to three years, but late recurrences are rare. And I don't know if that's necessarily a function of ITCs, but could also be a function of that. Our studies have just not captured so many later, but I think that is still a very small percentage. Thank you. Thank you both. And I would reinforce also the fact that we need to gather data all together like the studies that Flor suggested, et cetera. So that's important that we unite the forces. And thank you. Thank you again. And now I'll hand to the moderator responsibility to Dr. Matt Powell from Washington University School of Medicine. Matt. Hey, thank you, Dr. Mariani. What a wonderful session you put together. Thank you so much on that. Next up, we have a fantastic debate for you. And we're really wondering, is molecular profiling for post-op risk and adjuvant therapy decisions ready for prime time? And I really have two world leaders set up for you. We have Dr. Jessica McAlpin from University of British Columbia. She's the co-chair, the division head of the division of G1 oncology there. She is a G1 oncologist at the University of British Columbia. And she's really led the development of the PROMIS classifier. So the clinical implications of this, and she's helping us at the NCI. She's just so wonderful to be a part of this. And then we'll also have Dr. Remy Knaupt who is a radiation oncologist. And you'll know he's been part of all the PORTEC studies, lead author on the long-term follow-up of PORTEC-1 and PORTEC-2. And he's the PI on PORTEC-4a. So we're just really thrilled to have such a talented group here with us. We'll also have Dr. Anuja Jhingram, and many of you may know at MD Anderson Cancer Center, will be part of our panel in helping stimulate conversation. She's been really a leader with us at the NCI, helping move this information forward to patients. So with that, Dr. McAlpin, please begin your argument. Are you muted, perhaps? Let's see. Very sticky. Can you hear me now? Perfect. So thanks, Matt, and thanks everyone for joining us. It's an exciting time in this disease site, and it's a pleasure to talk about something that I think has been truly transformative in endometrial cancer research and clinical practice. These are my disclosures, not related to the current presentation. So we've been tasked with talking about why molecular classification now, are we ready? And I think it's particularly the focus on early stage endometrial cancer. So what is the value added with it? And I'll start with consistent categorization. So unlike ovarian cancer, which we're all familiar with, where a group of pathologists can be brought and discern the five epithelial subtypes with very high inter-observer agreement for endometrial cancers, those same respected pathologists will have major disagreement or a complete lack of consensus in about a third of cases. So a pathostatistic of 0.55, consistent with only a moderate level of agreement. Core reproducibility also of grade, and that may be in the final hysterectomy specimen, and of course, differences between original biopsy and final hysterectomy specimen. And grade and histotype are the two major, or two of the major components that go into most risk stratification systems. So you're compromised with that information and the same tumor might be, therefore put into a different risk category and get very different treatment with all the sequelae that go with that. And then clinical trials have batched very molecularly diverse tumors. So trying to interpret treatment efficacy within these becomes nearly impossible or certainly very limited in holding us back. So inspired by the TCGA, series of pragmatic molecular classifiers have been developed. The testing is arguably much more objective and you identify still these four molecular subtypes and we'll talk about the prognostic capability shortly. So very focused immunohistochemistry for mismatched repair proteins in P53. These are proteins in testing that people are familiar with in the majority of pathology centers. And then very focused sequencing from panels to allow for looking for pathogenic poly mutations. And the order of pulling out in this algorithm allows for those 3% of endometrial cancers that may have more than one molecular feature, which we can talk about as well. And I think very excitingly, you can actually do a molecular classification on diagnostic biopsies. And the antigen preservation, of course, from a pipel that you've got in your office and put in formalin immediately is actually much greater than that hysterectomy specimen that might stay in the operating room for hours. Very high level of concordance between biopsy to final hysterectomy. And of course, this is in contrast to the level of concordance in grade and histotype between biopsy and hysterectomy. Prognostic value, initially, of course, shown in the cancer genome atlas. This very highly favorable outcome group and those with pathogenic poly mutations or the ultramutated phenotype, worse, of course, in copy number high. But this has been recapitulated with the pragmatic classifiers, certainly in the PORTEX series, intermediate, high intermediate risk, in population-based series by our group and others, but even in subgroups. So young women, less than 50 years old, you would think they might all be quite homogenous, NSMP tumors, high estrogen, et cetera, but there's different subgroups within and they separate out based on molecular classification. This is a very telling study in grade three endometrioid tumors brought together through international collaboration. This survival curve is within stage one grade three endometrioids, which are all treated arguably the same and look at their very, very different outcomes. And then Deborah Dallaire, as