Sorry, this presentation focuses on uterine serous carcinoma, but I just start with a use just brief general slides of where we are at the moment. And I think most of you are aware, but just to rehearse, there has been a lot of changes in how we look at endometrial cancer over the last decade. And this has been largely due to the analysis of the Cancer Genome Atlas published in 2013, where they had a comprehensive molecular analysis and I will just put on the laser pointer, where they had a comprehensive molecular analysis and they were the first to describe four subgroups of endometrial cancer. So it's a heterogeneous type of cancer. And there are four defined molecular groups. The first one is pol E mutant, which has an excellent prognosis. And they are ultra mutated. And on the other side of the spectrum, you have a group that is called copy number high, or serous like these are almost all p53 mutated and they have a relatively poor prognosis. And then there are two subgroups that have an intermediate prognosis. And one important group are those that are MSI high or what we also call mismatch repair deficient tumours. And then the largest group is the remaining group. And for that there is a new abbreviation. They were copy number low in the Cancer Genome Atlas, but we also refer to them as NSFP, which stands for no specific molecular alteration. So this was done with complex molecular techniques. And we are now able with surrogate markers, mainly immunohistochemical markers for p53 for mismatch repair deficiency to classify these tumours. The only remaining complex analysis is that for pol E. There are nowadays hotspot mutation kits available and this is becoming more and more clinically available to do this. There have been different groups and I only showed two groups here who have with use of surrogate markers demonstrated that you can achieve similar results as was being done with more complex molecular techniques in the Cancer Genome Atlas. So this is now become more widely available due to the use of these surrogate markers. In 2021, the ASTRO ESP guideline was one of the first or the first guideline that actually integrated molecular information into risk group classification. And that I think is an important step. Risk groups in general for this management of uterine carcinoma, because the majority of patients have actually of endometrial cancer patients have a good prognosis. They are diagnosed at a low stage and we really have to use risk factors to determine the patients that may benefit from adjuvant treatments. And that is where these risk factors and these risk groups are for. And what was the basic message in 2021 was that stage one to pol E mutated carcinomas have a very good prognosis and they should be regarded as low risk. But patients with stage one to four A with P53 abnormalities were high risk. And at that point, those with without invasion with P53 abnormal were found to be intermediate risk. That was 2021 guideline. Another important shift that happened at that point in time was a shift from historical risk groups. Up to then, endometriate stage one, grade three and two, or those with substantial LVSI were were originally found to be high risk. But because of the good outcomes in randomised trials such as PORTEC3, but also GOG249, they have been shifted to the high intermediate risk group. So that's an important shift. And with that, traditional high intermediate risk patients such as endometriate low grade 1B with deep myometrial invasion or high grade with superficial myometrial invasion were shifted from high intermediate to intermediate. So there are also shifts in historic groups in this and the integration of molecular information. But in 2023, there is now an update of FIGO staging of the endometrium. And this is not only anatomical becoming much more complex than it was, but also here molecular information is integrated and it's focused mainly on pol E and p53, but it's more than that. And different publications have shown what the implication is of shifting from 2009 FIGO to 2023, where you see that there is quite some shifting of different patient populations. And also, it has been shown that it has improved prognostic power with the use of the 2023 FIGO staging. There has also been criticism. And this is mainly because the integration of molecular information is complex, and also the anatomical description is quite extensive. Another new, more recent finding has been the importance of ER status in the NOS-specific molecular profile group. And basically patients that are ER negative in the NSMP group have a prognosis that's more similar to that of p53 abnormal tumors. And what works best, this has been what was found in the Vancouver group, is the combination of NSMP hydrate or ER negative to define, let's say, the patients with an unfavorable prognosis within the NSMP group. So the escrow ESP guideline is currently updated. And in this update, and I know this is too small, and I just want to show it, it still needs to be published. But the main message I want to show is that it integrates FIGO 2023 staging because it was at the basis of the guideline, but also, again, molecular classification. And in this guideline now, NSMP has been split into low grade and ER positive and NSMP hydrate or ER negative. And what is particularly relevant for the current case is that patients with any invasion with p53 abnormal status are regarded high risk. So now I come a bit better into uterine carcinosarcoma and some background information because these have traditionally been defined as a B-phasic tumor that consists both of sarcomatous and carcinomatous components. But it is seen and basically treated as an aggressive form of carcinoma because the carcinomatous component drives the prognosis. And the majority, and there are different groups that have now also profiled large populations of carcinosarcomas, and most of them are classified as p53 mutated. And if you look more closer to them, they also feature more serious histology in their carcinomatous component. So with that, you can also understand it is quite a complex area also for pathologists to correctly diagnose these tumors. And in general, for endometrial cancer, high grade endometrial cancer, it can be really difficult for pathologists to clearly indicate this is serious, this is carcinosarcoma, or this is undifferentiated. And especially in this group, there is a big value of molecular information. What I thought also relevant for our current discussion, and this is work from the United States, where they found that non-Hispanic Black population are two to three times more likely to develop uterine carcinosarcoma. And they also have a higher mortality rate in the