Well, good morning. My name is Wendell Bowman. I am the associate director of clinical trials will be in Cancer Institute in Charlotte, North Carolina. It's my pleasure to be the host for this tumor board advances and updates. What's new? What's next? the right therapy to the right patient. This is part of the IGCS 360 initiative, which provides education year round, even outside of our annual meetings. I want to, first of all, thank the folks that make this happen, Ashley Johnson and Lauren Cleary, who are technical people. And I want to introduce our faculty and I'm next slide, please. In just a minute, I want to remind everybody that this is being recorded. This will be available at the IGCS education portal by the end of the week. If you have questions, we will take questions at the end. If we have time, if you will submit these to the Q and a feature, the presenters will be the only ones who will be allowed to speak in this webinar. So the attendee microphones are muted. Next slide. I'd like to thank my faculty. We have two of the world leading experts in endometrial cancer and very pleased and honored to have them as part of our panelists to discuss these very challenging cases versus Remus Eskinder at the University of California, San Diego and Shannon Weston from the University of Texas, MD Anderson Cancer Center in Houston, Texas. Next slide. So our first case is a stage three C2 endometrial carcinoma that we will have polling questions. These are live so you can respond on screen so we can get an idea of how people will manage these cases. Next slide. So this is a 64 year old woman who is referred with a history of endometrial cancer. She has about a month of bleeding and the biopsy reveals a grade one endometrioid endometrial cancer. Her past medical history is significant for hypertension and diabetes. Her past surgical history is C-section and laparoscopic folliculostectomy. On exam, her uterus is minimally enlarged with an 18 millimeter endometrial stripe. Next. So first question. What is your routine evaluation for a grade one endometrial cancer prior to surgery? One, no further therapy. Two, do you get a CT scan, an MRI, a PET scan, or do you do more than one imaging modality? And we have the results. So interestingly, 22% of people get a CT scan, 44% of people get an MRI, and 18% get more than one imaging modality, only 16% known images, very interesting. Next slide. So what surgery do you plan? Do you plan a laparoscopic or minimally invasive hysterectomy, BSO? Do you do sentinel nodes? Do you do nodes based on intraoperative assessment? Do you do a full left head anectomy? Do you do any of those same choices open? Please vote. Can we have the results, please? Wow, so 54 percent do a sentinel node. It looks like almost everybody is converted to laparoscopic or minimally invasive robotic surgery. Next slide. This patient does undergo a laparoscopic hysterectomy BSO, the sentinel node dissection. All of her nodes, the nodes that were not removed appeared normal, but there was a prominent left obturator node that mapped. The IGC mapped to the right periortic area, and all other nodes were negative. Frozen section of the left obturator node showed this to be positive. So you have a positive pelvic node, grossly positive pelvic node. Next slide. So in the face of a grossly positive pelvic node, what would you do? Would you stop? Would you complete the lymphadenectomy? Would you do a pelvic and periortic lymphadenectomy, or would you do something else? Please vote. All right, can we have the results? Interesting. So 63 percent would do a full pelvic and periortic lymphadenectomy in that case. 11 percent, nothing more. Next slide, please. So the pathology shows a 3.8 centimeter well-differentiated endometrioid endometrial cancer. It is ERPR positive. There's deep myometrial invasion, 72 percent through an 18 millimeter wall. There's a MELF pattern with lymphascular space involvement. There's a macroscopically positive left obturator node and a microscopically positive right periortic node. The tumor is MMR proficient. A CT scan of the abdomen, chest, and pelvis is negative. A PET scan was ordered and is also negative. So we have a stage 3C2 grade one MMR proficient endometrioid endometrial cancer. Next slide. So how would you treat a 3C2 endometrioid endometrial carcinoma that is MMR proficient? Whole pelvic radiation with extended field up to the periortics with or without brachytherapy. Chemotherapy plus brachytherapy. Chemotherapy plus radiation in the pelvis. Chemotherapy plus radiation in the pelvis and periortic area. Immunotherapy, immunotherapy with radiation or some other treatment. Can we have the results? There's a lot of controversy for you there, Dr. Eskander. So it looks like the majority is chemotherapy plus pelvic and periodic radiation, but there are a lot of other people who do other things, including just chemotherapy. Next slide. Next slide. So she received six cycles of chemotherapy without radiation. There's no residual neuropathy from the chemotherapy. She does well for about three years, but returns with a cough. That CT scan at this point shows multiple non-calcified lesions in the lung, the largest of one centimeter. The biopsy confirms that this is endometrial carcinoma consistent with her original tumor. A CT scan shows no other evidence of disease. Next slide. So a 3C2 grade one endometrioid endometrial carcinoma, MMRP, ERPR positive, surgery followed by chemotherapy with small volume multifocal distant recurrence at three years after completion of primary therapy. Next slide. So what would your treatment option be at this point? Would you go with endocrine therapy? Would you go with a combination of an aromatase inhibitor and an mTOR inhibitor like everolimus and letrozole? Would you go back to chemotherapy with platinum and taxane? Would you use some other chemotherapy? Would you use pembrolizumab alone? Pembrolizumab plus chemotherapy or pembrolizumab plus lenvatinib or some other treatment? Can we have the results, please? All over the board. So, gonna be a very interesting discussion. All right, next slide, please. So this patient actually was started on a progestin and tamoxifen combination, similar to one of the GOG trials. And she actually had a complete response for approximately 12 months, but now has a recurrence in her lungs. So it's a pleural-based lung recurrence. So she's 12 months out from endocrine therapy. Next slide. At this point, what would you recommend? Switch to an aromatase inhibitor? Would you go back to chemotherapy? Would you give her either platinum taxane or other chemotherapy? Pembrolizumab, Pembrolizumab plus chemotherapy followed by Pembrolizumab, or Pembrolizumab and Lamvetinib, or some other combination? Can I have the results? So, lumbatinum and pembrolizumab, 44%. There's some argument to switch to a ruminantase inhibitor. Okay, next slide, please. So, our discussant, he is an expert in the field of uterine cancer and is the PI for GY018, which I don't know if you're gonna talk about, but we're very pleased to have Dr. Ramez Eskander from University of California, San Diego. Thank you, Dr. Nauman. Thank you all for joining us from all of the various places that I know you are joining us from. I will take a moment just to share screen and go to presenter view. Please let me know if there are any issues seeing the screen or hearing me, hopefully not. So, this is an interesting case because I think it's both clinically relevant, it's quite pragmatic, but it also reflects the controversies or what I like to think of as the opportunities for management of patients with endometrial cancer. We know quite a bit, we've learned quite a bit, but yet there's still much that we need to figure out. So, in the interest of time and in the context of what we're gonna cover, we'll move forward. I do wanna highlight that although endometrial cancer historically was thought of as a disease that is managed quite easily with surgical intervention, particularly for patients with early stage disease, we do know that the proportion of patients that are affected by disease recurrence and the proportion of patients that are affected by more aggressive histologies, Dr. Weston's gonna talk about clear cell, with our second case continues to