Okay, so I'm just going to go through, I know I'm limited on time, so I don't have the longest case presentation, but this was a patient that really stood out to me. She was a 72-year-old postmenopausal female who had come to me for postmenopausal spotting for a couple of months. She was obese, she had a BMI of 38, type 2 diabetes, hypertension, things that come along with that. She didn't have a surgical history. She had two prior vaginal deliveries, and on my in-depth family history, she denied any GYN or GI cancers that she knew of, maybe an uncle with prostate cancer. Sometimes the frustrating part is I try to delve into the family history as the unknown, and I try to see if they can go out and get as much, because we know how important family history is. And then I delved in with her on review of systems, and as I probed and asked more questions, she said, yeah, I do have intermittent abdominal pain, but I think it's when I do more strenuous activity, I find that patients like to find a reason for why they may have symptoms other than potentially being at advanced cancer. She actually did have some mild changes in her appetite, but she said, I think this could be just anxiety, but when you probed, it had predated her actually knowing the diagnosis. She didn't have any GI changes, she just had stable intermittent constipation and really no other symptoms. So she had had an endometrial biopsy done and came to me with that diagnosis of adenocarcinoma, and it was suspected to be a moderately differentiated endometrioid. But to me, the clinical picture wasn't really quite fitting, because as I probed her more, she had more symptoms. So if I go grade one or grade two, that you suspect should be confined to the endometrium and not spread, shouldn't really have any other symptoms. But her symptoms of this changes in her appetite and this pain and mild pain that came at different times probed me to do more workup, which I may not have done on just a grade one, grade two diagnosis. And indeed, her CT, while not very telling with discrete masses, there was no discrete masses outside of the uterus. She had some, obviously, thickened endometrium and some mild haziness in her omentum. And then looking at the pictures, it was not the most normal looking omentum. And I did do a C125, and indeed, it was elevated at 247, like you are cut off as anywhere, depending on the lab, 2130 or 35, mostly being 35. So I took her to the OR. I had really prepared her and her family that I suspected that she had an advanced cancer, even though it was really not clear on the imaging and patients here, you know, they rely on that imaging. If there's no masses, they believe that, you know, there's not going to be an advanced cancer. So I did put the scope in first. And indeed, she had carcinoma tarsus on the peritoneum, thickened, dense omentum. I did do an X lab. And on our frozen, I tried to give them a good amount of tissue. They felt it was adenocarcinoma, a serous type, not an endometrioid. And I opened and proceeded to do a HISS, BSO, omentectomy, peritoneal stripping, and was able to remove the disease. And the bowel, it was really more mesenteric deposits that are gone, ablated. And so she had an advanced stage uterine serous carcinoma. And so in the time that we have, I'm just going to, you know, saying to give a talk on endometrial cancer, you know, could take hours and hours and hours. And so breaking it down into individual types of cancers is the way I find I can grasp it most easily. But overall, you know, an adenocarcinoma, the endometrium is the most common histological site that we see here in the States. And we divide it into two subtypes. And that's strictly based on histology. Type one is endometrioid, grade one and grade two. That's what the majority of cancers are diagnosed here, 80% of them, estrogen related, associated with a pre-cancer, which is all estrogen driven. And basically it's on the pathology. And I know we have pathologists on here, so I don't claim to be one, but we see lots of glandular proliferation without any intervening stroma making that diagnosis. And then type two is our serous and our clear cell histologies. About 10 to 20% of the uterine cancers that are diagnosed are in this category and definitely a more aggressive. Now the grade three endometrioid, where does that actually fall into? And I think the vast majority of us would say type two, because it really is a much more aggressive and does stand out separately by the way it presents, at what stage it presents it and how it responds differently. But the exact categorization sometimes causes a little conflict between us. But the point is that it is a much more aggressive and acts more like type two than a type one, grade one or grade two endometrioid. So we're going to just talk in the short time we have remaining on uterine serous carcinoma. And so is endometrial and intraepithelial carcinoma, is it a precursor or is it just an early form of the carcinoma? It's a lesion associated with malignant transformation of the endometrial surface epithelium in the background of endometrial atrophy, which sets it apart from our other histologic type, which is associated with lots of hyperplasia, all estrogen driven. So usually you see this confined to a polyp or in one area in overall endometrial atrophy. And we have seen endometrial and intraepithelial carcinoma associated with extra uterine serous carcinoma. So I think the idea of it, is it a true precursor, meaning it takes time for it to progress, break the basement barrier and become a cancer, or is it just an early form? Still trying to figure