well as our group, have looked at, again, different outcomes within clear cell cancers. Again, a group you might think are all P53 abnormal and again, the diversity shown. There are other things that are prognostic, other risk stratification groups may be prognostic. Worrisomely, if you cross-tabulate the diversity within each molecular subtype of ESMO risk groups, there's 10 to 15% that are P53 abnormal classified as low risk and might not have had any treatment. And we know how the outcomes are within that subgroup. PERIL-C index is a type of test that looks at the ability of a tool to discern outcomes, such as overall or disease-specific progression-free survival. And molecular classification outperforms classic risk group stratification. I think the point here is more, though, that you can improve upon molecular classification with adding certain features, LVSI or traditional clinical pathologic features. And we're now looking within the framework of molecular classification at the added value of different molecular tools, such as beta-catenin mutations, immune profiles, maybe L1-CAM as a single marker, not as valued, but within molecular subgroups, adding value and for refining prognostic ability. And I think these other aspects have been touched on in many of the really good presentations from this meeting. Certainly looking at practice patterns across Canada, we saw as low as five to 10%, up to 90% of routine MMR performance across cancer centers. Not surprisingly, the rate of hereditary cancer program referrals is much lower in centers that are not doing routine MMR testing, and the rate of pickup of Lynch syndrome lower. So huge consequences for patients. We have an FDA-approved therapy for mismatch repair efficiency, so beyond Lynch, but any even somatic or hypermethylated MMRD tumors with an opportunity in therapy. And then several oral plenaries and posters looking at the association of MMRD with LBI, positive nodes, and worst prognosis. And should these patients be managed differently? If you are in a place that normally allows grade ones to be managed in the community, is that appropriate if it's an MMRD tumor, or do you need to do those nodes? I'll just talk about two quick case examples where I think molecular classification made a difference. First, a 65-year-old, very indolent appearing tumor based on her stage grade would have normally received no treatment. Lucky to be in a center that has embraced some aspects of molecular classification somewhat more routinely, and P53 was performed on this. We saw at a higher power that there was some nuclear atypia, and with P53 immunohistochemistry, there was complete loss of protein expression consistent with the non-mutation pattern, which is a P53 abnormal case. And we know actually about 5% to 10% of low-grade endometrioids will have P53 mutations that may be as high as 20% in grade twos. And these are different phenotypes. These are older women, and they have worse prognosis, needed to be treated appropriately. This is another case, a much more aggressive appearing tumor on high power, 55-year-old, deeper invasion. And she also had P53 done, which is probably done in a good majority of our high-grade tumors. And it showed the pattern you see in the lower right, where you have subclonal expression or overexpression of P53. So the very dark staining overexpression or missense mutation pattern compared to the right part. And this was classified certainly by the Leiden Group as really being a sheep in wolf's clothing. This woman went on to have polymutation testing, and it actually should have an excellent outcome, not at all consistent with what was seen initially under the microscope. Predictive value, I'm gonna leave to Dr. Newt to discuss. I fully admit that most of the very, very exciting predictive studies in molecular classification are retrospective. We'll talk about where we can go from there, but I still think today we have some things that can direct treatment. Certainly, again, FDA approved immune blockade therapy for mismatch repair deficient tumors. The exciting implications of what may be for P53 abnormal tumors, certainly knowing these women need more treatment and the potential role of chemotherapy, as well as what is often studies in serious cancer, of course, the majority of which are P53 abnormal and seeing signals of homologous recombination deficiency, HER2 amplification, both of which are targetable in a very exciting era to look at de-escalation of therapy in polymutated tumors. I think the point at why you say, why does it guide even today, even if you can identify patients and appropriately triage them to subtype specific trials, we're at a huge advantage. And Dr. Newt will also talk about rainbow initiatives and others for subtype specific clinical trials. So in summary, this isn't a fad. Molecular classification is here to stay as Dr. Kreutzberg said earlier in this meeting. We have the WHO fifth edition pathology blue book that is describing for pathologies how to integrate molecular classification to standard of care. You will see this in your reports increasingly. And I say, we're ready. The consistent classification is essential, especially in early stage disease. And we can talk if there's time about why maybe we don't need it in the very, very low risk. Maybe we don't need poly testing in the very, very early and low risk, or maybe not in the advanced stage, but the higher importance of it across those intermediate and high risk early stage disease to tell the good tumors from the bad and to enable stratification to intelligent clinical trials that will have interpretable results. The prognostic value is unquestioned. And we're now at a level where we can refine this within molecular