rise. And there is an oncologic and survival burden for those patients. And it would be remiss of me not to take a moment just to highlight, this was an article in the New York Times from June of 2022 that highlighted the fact that uterine cancer was on the rise, but also talks about the disproportionate impact on racial and ethnic minorities. And unfortunately, due to time, we can't invest much in that conversation today, but I do know that we can talk about that for quite a bit because of the relevance as we try to make an impact on improving outcomes for these patients. I wanted to start by talking about lymphadenectomy and endometrial cancer. In the beginning of the case that was presented, we had a question, a poll question about what would we do in the face of a grossly positive obturator node? And I just highlight the two trials that we most commonly reference when we talk about the utility of lymphadenectomy and endometrial cancer, understanding there are clear limitations to these trials, just as there are limitations to many of our prospective clinical trials, but the existing data suggests that lymphadenectomy itself is not a therapeutic intervention, but it does prognosticate patients and subsequently inform adjuvant therapy. And those two trials were the ASTEC trial, as well as the PNICHI trial, one published in 2009, another in 2008. As you can see, these are large clinical trials. Nearly 2000 patients in total were enrolled onto these clinical trials. And you can see from the Kaplan-Meier curves for both of these clinical trials, both ASTEC on the right and the PNICHI trial on the left, that there was no survival difference in the patients that had a lymphadenectomy versus in those patient cohorts that did not have a lymphadenectomy. This is certainly not an answered question as reflected in the results of the poll where we had quite a divergent distribution. Although I think the majority, if I remember correctly, Dr. Nauman, would have done a comprehensive pelvic and periodic lymphadenectomy in the context of a grossly positive node, which is quite interesting. And I know we will be able to discuss that quite further. I also want to take a moment to talk about the initial adjuvant treatment for these patients. Historically, patients who had positive nodes were managed with pelvic radiation therapy. And we subsequently had trials that looked to augment the response rate, understanding that the pelvic or the extra pelvic recurrences were quite high in these patients. And the thought was if we incorporated a combination of systemic chemotherapy and radiation or substituted radiation with chemotherapy alone, we might improve oncologic outcomes. And those were two studies, GEOG258 and PORTEC3. GEOG258 led by Dr. Mattai and colleagues was a randomized phase three trial that looked at the utility of chemotherapy and radiation in patients with stage three and stage four endometrial cancer. Over 800 patients were enrolled. Again, a large clinical trial, 736 patients were eligible. And the two arms of the study were chemo radiation followed by four cycles of carboplatin and paclitaxel that was defined as the experimental arm or chemotherapy alone. So in essence, by using radiation therapy and chemo, can we improve local control with the radiation while in parallel reducing the risk of extra pelvic recurrences outside of the radiation field or is systemic chemotherapy alone sufficient? The primary endpoint for this trial was relapse-free survival. Secondary endpoints were overall survival, adverse events and quality of life. And you can see here, and this is a very important point for me personally, these patients had nodal dissections on GEOG258 and look at the proportion that were 3C1 or 3C2, nearly 75% of patients enrolled on this trial and treated balanced amongst arms or node positive. You can see here that nearly 20% were grade one, similar to the patient that we used in our patient example. And almost all of these patients had no gross residual disease. So it's a patient population that mirrors the clinical scenario that we discussed at the start of this presentation. And what we saw from the data that was presented, that there did not appear to be an improvement with dual modality therapy. So using chemo and radiation did not appear to improve oncologic outcomes in comparison to the use of systemic chemotherapy alone. That being said, if you looked at nodal recurrences, pelvic or periodic node recurrences, the frequency was slightly higher in the chemotherapy alone arm versus chemo radiation. And that did not translate into a proportion alive improvement, but it did impact the local recurrence in these patient cohorts. Sorry, one second. There we go. Now PORTEC3, I consider these sister studies, although they didn't overlap completely, looked at concurrent chemo radiation therapy followed by adjuvant chemotherapy compared to radiation alone. So you can see that that GOG258 was missing a radiation alone arm. PORTEC3 was missing the arm that incorporated essentially chemotherapy alone. So you have to merge these trials together in order to try to wrap our minds around what the appropriate intervention may be. Here we enrolled patients that had stage 1A with myometrial invasion, grade three, if they had documented LVSI, 1B grade three, stage two, and then you could see the stage threes as well as serous or clear cell patients. So slightly different inclusion criteria with respect to the patients that were enrolled on trial. Again, approximately 20% of patients had grade one disease. And here you can see a smaller proportion of stage three. So again, 75% of GOG258 was stage threes, approximately 40 to 50% of the PORTEC3 population had stage three disease. And if you look at the ITT population, you saw really no significant differences. If you looked at the stage three, that's where you saw a slight discrepancy between chemoradiation therapy versus radiotherapy alone, favoring chemoradiation therapy in the node positive stage three patients versus chemotherapy alone. This was a post hoc now survival analysis. It's important to note that post hoc analysis are really hypothesis generating. They are non-analytical because they're not necessarily controlled for all of the variables that may impact outcome. But if you look at overall survival in the stage three, again, the five-year overall survival appears to favor the combination chemoradiotherapy arm alone, as does the failure-free survival. But again, and quite importantly, there is no chemotherapy alone arm in PORTEC3, which was present in GOG258. So I will make the proposition that we still don't definitively have the answer in this statement. Do we need to add radiotherapy to improve oncologic outcomes in these patients or is systemic chemotherapy sufficient? That's gonna depend on how you interpret the amalgamation or the hybrid of the data that we just shared and presented together right now. I will also now pivot for a little bit to talk about how we think about endometrial cancer. Historically, we used to think about endometrial cancer using only clinical and pathologic variables, categorizing patients into risk stratifications that then guided and informed treatment options. We still use this to some degree, although I will argue now we've moved to incorporating molecular classification of disease, justifiably so. This slide summarizes the evolution of our systemic therapies for the management of recurrent and metastatic endometrial cancer. For the sake of time, I will just highlight that on the very right column, you see GOG209, which ushered in the backbone of carboplatin and paclitaxel as the standard of care therapeutic option in patients with metastatic or recurrent disease. This was a schema of GOG209. It was a comparison of carboplatin and paclitaxel versus the triplet regimen of cisplatin doxorubicin and paclitaxel. These patients had no prior systemic chemotherapy, importantly, and had stage three or stage four or recurrent endometrial carcinoma and did not require measurable disease. And you can clearly see from the publication in JCO in 2020, led by David Miller and colleagues, that there was no difference in survival outcome between the two arms. And there was reduced adverse events in the carboplatin and paclitaxel