Talking about endometrial cancer in high-income countries, just in terms of very brief epidemiology, for us in Boston, endometrial cancer is by far the most common gynecologic cancer followed by ovarian cancer and then cervical. Whereas of course, in Haiti and most other low and middle-income countries, cervical cancer is more common, which doesn't make endometrial cancer less common or ovarian cancer less common so far as we know. And when we've heard Milya and Dr. Ulysse talk about this classification, there's newer ways of understanding the clinical behavior of endometrial cancer in terms of the Cancer Genome Atlas Project. But in terms of our work clinically, it's still very useful to think of endometrial cancer as type one, which is predominantly endometrioid cancers, grade one and two, and type two, which is the other cancers we'll speak about in a minute. So the majority, particularly in the high income setting and among obese women, these endometrioid cancers predominate. They're about 80% of what we see in Boston. They're estrogen responsive and express estrogen and progesterone receptors on immunohistochemistry. They're usually stage one. They typically have a good prognosis with 80% overall five-year survival. And their management is hysterectomy with BSO and lymph node sampling. In younger women, we can consider doing a hysterectomy and leaving the ovaries with a grade one. That's something, if the ovaries look normal and it's an early stage. We can also consider doing fertility sparing treatment or progesterone treatment for women who are very poor surgical candidates. So something we could think about with this patient, if and when she either completes chemo or gets surgery. And so this, and I encourage you, particularly John Joel, to read the, there's a 2020 New England Journal Review of Endometrial Cancer by Dr. Liu, who's the department chair at MD Anderson for gynecologic oncology. And this is a very, very good article. And this shows the endometrioid histology and the left panel shows the sort of types of genetic alterations that we see from the Cancer Genome Atlas Project, but shows the sort of presentation changing among patients with endometrioid cancers. So there's sort of endometrioid and endometrioid, but the grade threes genetically are a very different group than the grade ones. This is interesting in that from that same article, this shows you that normal weight women with a relative risk of one. So normal weight women, say BMI 20 to 25, have about a 3% lifetime risk of endometrial cancer. And that risk increases 50% with every change of five in the body mass index. So that by going up 10, you have a threefold increase in risk. And that curve continues with really very obese women. So definitely a hormone sensitive tumor, whereas the type two or non-endometrioid cancers, we think of differently clinically. So this is serious cancers, carcinosarcoma, clear cell cancers, about 20% of endometrial cancer in high income countries, probably more in Haiti. They're more often advanced stage and only have a 45% overall five year survival. The management therefore is adapted to the understanding that they have a higher risk of spreading through the peritoneal cavity in particular. So we do a hysterectomy, both tubes and ovaries, also a lymph node dissection, omental biopsy and peritoneal washings. So here we show, and I won't try to, we'll have to ask Carlos in a future session to teach us more about the serious carcinosarcoma and clear cell histologies, but there's a prominent genetic feature where there's HER2 new overexpression in a lot of the serious cancers, this ARID1A mutation in clear cell cancers and prominent P53 mutations in all of them, but particularly in serious cancers. When we think about staging, so here's the answer to your question, Jean-Joel, in terms of tumor staging, the FIGO system, stage one of course is tumor confined to the uterine corpus, including endocervical glands. Inner half is stage 1A, outer half of the myometrium is a 1B. Stage two now is adapted to invading the stroma of the cervix, but not going beyond the uterus. Stage three is the uterine serosa or the anexa, so that would include the ovaries or the vagina or the parametrium. So you see my concern that once it's in the anexa and the serosa, could it also be in the parametrium? The 3A is just serosa or anexal, 3B is vaginal or parametrial involvement. And then stage 4A would be involving the bladder mucosa or bowel mucosa. And then 4B of course would be any spread into the peritoneal cavity with this disease. There's a lot of talk we can think about another day about isolated tumor cells in a lymph node versus micrometastases versus macrometastases. For our purposes, people with any nodal involvement, we would want to offer them chemotherapy after treatment. So post-surgical management. So the idea, as I said, is to get most of these patients to surgery for hysterectomy and the other components. The patients who have a stage 1A, grade one or two, and that should be most of these patients with grade one endometrioid, they have 97% five-year survival and just need close clinical follow-up. Patients with stage one high intermediate risk, which has been defined by trials by the GOG and by the European groups a little bit differently, but basically is age either over 60 or 70, depending on what you say, more advanced grade more than one, so grade two or three, and more than one half myometrial invasion. We know this group has a higher risk, but it hasn't been shown that whole pelvic external beam radiation improves their survival. And so these days we just give them radiotherapy to the vaginal cuff with vaginal cylinder brachytherapy. And the same for patients with high risk stage one, those who have both grade three and deep invasion, they get either pelvic RT and there's a clinical trial studying whether they do better with pelvic RT or just vaginal brachytherapy. Patients who have node positive cancer, this you guys have heard me talk about over and over again, because it's a very confusing area in GYN oncology. There was a trial called PORTEC-3 done in Europe, which studied chemo radiotherapy to the pelvis plus four cycles of Taxol and Carbo. And that led to better survival than pelvic radiotherapy alone for women with node positive disease after endometrial cancer surgery. The GOG-258 trial you hear me talk about showed that Taxol and Carbo for six cycles had the same results with lower morbidity as pelvic radiotherapy plus four cycles of Taxol and Carbo. So sort of a mixed confusing picture here and leaves us not really knowing how to treat the patients with node positive disease. What we typically do is give them six cycles of Taxol and Carboplatin and then re-image and reevaluate. Those women who we think are for some reason at increased risk for local or nodal recurrence like really bulky lymph nodes or bulky cervical involvement, we usually treat with radiotherapy. Some recent advances and almost done recent advances that sort of show gaps or areas for potential future improvement for us at Mirablé. Laparoscopic surgery has clearly been shown over the last 20 years to have the same oncologic outcomes with lower morbidity for women with endometrial cancer. Now we're doing sentinel lymph nodes and again, same oncological outcomes, definitely lower morbidity. There are some structural barriers to being able to do sentinel lymph nodes at Mirablé that we can all talk about in a future session. We have standard screening for Lynch syndrome by using microsatellite instability and we have molecular specific treatments. A lot of patients with serous cancers will have HER2 new mutations and can be treated with Herceptin. Patients with P53 mutations can be identified as those more likely to benefit from chemotherapy and patients who have MSI high tumors with advanced or recurrent disease could be treated quite effectively with something called Pembrolizumab. A couple quick references in closing on neoadjuvant chemotherapy for advanced stage endometrial cancer. Some of my colleagues at Harvard recently did a review of our experience at the Brigham and Women's Hospital and Mass General with giving neoadjuvant chemotherapy for endometrial cancer published in Gynoc Reports last year and found that neoadjuvant chemo is a feasible option to allow for interval cytoreductive surgery that patients who were able to get surgery after chemo had significantly improved progression free and overall survival. That said, this is not like our patients who had neoadjuvant for ovarian cancer and the overall survival in the patients who got neoadjuvant chemo and a successful surgery was 24 months. So in terms of thinking about the risk reward, this is a different situation. I think we should be a little more cautious about taking these patients to surgery based on that understanding. Also a group at a multi-center group basically did a systematic review also published last year in Gynoc Reports of neoadjuvant chemotherapy for advanced stage endometrial cancer. They included nine studies with about 6,000 patients. These were all reviews, not clinical trials. But they found that neoadjuvant chemotherapy followed by interval cytoreductive surgery reduces the perioperative morbidity while offering the same overall survival. So it is like an established and effective strategy in terms of management of advanced stage high risk endometrial cancer.

endometrial cancer

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neoadjuvant chemotherapy