subgroups. Prognosis is a value for patients. I think we forget that sometimes as well. And with earlier information, it may help both the patients and the clinicians with their decision-making. If you're a young woman considering fertility, sparing conservative management, is that appropriate if that tumor is P53 abnormal or mismatch repair deficient? And again, the predictive aspects, I'll leave to my colleague and we'll talk about that exciting aspect. I'll let questions go to the end. Great, thank you so much, Dr. McAlpin. And thanks for bringing up HER2 targeting. We have a new trial opening worldwide that hopefully will do that for early stage P53 aberrant tumors. And with that, I'll lead into to Remy and Remy take it on to why we shouldn't be doing this yet. Not ready. Thank you. So hello everyone. And I would like to start with thanking IGCS and the program committee for the opportunity to speak on this very interesting topic. So for me, the challenging role in the debate to oppose Jessica and that molecular profiling is at the moment not yet ready. So I have no relevant disclosures other that as you already told, Matt, I am quite involved in the PORTEC trials and it will be shown later that we are quite invested in molecular classification. So that brings me to a challenging point to debate that we are not ready for that. So first to start with post-operative risk stratification, that's the first part of the title. And I would say that we have now really a lot of data starting of course, with the most important paper in nature by Kandos from the Cancer Genome Atlas Group, but then repeated using more straightforward testing in different cohorts, both selected and unselected with large numbers of patients. And really you see this repetitive curves, different differentiating prognosis for PPC3 abnormal patients, OE mismatch repair deficient. Also, when you move to more high-risk disease, on the left you see the same curves from high-risk patients from PORTEC3, as well as in the middle, grade three, all stages or stage one, grade three. So especially I would say in these high-risk and also high-grade histologies, there is really a clear message that these molecular risk stratification, molecular risk groups, have a very important prognostic role. And then moving to more rare subtypes of what we then group as non-endometric type, there are several studies. And of course this is challenging because the numbers are small, but there are now several studies that indicate that you can also see clear separation of these curves in the more rare histological subtypes. But I would say that if you look at the numbers and the curves at the moment, we do need more data in non-endometrial tumors to really feel more confident. So with regard to molecular stratification and the role in prognostic, as a prognostic tool, I say yes. There are multiple prospective large cohorts also of prospective obtained data from trials to inform about prognosis. And I think it's an important point in the patient perspective. Suppose the non-endometrial subtypes, the more rare histologies, we could use more data. And another point I think is that within these subgroups, we still can learn a lot from additional molecular alterations. So for instance, the role of beta-catenin, HRD, R2, it was also already mentioned. So this I think is a very important first step, but I hope that in the future, we can even learn more about prognosis even within these subgroups. And I would say that one of the major challenges at the moment where we are now is how to integrate this molecular information with the current used clinical risk certification that we use all over the world in clinic. Because that is something I think that we really need to move into and to grow. So that brings me to the topic of for adjuvant treatment decisions. And then it's important I think for a debate to discuss prognostic versus predictive because prognostic informs about a likely outcome independent of the treatment received. And the important thing about predictive is that if the treatment effect is different for biomarker positive compared to biomarker negative patients. So you need to perform a test for interaction. So it's also a statistical important difference between prognostic and predictive. So I want to show you one example where we try to integrate molecular classification into the current classical risk certification. And here you see, this is PORTEC1 and 2 data where high intermediate risk and in vitro cancer patients are classified into favorable, unfavorable or intermediate. And it starts with the selection of course of high intermediate risk. So that is already a selection based on classical prognostic factors. And after that, there is a grouping into favorable with POL-E, unfavorable with P53 and also substantial LVSE and L1-CAM overexpression. So we showed in this study that patients with favorable risk factors of course have a very good outcome compared to unfavorable. And by using such a classification about 55% of high intermediate risk patients would be classified into a favorable group. In such an analysis, there has never been a test for interaction. So that's important. So there's no statistical predictive data in this. When we look at PORTEC2 tenure results, we see on the left, again, as you are now well aware of the separation of the molecular groups. We also see that in PORTEC2. When we look in the middle, this is the pelvic recurrence risk by treatment type. So you see pelvic lymph node recurrences are higher in patients who received practice therapy. It's still a very low percentage, about 5%. So we wanted to learn more about this group of 5% that has pelvic lymph node recurrences in PORTEC2. And we looked at