arm, better tolerated as we anticipated. And thus, carboplatin and paclitaxel emerged. I will call your attention to the right side of the survival curve and just say that nearly 30% of these patients didn't recur. And that's not what we see in clinical practice when we talk about metastatic recurrent endometrial cancer. These patients are usually disease recurrence, refractory therapy. So I will suggest to us collectively, is there a cohort of metastatic patient that does inherently well? And can we figure those patients out? Are these the pole E? We weren't talking about pole E in this study. We weren't talking about DMMR assessments in the way that we do now. We weren't talking about molecular predictors of a potentially better oncologic response. Maybe these are low grade, one node positive, completely resected patients. So we have to figure this out as we move forward. The NCCN guidelines that were updated in 2022 highlight the systemic therapy, again, carboplatin and paclitaxel as the backbone, but add anti HER2 treatment for HER2 positive, uterine serous carcinomas, although I will tell you that there's also HER2 positivity in clear cell and carcinosarcomas that may be about 15 to 20%. I think Shannon may touch on that. We will also talk about the bottom of this table, which for me is the most exciting. This idea of biomarker directed therapy in endometrial cancer. This is a language that we need to incorporate into clinical practice. These are biomarkers that we need to better understand for our patients because they will undoubtedly influence how we think about systemic therapy and future treatment. And this is related to immunotherapy and alternate targeted agents, the rare N-tric fusions. If you have the ability to test via NGS, you may identify this and it can impact your response, but hormonal therapy should not be forgotten. I know we talked about that collectively as part of the patient case as a treatment opportunity, but I will just mention that it is listed as a systemic therapeutic option in endometrial carcinoma that's recurrent and cannot be overlooked because there may be therapeutic efficacy. I will also mention antiangiogenic therapy. Just briefly, GOG86P looked at chemotherapy in combination with alternate treatment strategies. These included Bevacizumab, Temsorolimus, and Ixobepilone. If we look at the combination arm of chemotherapy with Bev and maintenance Bev, and we did a historical comparison to a matched cohort from GOG209, we see that those patients that were on chemotherapy with Bev and maintenance Bev appeared to do better, and that is suggestive of a potential response. Something very exciting was translational work that emerged out of GOG86P led by Kim Leslie and her colleagues that showed that P53 mutated malignancies appeared to have more favorable responses to antiangiogenic therapy with chemotherapy. So what we see here essentially is an evolution of how we think about biomarkers in the treatment of endometrial cancer. And GY012 is asking similarly the TKI siderinib alone, olaparib alone, or the combination. I will just say that the arm that received olaparib alone had a median, or siderinib alone, excuse me, had a median PFS of 3.8 months. The olaparib arm underperformed from what they anticipated when they designed this trial. With a median PFS of only two months. And that really calls us, makes us think critically about the molecular signatures of homologous recombination deficiency in endometrial cancer. Have we figured that out? We were thinking that PARP inhibitors may capitalize on a cohort that is HRD. We didn't select for it in this trial. If we're starting to use agents like this in endometrial cancer, do we have to be more thoughtful about how we select these patients and what the implications are? I do want to also briefly discuss the chemotherapy in combination with tristuzumab. This was led by Dr. Nichols-Fader and Dr. Santin. And if you look here at the PFS curve for this trial, this was primary stage three or four or recurrent disease. And HER2 was defined by positive IHC 3+, or if it was 2+, positive FISH. Less than or equal to three prior lines of therapy. And if you look here, it was 12.6 months versus eight months favoring the anti-HER2 combinations. And that benefit appeared to derive most importantly in patients who are chemotherapy naive, advanced stage disease. And when you look at the overall survival data that was published in 2020 from the same trial, the benefit was particularly striking in the stage three to four patients. The overall survival of 25 months in the control arm and not reaching the experimental arm hazard ratio of 0.49. These findings have prompted us to better understand the relevance of anti-HER2 therapies and how we are going to assess that in our patients. I mentioned it's nearly 30% of uterine serous cancers. It's about 15 to 20% of carcinosarcomas and clear cells. And many of you guys may have heard about the exciting data in ASCO of the anti-HER2 antibody drug conjugate and the DESTINY breast trial that was positive even in HER2 low. So if we now incorporate anti-HER2 in our patient populations and we add the HER2 low, which is probably another 20%, we may have 40 to 50% of our serous patients that may derive benefit from an anti-HER2 treatment, but we have yet to define this. GY026, this was provided to me with permission from Dr. Erickson, is going to be looking at incorporation of anti-HER2 treatment in patients with early and advanced stage disease. And it's a three-arm trial that's going to be hopefully active and accruing patients soon. I will take a moment here to talk about molecular granularity. We are now dividing our endometrial cancers appropriately so into molecular subgroups. We have POLE ultra-mutated, the mismatch repair deficient or MSI high, the copy number low P53 wild type, copy number high P53 mutated. And this is particularly important because response to interventions may be different. And here's an example from the PORTEC3 subset analysis looking at molecular subtypes. And you could see that the P53 abnormal endometrial cancers appeared to benefit substantially more so with chemotherapy incorporated in combination with radiation. And that wasn't seen with the P53 wild type and SMP molecular subgroups. And if you look at the mismatch repair deficient cohorts, addition of chemotherapy did not appear to benefit these patients over radiation alone. And that has prompted future studies such as NRG GY020 looking at pelvic radiotherapy with immune checkpoint inhibition in mismatch repair deficient high intermediate risk endometrial cancer patients. So blending the molecular signature with the clinical pathologic variables that we used previously. I don't want to forget about hormonal therapy. It is important. It is relevant. I will mention that GOG153 and GOG119 which were our two most positive endometrial cancer trials allowed for no prior hormonal therapy and no prior chemotherapy. But I will argue that systemic hormonal therapies and combinations can shrink tumors. This was a combination of letrozole and everolimus, a study led by Brian Slomovitz and his colleagues that showed a 25% complete response rate, a 5% partial response rate. Almost all of these patients came off for progressive disease. CTNNB1 mutations may have been a biomarker predictive of response, but this is only hypothesis generating. I know some people use this to inform these decisions, but I will just guard and say take that with caution. Small cohorts and this is more hypothesis generating than should be practiced driving. And if we look at 3007, I just want to skip to this slide for the sake of time. If you look at the response rate in the chemo naive, no prior therapy, it was 53% with letrozole and everolimus combination therapy with a PFS of 21.6 months, which compared favorably to the GOG209 historical cohorts. Again, cross trial comparisons are limited. I know we do them, but they have many limitations because these patient cohorts are not identical, but it does speak to the potential utility of antihormonal therapy. We did see Dr. Mirza presented the letrozole with placebo versus letrozole-palbocyclib clinical trial, the NGOTEN3, the paleo trial. And what we saw here was an improvement in the progression-free