US, independent of age stage, body mass index, and adjuvant treatment. So I think that is really important. And there are some indications that it has to do with the type of p53 mutations observed in this population. So to summarize, approximately 70 to 90% have p53 mutations in uterine carcinosarcoma. And PoE is quite uncommon. And this is from a large series around 1800 patients, 2.6%. And also only a small population, about 7% has mismatch repair deficiency. ER positivity is more frequent, around 20 to 50%. And HER2 positivity is 10 to 20% relatively low. And that is information that can be relevant for any subsequent management, also when there is recurrence. In terms of surgical management, it's really important to understand that even in patients that have no invasion, that the diagnosis made in a polyp, or there is no myometrial invasion, there can be lymph vascular space invasion and risk of metastasis. And studies that have performed surgical staging in these patients find around 20 to 25% of also omental disease or disease in the abdomen in these patients that have no invasion in the myometrium. So historically, full lymphadenectomy was recommended for staging. But nowadays, there is data that central node alone is also an acceptable alternative. When we go to adjuvant management, it has been considered high risk. And I think that was clear also from the guideline slides that I showed. The risk of distance recurrence is particularly high in these patients as high as 60% in early stage. And in general, the recommendation is a combination of chemotherapy and radiotherapy for these patients. And a little bit background, this is already a very old study, GUG 150, that compared whole abdominal irradiation with cisplatin ephosphamide. And just to highlight that whole abdominal radiation is no longer in use. And this study also included patients with large residual disease in the abdomen. In this study, chemotherapy was found to have a better survival than whole abdominal irradiation. However, this has been criticised again, because of the amount of disease and the fact that whole abdominal radiation is no longer in use. But this is often cited. That's why I show it. This study is often cited by medical oncologists to urge for the importance of chemotherapy. PORTEC-3 has shown in particularly in stage three, in general, overall and progression-free or event-free survival benefit of the combination of chemotherapy and radiotherapy. Here you see the relapse-free survival rates for the different molecular subgroups, again, highlighting the poor prognosis of P53 abnormal patients. And here you can see that this is particularly a group that benefits from the addition of chemotherapy on top of radiotherapy alone. So that's important in this, one of the important outcomes of this analysis. And also a separate analysis in serious patients described a similar benefit. And of course, you can understand that as the majority of serious cancers also have a P53 mutation. Another important trial to know for carcinosarcoma is ERTC study 55874, which included 40% carcinosarcomas. This was a study focusing on uterine sarcomas, but 40% were uterine carcinosarcomas. And there was no progression-free or overall survival benefit of radiotherapy. But there was an improvement in local control, pelvic control in these patients. And that was with a dose of 51 in 28 fractions. And another study just to complete this discussion, GOG261. This was a randomized trial that was more recently published, but has been completed quite a while ago, which included patients stage one to four uterine carcinosarcoma, randomized between ifosforamide paclitexel versus carboplatin paclitexel, and clearly found no difference in survival between these two cycles. And the conclusion from this study is that the combination of carboplatin paclitexel is preferred because of the improved side effect profile in these patients. So on top of the discussion that Solomon really very well presented, and thank you for bringing this really beautiful case, I would also like to question for the audience, right, what is the availability of molecular markers in your practice? Apart from the discussion, is vaginal brachytherapy alone enough? What about vaginal brachytherapy boost? What do we find is an optimal dose? And a discussion in the non-invasive tumours, what type of, is there a role for adjuvant therapy and what type? With that, Alex, I give the word back to you. Thank you. Thank you, Remy, for a fantastic summary. And I think it's shown how endometrial cancer has changed. And I have to say how complex it is, it's going to get even further as we go down. But it's showing that this is really a molecularly sort of driven tumour and we're going to learn more about, even more about the relevant groups. I think I'd ask, Susan was going to do a quick poll and I think that led to your question. Just asking everyone here, do you have, who has access to full molecular classification? And by that, we mean having poly as well as p53 and MMR status. And if you can tick, we will see. I'll give it just a, you know, just a little bit of time so people can answer it. I like to try to get to at least 51 percent. So, oh, we are at 73 percent. OK, so I will go ahead and end the poll and share the results. OK, so that's probably higher than I thought, actually. And I suppose my other question, I don't know, Susan, if we can just add this on. Well, we can come back to it, we can add it, or I can ask maybe a few people that have it to comment. How quickly can you get, do you get it back? Because obviously, for those of you that are used to sort of seeing when we talk about molecular classification and also the new FIGO staging, we have a case that has p53 mutation, which would put it in the high risk category. And then if several weeks later it comes back with a poly mutation, it makes it low risk. But often you're making decisions through. So it's sort of important. Remy, I don't know how quickly you get your results back. Oh, thank you. I was already wanting also to make an additional comment because it is recommended to do this molecular analysis on the curatage material, so the biopsy specimen, because it is better fixated. Often the uterine, the hysterectomy specimen, there are artefacts and the fixation is less optimal. So it is actually recommended to do it on the biopsy. And with that, usually you have some time because the patient also still needs to recover. But in terms of taking it into account in your surgical management, but that there's very little data on that yet. But I agree. So for us, it

uterine serous carcinoma

endometrial cancer classification

molecular subgroups

p53 mutations

treatment strategies