the risk factors. And on the right side, you can see the curves of patients with brachytherapy or external BREAM having or not having risk factors and you clearly see that patients who had risk factors, so the P53 group or L1 chem overexpression or substantial LVSI had a significant increased risk of pelvic lymph node recurrences and look at the risk in the other groups, it's very, very low. So that formed the basis for the PORTEC4A study in which the molecular integrated risk classification is compared to standard indications for adjuvant treatment. In a 2 to 1 randomization, favorable patients will be observed, intermediates receive the standard therapy, brachytherapy and unfavorable will receive external BREAM radiotherapy and the current inclusion is over 350. So I think this is an important step in high intermediate risk to try to bring the molecular risk classification into the clinical arena, but it is in the framework of a study, a randomized study. So that brings me to PORTEC3. This data was also just shown by Dr. McAlpine. Here you see, I think that's very important, the P53 abnormal group. You clearly see that there is a benefit of the addition of chemotherapy to radiotherapy in these patients. But importantly, from a statistical point of view, there was no, there was done a test for interaction, but it was not significant. And the other subgroups, there was no significant difference between radiotherapy or the addition of chemotherapy to radiotherapy. And you see in this high risk population, an excellent outcome for polymutated tumors and also fairly good for mismatch repair deficient. So in high risk disease, this is, I believe the next step where also molecular classification is brought within the framework of a study into the clinic. And it was already also explained that within the P53 abnormal group, it will be very interesting to look at the role of PARP inhibitors. So there is a group that will lead the study in which there will be a randomization between the standard chemo radiation versus chemo radiation followed by PARP inhibition. In mismatch repair deficient tumors, there will be a study randomizing between radiation or the combination of radiation and a PDE1 inhibitor. In the non-molecular, non-specific molecular profile group, there will be a study randomizing between chemo radiation or radiation with hormonal treatment. And in polymutated, there will be a study which will be more a registration study looking at no-adjuvant radiotherapy. So as part of the discussion, I think it is also important to look at the role of molecular risk certification in low risk patients. So low risk patients are the majority of the patients out there. We think approximately 50% of the patients who fulfill stage 1a grade 1 to 2 LVSI negative, they have excellent prognosis with surgery alone without lymphadenectomy. So the question is, do we need a molecular profile in this group because they already have a very good prognosis? So I would post that in these patients, mismatch repair deficiency status is important because it is the initial step in screening to rule out Lynch. P53 status is important information, it's prognostic relevant. But again, we do not have data that it is predictive. But with P53 status, it could become important in inclusion for studies. And with regard to pol E status, I think you can question if it is a relevant information to know in this group, which already has a very good prognosis. And there you go into a discussion about the availability of pol E testing and cost effectiveness. So to summarize in the debate, I would say molecular profiling is not ready. For risk stratification, yes, because we have good information about prognosis. We might need more data for non-endometriic types. And I think the big question is how to integrate this with the current clinical risk stratification. With regard to decisions in adjuvant treatment, I would say not yet, but in clinical trials, yes. So we do not have proof of statistical predictiveness and studies are ongoing. So PORTEC4A and I think taking that forward into this rainbow program. And I would like to end with the question in law, do we need pol E status? We have to think about availability over the world and costs. So thank you very much. Thank you for that wonderful presentation from both of you. And it sounds like we're almost there and we're ready. We're excited. Just a lot moving forward. I'm going to invite Dr. Nuja Jhingram to make some comments. We have about three minutes here and then we'll move on to the next topic as we address some of the questions. But Dr. Jhingram. Yeah, no. So it was a very, very interesting debate. And I think what's come out of this is that we really should be doing the molecular testing at diagnosis, so not at hysterectomy. So that comes up. If you do know if it is a pol E positive patient or if it is a P53 abnormal patient, should we be doing lymph node dissection or do they need the lymph node dissection if we already know what their prognosis is going to be? Pol E is doing great. So do we need to know their nodal status? And P53, you're already going to give them chemotherapy. So do we need to know their nose status? So quickly, Remy and Jessica, can you tell us what you think or your thoughts on that? I'm sure I can start on it. I think actually two of the prior speakers spoke to that. I think Dr. Rossi and Dr. Bacchus, I think that's even with the caveats that it's retrospective data on the P53 abnormal, I think we're all impressed and that a high proportion of the P43 patients were early stage high-risk women. We know the nodal dissection is not therapeutic. We've said for our high-risk patients, we're going to image them to make sure we don't miss huge