survival looking at a combination of CDK4-6 with letrozole over letrozole alone. And you looked at disease control rate, it nearly doubled again. Was letrozole the right comparator? That can be argued because we know the response rate to letrozole in these patients is probably south of 10%. So nonetheless, it did stimulate our desire to better understand CDK4-6 and hormonal combinations because we feel there may be a path there based on our breast cancer colleagues. Clearly, the adverse events seen are in line with CDK4-6 TRUDIs, more hematologic AEs, which would be anticipated, but a tolerable regimen. Panos Constantinopoulos presented an SGO, the combination of letrozole and abemacyclib. This was a two-stage trial design. I will just say that in endometrioid patients, which was almost all that were enrolled on this study, we saw a 30% partial response rate, one unconfirmed. All of these were in endometrioid tumors, 43% with stable disease. Again, suggesting that there is efficacy with hormonal therapy and anti-CDK4-6 treatments and prompting us hopefully to continue investigating this in an efficient and effective manner so that we can answer this question appropriately for our patients and guide treatment. Here you see molecular signature matters. Even if you're endometrioid histology, if you're p53 mutated, almost everyone came off at first assessment. So the p53 mutated endometrioid adenocarcinomas may be the wrong patients to use such a strategy. And so we have to move beyond histology and we have to incorporate molecular signature. Many of you are aware about the efficacy of immune checkpoint inhibition in endometrial carcinoma. It was stimulated by the findings of Keynote 158 with a 57% ORR in the mismatch repair deficient endometrioid cancer patients. In the biomarker negative cohorts, as summarized in this table, the efficacy was minimal. You're ranging from 4% to 10%. So we still need to do better there and I will review how we did better. But in the DMMR cohorts, a substantial benefit. And this is where really a dramatic change happened for us. In the mismatch repair proficient, non-MSI high patients, IO alone, checkpoint alone was ineffective. So Keynote 775 was a confirmatory trial for the prior accelerated approval indication looking at the TKI Linvatinib orally with Pembrolizumab. These were advanced recurrent or metastatic endometrial cancer patients randomized to the combination versus physician's choice chemo of Doxorubicin or Paclitaxel. And what we see was a statistically significant and meaningful improvement in progression free survival and overall survival in both the PMMR cohorts and in all comers. And I think this was reflected in the question and answer queue in the recurrent setting. I think nearly 60% of patients selected the combination of Linvatinib and Pembrolizumab at disease progression. This is the overall survival. You can see an improvement in the all comers from 11 to 18 months with a median follow-up of 11 months and from 12 to 17.4 months in the PMMR cohort. Again, highly significant and relevant. I did want to take a moment to talk about an alternate strategy, nuclear export inhibitor Selenexor. And I want to talk about the Siendo trial. This was presented at SGO. Prior to that, I think it was a virtual ESMO by Dr. Vergoat. And if we look at this trial, it looked at Selenexor versus placebo as a maintenance strategy in patients with advanced stage or recurrent endometrial cancer after taxing and carboplatin combination. And I will just say here, endometrial histology in nearly 54%. And what they saw was that if they corrected for an inaccurate stratification, which is an important caveat to consider, but if you correct for that, and it was seven patients, you saw that there was a statistically significant difference in the median PFS, 5.7 months versus 3.8 months in Selenexor versus placebo. But probably what was most provocative was the biomarker cohort in the P53 wild type, where there appeared to be the greatest benefit, 13.7 versus 3.7 months again, calling into question what we are going to do in the P53 wild type endometrioid. And this is informing a future trial that's really going to focus on this patient population. So what's the future going to bring? And I know I have to move quickly here, but basically the relevance of immune checkpoint inhibition may move earlier on in therapy. And how are we going to then integrate anti-hormonal treatment? How are we going to rationalize IO versus hormonal therapy? How are we going to rationalize sequencing? Is it going to be based on histology or biomarker? These are all questions that we have yet to answer. B21 is looking at chemotherapy, radiation at physician discretion with or without pembrolizumab in a completely resected high-risk patient population. This is the schema, and I'd be glad to share this with anybody. This is a slew of studies that's now looking at systemic therapy with or without checkpoint in patients who have advanced stage or recurrent endometrial carcinoma with measurable disease or stage IVB non-measurable. These have, some have completed accrual and we're awaiting results, but accrual thankfully has gone quite well. LEAP001 is looking to bring Linvatinib and Pembro to the frontline rather than the keynote 775 recurrent patient population. And the ATEN trial was a tezolizumab with chemo versus placebo and recurrent endometrial cancer being performed in Europe. And I will just highlight molecularly driven trial design. This is the taper or rainbow trial, the transportex study looking at patients, then taking their molecular stratification and then randomizing to an intervention based on that molecular stratification. And I am proud to say that I think this is the future. As we are designing our current endometrial cancer trials, we are taking into consideration molecular signature to inform treatment design. So it's a dynamic and promising time in endometrial cancer therapeutics. There are multiple trials looking at various single agents combinations. Biomarkers right now are really mismatch repair deficiency and MSI high, HER2 new potentially emerging as an opportunity, P53 wild type with future studies looking at nuclear export inhibitors. I can't be more thrilled to say that we are evolving in this way in the endometrial cancer space. I'm excited for what the future will bring. And I really thank you guys for inviting me to be here and for your time. Thank you so much. That was an incredible overview. It is just amazing what's happening in endometrial cancer. And I think we'll take some questions for you at the end. I'm sure there's going to be some controversies there, but thank you for that overview. And again, I think it's obvious why we're lucky to have you as a panelist here. So our, our second case is a case of clear cell endometrial cancer, relatively uncommon type of cancer. Next slide, please. So this is a 69 year old woman who presents in the usual way with some postmenopausal spotting. There's a four centimeter intrauterine mass on ultrasound. And the biopsy does reveal a clear cell endometrial adenocarcinoma minimal past medical history with a little bit of hypertension. It's well-controlled past surgical history, none and an enlarged uterus. Next slide. So now again, this is a different cell type. The prior cell type was endometrioid grade one and same imaging question though. What is your imaging strategy on this patient? Please look. All right, can we have the results? Yeah, so I think that the imaging is a little bit more frequent here. So next slide, please. Again, and somebody with a high risk histology, how would you approach this surgery? Same options as we had with the first case, minimally invasive with sentinel modes, or we already know it's a clear cell, but intraoperative incision or a full lymphadenectomy or open hysterectomy in this patient because she has clear cell. Please vote. All right, can we have the results? I think people are still doing, for the most part, sentinel nodes. I think they're a little bit more likely to do abdominal hysterectomy, if I recall. Next slide, please. So this lady does undergo a minimally invasive procedure in sentinel nodes. At the time of surgery, the nodes map on both sides. Sentinel mode dissection is performed. The