nodal bundles that might not light up. And I think and hope we would move toward potentially going away from nodal dissection in these, with the exception being if you're in a center that is rigid and is not going to treat them unless they're advanced stage, or I guess the weird exception of if it's confined to a polyp. In terms of polies, I'm impressed that in our big collection of meta-analysis, sure, there's 5% that are node positive, but they're not even necessarily the ones that recur and they do very well. So I'm not sure the value. Dr. Naat? Yeah, thank you. Yes, I completely agree. I think that we are really in the time that we should use this information that we can have so early on in time, even before surgery, we have studies that show this molecular factors, of course, are overlapping in your surgical specimen and in your corotage or biopsy. So I'm really looking forward to data where this is taken forward, also in time, and surgical management is really also adapted, taking this information in mind. Absolutely. Perfect. Thank you. And I think that really does give us all the time we have so that you can move on, but great debate and great topics. And it'd be interesting to start doing it at time of diagnosis, right? Because that really will change your entire management of everything. So again, thank you, everybody. Matt, you're on. Yes. Thank you so much, Anuja. And you didn't give me really time to fight all the radiation that they're using in the RAINBOW trial, but we'll have to save that for another time. Yeah, there was a reason for that. From here, I really want to bring up our next session and this will finish up the master session in uterine cancer and invite Dr. Mansoor Mirza from Copenhagen University in Denmark to join us. He's the Chief Oncologist in the Department of Oncology. As you know, he leads the NSGO and a leader within NGOT. He really doesn't really need much of an introduction as he has probably been one of the most prolific clinical trialists within G1 oncology over the last decade. And just really honored to have him here to talk to us about current and future directions in the management of advanced recurrent endometrial cancer. Dr. Mirza, thank you so much for joining us. Thank you, Matt. Thank you for such a kind introduction and thanks to IGCS to let me join this very extremely interesting session. I would say I learned a lot from the surgeons from today and it was great to be here. These are my disclosures. So what I'm going to talk, I'm not going to talk about early stage treatment because that is already covered. I would be moving you from the locally advanced and to the metastatic disease. And I'll go back to the basic, which is chemotherapy, and go back to many, many years ago when Randall presented the trial. These are the trials which has brought us to the treatment we are giving today, which is Pactitaxel and Caboplatin. So if you start with the GOG study with Randall presented, comparing all abdominal radiation therapy with chemotherapy, that was a superiority trial for chemotherapy. It was positive. And then very structurally in the randomized setting, we have moved from single agent to doublet. And even from doublet, we tried to go up to triplet in another trial where doxorubicin and cisplatin was compared to triplet when Taxol was available. It was significant both for PFS and OS, but extremely toxic. So we went back to do a non-inferiority trial, the GOG 209 TAP versus TC, which showed that Caboplatin Pactitaxel was non-inferior to triplet and much less toxic. So that is why this is our standard of care today. What happens when patients progress on Pactitaxel Caboplatin and we cannot give that treatment again? This is a very pathetic situation. We don't have anything available. We don't have any, and the treatment we are giving, we are just taking it from ovarian cancer and trying to give it, but you can see here, response rates are really pathetic. So we don't have actually anything available for these patients. We are trying to treat them with one thing or the other. When it comes to hormonal therapy, again, we don't have any level one evidence and the results are not that encouraging even in the endovitroid, even in the estrogen receptor positive disease. By history, we were using progestogens, but moving to Tamoxifen, Fulvastrand, and Aromatase inhibitor, but still the level of evidence is low and we need more stronger trials for that. And that brings me to the ESMO-ESGO-ESTRO consensus in 2016, which clearly says that the only treatment we have right now is six cycles of Pactitaxel carboplatin. And beyond that, we have nothing available and targeted therapy is still not there. And it hasn't actually changed much since then, apart from the IO, which I'll come back to. So now what happened? We tried to see if we can add antiangiogenic agents here. This is the METO trial, adding Bevacizumab to Pactitaxel. Initial results were positive. The latest results published were not. So it has not moved anywhere. There was another trial. It was not comparing to standard of care by Agajanian, but it was three experimental arms. One was with Bevacizumab, second was with Demsirolimus, and third was with Exabipilon and Bevacizumab with CARBO. And that has been compared to the standard of care for carboplatin-Pactitaxel in historic control, the black one. Again, you see that Bevacizumab, the arm is doing better, but this is again not a direct comparison to standard of care. We have finished a recruiting patient with another antiangiogenic tyrosine kinase inhibitor, Nentetanib, and we would probably be able to present these data next year in the patients who have stage 3, 4 disease or first relapse at Pactitaxel carboplatin plus Nentetanib