nodes otherwise appear normal. Next slide. Pathologically, she's got about a four centimeter tumor. It is ERPR positive. There is just under half myometrial invasion. The sentinel modes are negative. And this is, the MMR proteins are proficient. A CT scan of the chest, abdomen, and pelvis shows no evidence of additional disease. So again, a stage 1A clear cell carcinoma. So if you had this patient in front of you, what would your recommendation for her be? No further treatment, vaginal brachytherapy, pelvic radiotherapy, chemotherapy, chemotherapy plus brachytherapy, combination dual therapy, or immunotherapy, or some other treatments. Please vote. All right, can we have the results? Again, I think it speaks to the controversy of these type of cases here, because there's a wide variety of what we would do. Looks like the most common choices are chemotherapy plus brachytherapy or chemotherapy alone. But there are those that we treat with the pelvic radiation or chemo and pelvic radiation. All right, next slide. So this lady was treated with chemotherapy, standard patexol and carboplatinum. At her six month visit, she is noted to have a possible recurrence of the vaginal cuff and a prominent left groin node that is positive on PET scan with the SUV of 3.5. The biopsy confirms recurrent clear cell carcinoma in the groin lymph node. She also has a pelvic node. So what would your treatment be at this point about six months out from her initial surgery? Would you just use radiation? Would you use radiation plus sensitizing chemotherapy? Radiation followed by chemotherapy. Linvatinib and pembrolizumab. Nivolumab and ipilimumab. Radiation followed by linvatinib and pembrolizumab. Radiation followed by nivolumab and ipilimumab. Please vote. All right, results please. So, Wow, radiation. It's pretty much across the board here so excellent. So this lady actually was treated with radiation alone at her four month follow up visit she had no evidence of disease on examination but the PET scan is repeated. The initial nodes have resolved. But now there's an isolated node outside of the pelvis in the ready outside of the radiated field in the periodic area is noted on the PET scan below. Next slide. So this is a single focus based on PET scan. Now, if you had this patient in front of you, she's got a node right under the renal vessels. What would you do? Would you try to resect this either laparoscopically or open? Would you simply radiate it? Would you start her back on platinum based chemotherapy? Would you give non platinum based chemotherapy? Would you give single agent PD one with pembrolizumab or drostolomab? Would you give pembrolizumab and lanvatinib? Would you give nivolumab and ipilimumab? Please vote. Okay, can we see the results? So it looks like about 50% of people would resect this node either laparoscopically or open. Very interesting. Okay, next slide. So this, this lady actually does have a surgical resection. This was done laparoscopically. There was no extra capsular extension on the nodes, it was isolated the single node, there were nodes above it and below it that were negative. So I guess the question at this point, what would you do? Would you simply watch this patient? Would you give her radiation to the tumor bed? Would you give her radiation followed by chemotherapy, radiation followed by immunotherapy, chemotherapy alone or immunotherapy alone? Can we see the results? Wow, a third of people would not treat this patient further. Not a lot of interest in radiation alone. Pretty much all over the board. We picked some controversial cases here. Next slide. She actually declines therapy at this point. CT scan three months post resection shows a recurrence in the lung. She's nine months out from her primary therapy. Would you go back to platinum-based chemotherapy? Would you use non-platinum-based chemotherapy? Would you use pembrolizumab or distalumab, a PD-1 inhibitor? Pembrolizumab and lymphadnib, a TKI inhibitor? Nivolumab and ipilimumab, a combination with the CTLA-4 or some other treatment? Please vote. All right, can we see the results? So it looks like Pembrolizumab and Lumbatinib is the clear winner in this case. All right, next slide. So again, we're very fortunate to have Shannon Weston from the MD Anderson Cancer Center in Houston, Texas to discuss this. Of course, Shannon is a well-known expert in endometrial cancer, and I think this is a very controversial case, so I'm very interested to see what you have to say, Shannon. Yeah, thanks so much for that. Let me just get my slides pulled up here. Okay, so yes, I have the dubious honor of talking about this clear cell endometrial cancer case, and I was really intrigued by some of your answers throughout this, because I agree, so many decisions in this case, you know, talking about diagnostics, lymph node assessment, what do we do in the adjuvant setting, and then what do we do with multiple recurrences in systemic therapy? So I'm gonna try to touch on each of these controversies, find the data where we can, understanding that clear cell is a rare tumor, and so the data sometimes are quite limited. But first let's level set, you know, really the numbers for clear cell endometrial cancer all over the map, depending on the study that you look at or the area that you reference, you can see that it's about anywhere from three to 10% of endometrial cancers as a whole, does have increasing incidence with age, about 50% or more will present at advanced stage with worse outcomes. And looking pathologically similarly to what we've seen with uterine serous tumors, really, if you have a mixed tumor and there's more than 10% clear cell, you see the same types of outcomes as you would see for a pure clear cell cancer. So I think those are just important, that's important information for us to understand. And of course, what we've learned, and this was a really nice study by Dr. McMeekin back in 2007, looking at response and benefit from chemotherapy based on histology, you know, just first let's just look at how many clear cell cases were included, there were three. So 44 patients and only three lived, and that really drove, if you look at this red curve, it seemed that clear cell had one of the worst impacts on overall survival, even as compared to uterine serous. And similarly, when they looked at just pure response to therapy outside of overall survival or progression pre-survival, it did have lower rates of objective response as compared to uterine serous and endometriotype tumors. Now, Dr. Eskander showed you the wonderful breakdown of molecular features and molecular classifications in endometrial cancer. Unfortunately, this elegant data by the TCGA did not include patients with clear cell endometrial cancer. So what we know molecularly is really based on case reports and single institution studies and that type of thing. Now, this is one of the largest of these types of studies where they did deep DNA sequencing on clear cell endometrial cancer. And you can see some of the highlights of the molecular abnormalities that they found, including p53, aberrations in the PI3 kinase pathway like PIK3CA or PIK3R1, ARID1A, which I'll talk about. Dr. Eskander's led some great work around that. PPP2R1A, which I remember when this work came out, I kind of threw my hands up and saying, what is this? But actually there are some interesting data in ovarian cancer that indicate this might be a relevant mutation. And then SCOP and TAF1. In addition, they looked at microsatellite instability testing and found about 11% had evidence of MSI high. Now they did attempt to utilize the TCGA classifications to see if that might be relevant in clear cell. And you can see in the graph on the bottom that it did seem to be fairly consistent as far as the survival in those patients with p53 abnormal being the worst, followed by the no specific molecular profile and then POLE and MMRD doing the best. Now, just to remind ourselves about what was going on with our patient, she had an ERPR positive tumor. That's really uncommon in clear cell. It's not something we usually see. It's probably not gonna be something that's particularly actionable in this patient. And you heard from Dr. Eskander a masterclass on hormonal therapy. So we won't focus on that for this patient. However, our patient does have evidence of mismatch repair proficiency. So this is intriguing and could potentially drive our treatment strategies. And for a lot of you, it did. So first let's talk a little bit about some of the decisions that we had to make in the upfront. So first question that came to you all was what type of imaging would you could use? And as you saw, you guys are all over the map. We don't have a lot of data for clear cells specifically. What we can really extrapolate is the use of imaging in high-risk endometrial cancer as a whole. CT likely ideal, most ideal for peritoneal disease, looking for abnormal anatomy that might drive your decision-making around surgery, but really has a lower sensitivity and specificity for nodal mets, although it is more cost-efficient than say PET CT. And you can see here the numbers that, this was an aggregate study of looking at PET CT and the sensitivity and specificity to identify nodal mets. The sensitivity is about 53%, it's fine. Specificity is very high at 99%, but really is truly dependent on the size of your metastatic deposit. Now at MD Anderson, we had a prospective study in high-risk endometrial cancer. I'm gonna show you some more data on that in a moment. But one of the sub objectives was to look at the role of PET CT in identifying lymph node metastasis. So this was a group that had either grade three endometrioid, serous, clear cell, or carcino-sarcoma. And 19% of the patients were clear cell. 123 patients were included. All of them had comprehensive surgical staging, including sentinel node mapping, as well as full pelvic and periodic lymph node mapping or lymph node dissection. And 108 of them had a preoperative PET CT. You can see that it identified 19% of patients that had extra uterine disease. 17% of patients had positive lymph nodes, and 7% had peritoneal disease, leading to a pretty consistent sensitivity of 45%, which is what we've seen with CT actually. Specificity was 91%, positive predictive value only 61, and negative predictive value 84% for the prediction of positive lymph nodes. From a standpoint of peritoneal disease, similar, a little bit better positive predictive value and a little bit better negative predictive value. But the bottom line is, CT's probably reasonable for these patients. PET's probably unnecessary. I think a lot of us get it, but unclear if it's really something that you need to do. Okay, so that was our first decision. Now let's talk a little bit about the surgery. I think most of you guys are converts and are doing most of these cases laparoscopically. They certainly can be done safely. The question is, is do we have enough data to utilize sentinel lymph node evaluation in patients with clear cell or high-risk disease? So this was a FIRES trial published by Amorosi back in 2017. This was a large multicenter study. They had 385 patients, six had clear cells. So not a huge number with this high-risk histology. They did require that patients have a pelvic lymphadenectomy, but about a little over half also had periodic lymph nodes assessed. 86% were successful. The false negative rate, which is the part that we are most concerned with, was only 2.8%. And so there's clearly a high diagnostic accuracy of detecting positive nodes. The problem for this trial is it doesn't have a ton of high-risk patients. At our own institution, we did a single institution study looking at only high-risk endometrial cancer and the role of sentinel lymph nodes. There was 101 patients in this study. All of them were high-risk and 16 or 16% had clear cell. And this was the study that we talked about with the PET, but this was the primary objective was to look at the false negative rate in utilizing sentinel nodes in a purely high-risk population. These patients all had to have pelvic as well as periodic lymph node dissection. And again, the false negative rate was low, about 4.3%. So sentinel lymph node mapping is accurate in high-risk endometrial cancer. And for our purposes, it seems reasonable for patients with clear cell endometrial cancer based on our existing data. So now let's talk about clear cell adjuvant therapy, right? So do we give this patient with an early stage adjuvant therapy, or even if she was late stage? Again, data are very limited. I'm gonna talk a lot about the trials that you just heard Dr. Eskander speak about, but I'm gonna talk about them in the context of how many patients had a clear cell endometrial cancer and the bottom line is we have very minimal data around clear cell, particularly. This was a study looking at the National Cancer Database and they had included 4,298 patients with clear cell. So pretty nice, large study and found non-unexpectedly that survival was worse with increasing stage. However, when they teased out the different types of adjuvant therapy, and you can see in the table on the right, hysterectomy with vaginal brachy, hysterectomy with chemo, pelvic, chemo and pelvic radiotherapy, chemo and cuff, which a lot of you liked for the treatment of your patient, they didn't see any difference in survival based on the type of adjuvant therapy. You know, there's many smaller studies, 20 patients here, 40 patients here that have had mixed results as well, where we see some showing benefit and some not, but I feel like a lot of us tend to extrapolate from some of the larger studies that did include early stage clear cell tumors in order to determine what type of adjuvant therapy we wanna use. So this was the GOG-258, Dr. Eskander has already demonstrated, but just a few things to highlight. This, in addition to being primarily a study of advanced stage, stage three or four A endometrial cancer also allowed stage one or two clear cell endometrial cancer. And again, as he mentioned, the patients were randomized to the control arm, which was chemotherapy, Paclitaxel and carboplatin as compared to the interventional arm, which was the chemo radiation in addition to followed by the chemotherapy. Now, 3% of patients on this study had clear cells, so pretty low numbers. And of course, these were the data that he demonstrated that didn't demonstrate any benefit to the combination of chemo radiotherapy followed by chemo as opposed to chemotherapy alone. Forest plots, always interesting non-analytic endpoints, but especially with rare tumors, we always try to see if we can tease out something. You can see that they included clear cell as part of other. And there is a little bit of a leaning towards chemo radiotherapy, perhaps being better. But of course, this is just hypothesis generating and not something we can definitively decide. PORTEC3, which again was the study looking at radiotherapy as a control arm and then the chemo radiotherapy followed by chemo as the intervention arm here. Again, as we saw with GOG258, in addition to stage twos and threes, they also allowed serous and clear cell cancers, although the clear cell could be included up to the higher stage patients. They actually had a high proportion, 9%. It's a pretty reasonable proportion of patients that had clear cell in this study. And you can see, again, they did demonstrate unproved failure-free survival as well as overall survival for chemo radiation therapy over radiation alone. Missing arm here would be so lovely if we had a chemo arm in this group so we could really see if it's just the chemo that's driving this or if it is in fact the combination. And I know Dr. Eskander did a great job kind of really highlighting some of the controversy there. So I'm gonna bring it back to clear cell. And you can see here that this is looking at recurrence as well as survival in which one was favored versus chemo radiotherapy or radiotherapy. Here's clear cell lumped in with serous and other. It's kind of right in the middle. Same thing in regards to survival, really right there in the middle. So I think that lumping is hurting us in our inability to kind of tease out those patients and really flesh out what might be different about them. One thing that they did do, which I found really intriguing was looking at the type of recurrence and the location of recurrence. And you can see clear cell is in the blue and does have given the number of patients, the small number of patients does seem to have really a high proportion of patients with distant recurrence, just any recurrence overall, as well as smaller levels of pelvic and vaginal. So just some interesting, intriguing kind of guidance. And then finally, I'd be remiss if I didn't talk about GOG249, because again, our patient was initially diagnosed with a really early stage clear cell cancer. And you can see that this 249 did include that patient population. Patients were randomized to either pelvic radiotherapy as a scanner arm versus cuff and chemo, which I think a lot of us seemed to favor in the question where you were asked about your adjuvant therapy. 