or placebo. And this slide you have already seen, I think we have moved quite a lot in the molecular classification of this disease. And as beautifully said by earlier speakers that we are in the learning cohort, we have the early data, we have small trials which are telling us that maybe we can treat this way or that way. And I'm looking forward to the ongoing prospective trials to see if we can nail down how we are going to treat these patients in future. Another very nice way to put this is how these histological classifications of endometrioid, cirrus, carcinosarcomas, and clear cell coincide with the molecular classification, with the mutation load, with P53 mutation, PI3K alterations, and so on and so on. So all these data is there now, and we are getting more and more clever and we are trying to do more clever trials, which is the future for our patients. So if I might now move to the trials where we are in more like targeted therapy, mTOR inhibitors and PI3K inhibitors, there are data on quite a few trials on mTOR inhibitor showing moderate response rates and also one trial in PI3K, a couple of trials in PI3K inhibitors, a bit toxic, but we haven't really moved ahead with these agents except one trial was presented by Amitosa where the progression-free survival was positive by mTOR inhibitor against comparator, but overall survival was not affected by that. And that's a very small, that's a small phase two trial. Another trial was presented by Dr. Brian Slomovich, ever alumnus with letrozole versus standard of care. Again, you see that there is a PFS benefit. It's doubled. OS is not reached. So there may be some hints here that we probably have to find the right population when we are doing these trials, and that population should be tested separately, and we may get a better difference and better improvement in future. Another trial, now I'm moving to another molecule, which is called CDK4-6 inhibitor. And in CDK4-6 inhibitor, this is actually the first randomized trial, and the data will be presented as late-breaking abstract in one week in asthma. This is a trial in primary stage four disease or relapsed disease. Patients are estrogen receptor positive endometroid adenocarcinomas. The standard of care here is letrozole, and the patients have on top of that received a palpocyclic or placebo until progression of disease. As I said, the primary endpoint will be presented in one week. So get tuned to asthma this year for the oral session on 19th. So another way to work on, we have found that in this cancer, we can also have a very different way to affect cancer cells. Selenexor is a selective inhibitor of nuclear export. So normally what happens is that the good genes, P53I kappa B, they move from nucleus to cytoplasm and moving back to nucleus, but the cancer cells block their travel back to nucleus. And this drug, Selenexor, is not letting them come out of the nucleus. So these good genes remain in the nucleus and do their work, and that's why we can have some efficacy. A phase three trial is ongoing on both sides of the pond, which is led by a BGOG, and that trial is a maintenance trial in a primary stage three, four, or first relapse disease after chemotherapy. Patients have been treated with Selenexor or placebo would be very interesting to see the results of this trial as well. Now we move to something immune therapy. I think in the gynecological oncology, endometrial cancer is going to, I believe is going to lead immune therapy, and second would be cervical cancer. So here you can see why highest rate of MSI high observed in endometrial cancer if you look through the tumors. So there is a clear rationale to try to give checkpoint inhibitors, and the trial which was already presented with Dostolimab showed very impressive results, not only in MSI high population, but also in MSS population. Dr. Roknin is presenting the update data both on the deficient and proficient MMR this year in one week. Again, a late breaking abstract, so get tuned to that for next week, and we will have mature data available for a much, much larger cohort of this trial. What about the patients who are so-called cold tumors, which are not MMR deficient? There, I believe that we need to add something else to improve the efficacy of immune therapy, and Wikimarker presented beautiful data on pembrolizumab and levatinib, where 39.6% response rates, and that was enough to FDA to give a label to this drug over to US, and that was a common label for Australia and Canada included. These are the non-randomized trials, and there is a trial which will be presenting data, I hope, next year, 7.75, to show that this is really the case in the metastatic disease, and we will know the data. That has brought us that everybody's trying to see if we can bring immune therapy up front early stage, and there are multiple trials ongoing. The trial with immune therapy with checkpoint inhibitors, the trials in the EN6 ruby trial and the EN710 trial, as well as the G018 trial, are asking one question, if adding checkpoint inhibitor to chemotherapy and continuous maintenance is going to improve survival of these patients. While the LEAP trial, the LEAP1 trial, is asking a question, if we can completely omit chemotherapy in these patients, so it's a head-to-head comparison of carboplatin, paclitaxel versus pembrolizumab, levatinib, and the third trial, the last trial, DOE trial, is also asking a very innovative question based on the biological rationale, that is, that patients are starting with chemotherapy, paclitaxel, carboplatin, plus minus a PD-L1, drovalumab, and upon finishing six cycles of carboplatin, paclitaxel, one is adding olaparibar placebo on top of that. There is a clear evidence that there is a rationale to combine a PARP inhibitor with PD-L1, and this trial, phase three trial, is asking this question, if we can improve even more the outcome of these patients. Actually, you will again, I believe that you must consider tuning to ESMO next week, because there will be a very interesting, small but very interesting, proof-of-concept trial of this idea as well, in MSS tumors, combining PD-L1 with the PARP inhibitor, so that's another late-breaking abstract. I think I will stop here and conclude that chemotherapy is beneficial in advanced and metastatic endometrial cancer, but after receiving carboplatin, paclitaxel, we are sort of stacked. We don't know where to go. Now, all agents are being widely tested in endometrial cancer, and immune therapy seems to have a definitive place in the management of endometrial cancer, both as a single agent or in combination with other targeted agents. Management of endometrial cancer is to be improved considerably, but we are not there yet. Thank you very much. Thank you, Dr. Mirza. Boy, I haven't had you end on time, early before. You caught me by surprise. I threatened him. You can probably tell I threatened him greatly if he went over, so that's wonderful. Dr. Mirza, what do you think shows the most promise moving forward? I know you gave us a lot of teasers for next week at ESMO, but if you had to say, my mom has endometrial cancer. It's recurrent metastatic. This is what trial I want to get her on. What would you say? I would say that definitely I would do the biomarkers. I will check the PD-L1 status and MSI and MMR, and if patient is deficient for MMR, I would like to to put her on a trial which is using immune therapy as a single agent. If it is MMR proficient, that may be one of the way that you put on the pure plus minus PD-L1 trial, but I would be more curious to see if I can put her on a trial which is having a combination to even affect the patients with the immune therapy, and on top of that, something else. The only trial right now running is DOE, so that would be my preference in that case. On all, these are trials. These are placebo-controlled trials. We don't know the end results, but we are excited with the initial results of tostolimab, of wicke-markers, pembrolizumab, and libatinib, so I believe that we are on the right track. I think a lot of it has to do with your efforts. I mean, we're usually running one trial in the world in endometrial cancer. Now we have six or seven going on, very large trials. It's really a testament to, one, unfortunately, the disease burden that we're facing, and two, that we finally have some new targets to be capitalizing on, and that our industry partners are willing to treat a relatively quote-unquote rare disease, although we see it a lot as GYN-oncology specialists. It's not thought of as being a large disease burden for most areas of the world, so the future is bright, I think, for our endometrial cancer that we can definitely make some progress. Now I want to open it up for any of the other panelists, any other speakers for questions, not only of Dr. Mirza, but questions that anyone wants to address. We don't have any open questions on our Q&A, so I'll open it up to anybody that wants to make a comment or questions. It's getting late. I guess that's it. Well, I guess we could follow up from our last session, Dr. Mirza. As you said, you learned a lot from the surgeons and the radiation oncologists. What do you feel like, in your practice, the role of radiation is, as you balance GOG-258 with PORTEC-3? This is kind of this common question. We have quite diverse opinions across the ocean, and I want to hear from you. Do you feel like the radiation is adding benefit that we just couldn't see in 258, or what is the difference here? I may be biased, because I'm doing a trial on that as well, and we don't have data yet. My question is, are we improving survival of the patients by adding radiation? There are some retrospective subgroup analysis which may hint to that, but that's not strong enough for me to believe that we are making any difference other than the local control for these patients. We reserve radiation therapy in individual base. If patient has pyramidal extension in the pelvis or some sort of clear indication for radiation therapy, we add to that. Otherwise, I think we have enough data that chemotherapy is improving survival, and that's our standard of care. I'm sure that some of the panelists will be quite curious to answer this. Anuja and Rami, maybe? Anuja Dutta So, I can maybe briefly comment, because I would like to actually challenge. I think it would be highly interesting to learn from the molecular profile of GEOG258 also, because we clearly see if you look at the data in PORTEC3 about the molecular profile, that there is some difference within the strata. That also suggests which subgroups seem to have more benefit from the addition of chemotherapy than others. I think there are several reasons to give radiation, and one is also, as you pointed out, Dr. Massour, Dr. Mears said, the local regional control. I think that's also quite important. Another point that we, I think, still need to learn also from GEOG258 is the role of salvage radiation, which is also not completely clear yet. I think there are also still some questions surrounding GEOG258 that could also help a little bit further in understanding the precise role. Greg Phillips Rami, thank you for that. We have a team that's working on trying to get the translational data out of GEOG, not only 258, but also 249, to really try to help answer, are there predictors of who's going to do better with radiation and chemotherapy? I really have to commend you for all the work you've done within the PORTEC group and really