28 of these patients or 5% did have a clear cell cancer. There wasn't, they didn't find any difference between the combination of cuff and chemo or pelvic radiotherapy in GOG249 as a whole. But look at this kind of intriguing little forest plot down here. You can see that the population with stage one, two, serious and clear cell, it starts to lean a little bit more towards the cuff and chemo arm. So again, kind of troubled by our numbers, but certainly some intriguing data there. So bottom line, there's really no clear data. It's a joke, clear cell. Most will give chemo. I think you guys proved that. We also, most recommendations from experts are to give chemo. And I think we do that because we know they have such bad outcomes, even though our data are really all over the place. You can consider radiotherapy. And I have a colleague who always jokes, vaginal cuff is free because low risk overall. So it is something to potentially do to reduce those pelvic and vaginal recurrences. Okay, so then for the last few minutes, I'm going to talk a little bit about our lady's recurrence. So when we're talking about an isolated pelvic recurrence, now this patient had vaginal as well as some nodal disease, you can see that there's a couple of different options that would be considered, either radiation versus surgical exploration. You all pretty unanimously went ahead with radiotherapy, and that is a reasonable option. We do know with isolated vaginal recurrences, we have a pretty high salvage rate, 87, 90%. When it involves lymph nodes or just pelvic in general, we do see lower rates of survival, but this is something you can still definitively treat, so that was a very appropriate option. She then represented with a single site recurrence, and if we're looking technically at the NC-10 guidelines, when they look at that involvement of periordic or extravaginal disease, radiation is what's actually recommended here, and that's kind of interesting. I agreed with you all. Surgery does seem reasonable, and there actually are some guidelines that have been provided when you're trying to tease out when surgery might be a good option for single site recurrence for endometrial cancer. The options are good performance status, no other distant metastases, negative margins achievable. Our patient met all of those, and a lot of you chose surgery, as did our treating physician, and certainly it is a reasonable option when you're trying to avoid other more radiation and potential side effects. When we're looking at secondary cytoreductive surgery, it's always nice to see data just in general. The role of secondary cytoreduction, this is kind of the largest meta analysis. They looked at 14 retrospective cohort studies. It includes both advanced endometrial cancer as well as recurrent, so a little bit of a mixed bag, but they had 672 patients. Of those, 28 had clear cell, so not a big proportion, but still they were included, and you can see that median overall survival was positively associated with the increasing proportion of patients undergoing a complete surgical cytoreduction, and specifically each 10% increase seemed to improve survival by about nine months, so that is nothing to ignore. In addition, it did seem that receiving post-operative radiation therapy after cytoreductive surgery was also helpful in improving survival, so just something to consider when you're doing a cytoreduction in this setting of potentially utilizing radiation post-op. Now, you've seen the chemotherapy data that Dr. S. Kander promoted around specifically GOG209, which established paclitaxel and carboplatin as our standard of care. As I've been wanting to do this entire lecture, 3.5% had clear cells, so small numbers, and when we look at our forest plot, it really is smack dab in the middle between TAP and paclitaxel carboplatin, so no kind of teasing out of a signal there as far as which might be more beneficial, but we definitely use this. We've been using it for years now, and you give patients an opportunity to get that chemotherapy, but as you noticed, we did have some options around checkpoint inhibition, specifically immunotherapy. Now, where does this come from? Of course, we've had a really kind of interesting signal in clear cell ovarian cancer, and we always extrapolate from ovarian cancer and endometrial cancer, but looking at single agent response rates in platinum-resistant ovarian cancer, they're very low. However, if you start to look at some of those responders, you start to see a high proportion of patients with clear cell having benefit, so if you tease that out, this is from the study of pembrolizumab as a single agent that Dr. Matulonis reported. Again, looking at clear cell carcinoma, that seemed to be the population that was driving response to therapy to single agent checkpoint inhibition, and of course, we know that in endometrial cancer, patients with MSI-high or mismatch repair deficient disease do better with a single agent immune oncology checkpoint inhibitor. They did not tease out. These are all patients with MSI-high. There's no teasing out in any of these studies, believe me, I dug, of clear cells, so hard to know kind of where they are, but we do know about 11% will have MSI-high disease. Conversely, if we're looking at lack of response in those patients with mismatch repair proficient or MSI stable disease, none of them report the histology, except for the AveliaMab study did note that the responder had an endometriotype tumor, so really no signal yet in endometrial cancer as a single agent or I.O. as a single agent. We do, of course, have some really great data, both from the initial phase two study, as well as the randomized study of Keynote 775 of LENPEM, which you guys have seen and you know very well. Again, I'm going to bring it to clear cell 0.6% clear cell in this clinical trial. These outcomes were very consistent across mismatch repair proficient and deficient disease, but here, what can we look at with clear cell? These data were presented by Dr. Macra and start to tease out. Actually, the benefit is consistent across histology, so very reassuring. A lot of you chose LENPEM for your patient after her third recurrence. That's a good choice because it does seem that this combination can work just as well as it does in others, although when you look at the medians, these patients just do worse. They do worse with chemo and they do worse overall, so it's still worth trying and it's worth that potential benefit, but you may not see the outcomes that you see in the patients with endometrioid. Then finally, just a quick note, because I know we're running short on time, about the future. I gave you that laundry list of different molecular aberrations that are common in clear cell. There's a number of things we could discuss. Dr. Eskander has been leading a really intriguing study of tezometastat, which is an EZH2 inhibitor, that there are really interesting mechanistic data to indicate that may work best in patients that have an ARID1A mutation, which of course is quite common in clear cell. Then our own institution looking at clear cell ovarian cancer found that the presence of a PPP2R1A mutation was associated with long-term benefit from dual checkpoint inhibition. Again, in ovarian cancer, but we are now enrolling on a single arm of endometrial cancer with that aberration as well. Bottom line, clear cell is a unique entity, often going to be lumped in. You really can do whatever you want right now, because we have such a paucity of data. I hope we can continue to do more studies like Dr. Eskander is doing of truly clear cell focused research, and fingers crossed that immune oncology agents will hold promise. Thank you all so much. Thank you, Shannon. That was an outstanding review. I think it demonstrates that both these cases demonstrate that there's not a lot of consensus, even if there is a lot of data. I'm not surprised that there's not a lot of consensus in clear cell. I have a couple questions, and then we're going to open up the questions in the Q&A, if you want to submit questions. Again, I want to thank everybody for the outstanding lectures. This program is, again, part of the IGCS 360 initiative, and it is supported by an educational grant from ESI, and I want to recognize that. I have a question for Dr. Eskander. The first case has somebody who had a long response to platinum-based therapy. I know we talk about platinum sensitivity in ovarian cancer. Is it reasonable or unreasonable to take that concept to endometrial cancer? Do you think that in light of 775, is there a role for platinum-based chemotherapy and recurrence over immunotherapy? I think it's an important question that many of us actually struggled with in the beginning. I will say that the extrapolation from ovary is something that we have to be thoughtful about, because it's unclear, and I don't think we have sufficient data. Even in the ovarian cancer space, the concept of platinum rechallenge is evolving over time, even though we have a tremendous amount of data. There was a study, retrospective, that looked at the relevance of a platinum-free interval that was published in the journal GYN Oncology a couple of years ago, suggesting that the longer it is, the more likely the patient was to derive benefit. That being said, I think linvatinib and pembrolizumab, what's most appealing is, again, the magnitude of benefit in those patients who do respond. We know that chemotherapy can elicit a response, but you're not usually seeing a durable response, even when you're rechallenging and seeing a benefit. For me in clinical practice, I think the longer the cancer stays away, the better, undoubtedly. The patient tends to feel better, they have a better performance status, and for me, that's the prime opportunity to try to get a benefit with linvatinib and pembrolizumab as a combination, because if they respond, my hope is to drive that response for as long as I can, knowing I can always go back to chemotherapy if they progress on that regimen, or obviously a clinical trial if they're eligible. Excellent. Shannon, again, it was a great overview of clear cell, and I learned a lot. I guess it was my impression that in keynote 158, there were like four clear cells, and all of those patients had a response to linvatinib and pembrolizumab. Is that the case? Yeah, I think it was something small, and the majority did have benefit. I think 775 is a little bit more indicative, because a larger number of patients, so we're probably getting a little bit better idea. I think the bottom line is that immunotherapy is likely going to be something that we're going to incorporate in our treatment of patients with clear cell. The question will be really the best strategy as far as single agent, dual checkpoint, or something like linvatinib and pembrolizumab. I think for the here and now, lenpem clearly has the best data and is the strongest choice, but I'm eager to see some of these other studies and see if we can get a similar benefit, but maybe with less toxicity. Again, the curve you showed that Scott McMakin put together that had three patients survive clear cell carcinoma is just a little bit depressing. I do wonder if chemotherapy is the right answer for those patients. It looked like in that larger study there might have been some benefit to the combination of chemo and radiation in the clear cell combination. I do tend to treat those patients a little more aggressively. I definitely do as well, because you just feel like you know they're going to do poorly, and if there's anything you can do on the front end to try to prevent that, you want to. I had one of the questions that came in, and again, please submit your questions through the Q&A chat if you want to. Is there a role, do you think there's going to be a role for new adjuvant therapy in advanced endometrial cancer at some point, and even whether it's in general or based on molecular subtype? Well, I mean, I think we're seeing, we're doing, I know I'm doing it more and more, you know, because again, it's grappling from ovary, because that's what we do with advanced uterine cancer. You know, I think that if you've got a patient that's got disease outside of the abdomen and pelvis that you know you can't debulk, it just makes sense to try to give chemo first, get a sense of if the tumor is sensitive to chemo at all, and make a good decision. I think we've got some retrospective data, not inclusive just of clear cell, but of just advanced as well, and it seems like it might be a reasonable opportunity for patients with advanced endometrial cancer, but I mean, I think right now we're definitely extrapolating. I will say, I think that in conjunction with the data that we have that the frequency of the disease is increasing, we're also seeing patients who have more advanced stage disease on presentation, and we can't resect, right? They have a super clav node from endometrial cancer, they have multifocal lung mets. I will say I have two patients in practice that not long ago started my care before C93 was open, or some of our frontline I.O. and chemo, but they had metastatic disease to the vagina and vaginal entroitis. Both happened to be mismatch repair deficient, both had a CR to chemo, and then had surgery except for residual disease in the uterus, but I think there is a role for neoadjuvant chemotherapy and endometrial cancer, and we're seeing more and more of these patients that are not amenable to resection at presentation, so it's an important question to answer. I mean, obviously you're the PI on GY018, and so that, of course, incorporates pembrolizumab in the upfront setting. One, when do we see the results, or when is that trial going to be enrolled, and when is the projected readout, and how would that change your treatment of second line therapy, just in terms of projecting if it is a positive trial? We face this in cervical cancer now, this is a big deal, so. Yeah, I think this is, I wish I could predict the future. I'll tell you that I know that we're getting close to completing accrual, hopefully, thanks to the efforts of everybody who has the trial active and are putting patients on, so hopefully we'll complete in the next four months or so everybody on trial, and by the way, you know, I have to shout out to Dr. Weston, who's also the PI of DUO-E, which is a sister trial in the same space, and I will just say that if any of these trials are positive, including LEAP-001, where now you have immunotherapy with chemo or linvatinib pembro, we're going to have to rethink our paradigm altogether, and we're going to have an entire cohort of patients where I say it's the post-checkpoint population, and what are we going to develop in that space to hopefully continue to get meaningful responses, because we know that these patients respond, but many of them still recur, aside from the DMMR cohort, where we're hopefully going to cure more patients, but we'll see. Time will tell. Yeah, thanks. Well, we are actually at the limit of time. Again, this was just a wonderful review. This will be available on the IGCS website. There's a tremendous amount of information here that you may want to go back and look at. It'll be available through the IGCS portal. I do want to put in a plug. We are going to have our live meeting in New York this fall in September. Please join us September 29th through October 1st in New York City for this. Register now. You can register through the portal, and I look forward to seeing all of you there. There will be a follow-up email for this in terms of the link to get to the website. I appreciate everybody's participation and for everybody's attention throughout the program, and I think we're going to end now. Thank you very much. Bye-bye. Thanks.

IGCS 360 initiative

education

personalized therapy

cancer patients

endometrial cancer

challenging cases

64-year-old woman

stage 3C2 endometrial carcinoma

treatment options

chemotherapy

molecular subtyping