getting us to understand the predictors and response. There is a question for Dr. Mirza. Patient with recurrent stage 1a clear cell cancer of the endometrium recurred quickly after surgery from carboplatin-paclitaxel has a PD-L1 score greater than 20%. What would you give this patient? That's a great question. Well, we don't have a clear answer to that. I wish we had some sort of PI3K inhibitors or something like that, which we could treat these patients with. We don't have even a trial running at the moment. Hopefully we will have a trial. But for me, I would go back to chemotherapy and do the second-line chemotherapy if they have progressed on primary chemotherapy. But the efficacy of that is questionable. So the PD-L1 marker in endometrial cancer really hasn't been very predictive, if you'd have to look across most of the datasets. Absolutely. Do you have any sense of why that is, or are we just not measuring the right issues, or even when it is positive, it doesn't work for the vast majority of the proficient tumors? Well, what you're saying is it's not working for the proficient tumors, not that much. The results are quite low. If you look at some of the drugs, it's 6% with avilumab, and fortunately, it's much higher with drostalimab. Vembrolizumab is somewhere in the middle. But if they are MMR proficient, I'm not sure that I will have anything valuable available for these patients with clear cell carcinoma to treat. Not sure. We have to have more trials on that. And we have clear cell included in all of our trials, so we will have enough data in future to see if they are MMR proficient. If they're deficient, then it's clear. You proactively answered another question we had on PIK3CA mutations, and so we'll turn to that. There is a question that came in about the patients that are getting sentinel lymph nodes and that they were not injecting the uterine fundus. What about this 20% false positive in the periodic region? And I think that I don't know if Dr. Bacchus or Dr. Tanner or anybody would like to comment on the question that's there about are we forgetting the periodic region with sentinel lymph nodes? And I think Dr. Tanner had a pretty good comment on that in his talk, but if anybody's on that would like to challenge that question. Maybe people are locked out. I don't know if that's possible. Go ahead. I would invite both Emma and Ed to comment about that. Yeah. I mean, I think from my perspective, I think that those isolated periodic node metastases, they certainly may be occurring. I don't know that we were always finding them anyway traditionally. I don't know that 100% of patients with high-risk histologies were always getting an infrarenal periodic node dissection routinely on everybody. That's one comment. And then the second comment is, as we've talked about extensively today, I don't know that that really changes the adjuvant therapy prescription of chemotherapy. And if these are microscopic isolated periodic nodes that we're missing, there's really no good evidence that that really impairs survival for these patients. Ed, do you have any comments? Yeah. I would just add that I don't think it's coincidence that the rate of isolated, just in general, isolated PA nodal metastasis, the rate of isolated PA central node identification are the same with cervical injection. I mean, I think that the cervix does appropriately map the PA region. When you look at the, I mean, patients who mapped the fundus, they have such a high rate of PA distribution of central node identification. It just doesn't reflect the nodal burden of patients who have metastatic disease. So I think that thinking about it from that standpoint, really the cervix reflects the way nodal metastasis tends to spread for patients. I mean, this does get back to the other question of whether to do a PA node dissection in high-risk patients, but that's different than saying that we should inject the fundus, I think. You'd end up doing a ton of PA node dissections, almost all of which would be unnecessary. Great. In the last few minutes, I'd like to invite Dr. Jensen and Dr. Mariani to make some closing remarks and then thank everybody for joining our session in this last two minutes. Dr. Jensen. Yeah, thank you very much for a very, very good session. I was really delighted. I would have loved it to be longer so that we could have more discussion and more, yeah, I think there are a lot of questions that we could bring up and especially I would love to have a talk with Emma and Ed afterwards, but I think we had a really good talk together. Thank you. I really thank everyone for this great session. I reinforce that, again, the battle is lost at distance in endometrial cancer and so both radiation and surgery can help for controlling the disease, but we really need to also focus a lot about how we can identify patients at risk for distant recurrence and systemic disease. Thank you for that. All right. With that, I think we'll conclude the session. Thanks everybody for joining. I think we hit close to 330 or so participants. I'm sure there'll be a lot of people looking down the road and thank the IGCS staff for being so accommodating and making this a seamless process in the virtual format. Everybody enjoy the rest of the meeting. I think we're going on now to the next session, which is the Immunogen Industrial Symposium entitled Promising Agents in the Development of Recurrent Ovarian Carcinoma. Thank you. Thank you.

low-volume metastasis

sentinel lymph nodes

endometrial cancer

isolated tumor cells

micrometastases

adjuvant treatment

institutional data

risk factors

histology

chemotherapy regimen

hormonal therapy

anti-angiogenic agents

immune therapy

checkpoint inhibitors

targeted agents