that out, but it is associated and making the diagnosis on a biopsy can help us realize that we have to be more aggressive with our next steps. You know, we are learning more and more about molecular pathogenesis of all of our cancers. And so a uterine serous carcinoma looks different than our type one endometrioids mutationally. It's associated with most commonly P53, and then going down in percentages, PIK3, FBXW7, and then also associated with HER2 overexpression, which correlates with what we saw with our patient on her analysis, and then CCNE1 amplification. And as we learn more about mutation pathogenesis, we understand the biologic behavior of them, but also can now start to realize that we can target agents. You know, and histologically, it's a complex papillary architecture with marched nuclear atypia and sonoma bodies, which are, I think that is a Greek word coming from like grands of salt. So it looks that way under the microscope. And it's deposits of calcium salts that give us that look of what it, under the microscope. So the biologic behavior, you know, definitely more aggressive, more aggressive at presentation, which is clear by your patient today. My patient was a little less evident of the aggressiveness initially on her presentation, but it became very clear with some imaging. But your, you know, your patient presented with clearly much more beyond just simple lymphovascular space invasion with parametrial invasion and sidewall extension. And, you know, when we think of uterine cancer and we think this, the most common uterine cancer are FIGO grade ones, we think, okay, well, the grade and then the depth of invasion, those are predictors of lymph node metastasis. But here, the depth innovation is not at all a predictor. And we can see extra uterine spread in serous carcinomas that have barely to even know invasion into the myometrium. And I can think of, you know, many cases where I've had patients with the uterine factors don't seem that aggressive, but they do have metastatic disease. And in about 60 to 70 cases, percent of cases, we will see disease outside of the uterus. And so already at baseline, they're starting at an advanced stage. And we know we stage people, you know, I always say, ask my residents and fellows, why do we stage people? And everyone says to dictate treatment, which is part of the reason. But the reason we stage people is to really give a sense to our patients, what the biologic behavior of that is going to be and what their prognosis and outcome is going to be. So most of the patients with, many of the patients with uterine serous are advanced stage and will have less of a good outcome, unfortunately. This may be a little bit hard to see, so I apologize, but, you know, I just like it because it shows you here, the serous carcinomas had a 25% rate of having positive pelvic lymph nodes and 17 of periodic lymph nodes, which is much higher than what we see in our grade one and grade two here. So, you know, I think when we think of a serous carcinoma, we have to sort of, the expectation should be that we will find disease outside of the uterus and therefore look for it, treat and act aggressively. And if we don't find it good, but expect that we will. So what are the risk factors of this, of serous cancer age, you know, age is a risk factor for any cancer. So I always have to put it up there, but the average age of diagnosis is 62, which is common to our type one endometrial cancers. We often don't think as obesity is being a risk factor, but actually there's more data to suggest that it probably is. When we think endometrial cancer and obesity, we think FIGO grade one or grade two are endometrioid types, but there is some more data emerging that obesity is probably a factor there too. We know that obesity is a risk factor for many other cancers too. And so overall obesity, you know, is a bad other comorbid disease in itself to have putting us at risk for many different cancers. Racial disparity is also seen, and there was actually a very interesting paper just recently published showing that it within every increase, 1% increase in African ancestry, there was a 1.1 increase in the probability of a diagnosis of serous endometrial cancer. So I think understanding that and getting more data to look at exactly what the racial disparity is and what the mutations may be underlining, are they different or are future directions that will elucidate us on treatment? And parity is actually a risk factor for not having any previous pregnancies. So clinical features and your workup. So symptoms as with across the board, all endometrial cancer, abnormal uterine bleeding, whether it's most often, you know, the age being 62, most of the patients are postmenopausal. So new onset postmenopausal bleeding or discharge or any in a premenopausal woman, which we see less of though, any other kind of changes in their bleeding pattern. And then any symptoms related to distant disease. And so, you know, that's where the review of systems becomes very important, sitting down and trying to make the patients correlate what symptoms they may be having to what, where the disease might have spread to. So we always start with an endometrial sampling to make the diagnosis here. You know, we do office biopsies, which are very sensitive to making the diagnosis. However, we, like your case, we always come into some difficult, there's always, you know, a small percentage of patients where making the exact diagnosis is difficult and may have to do a DNC hysteroscopy in the office and, you know, may not always get a correct diagnosis. And I say this, you know, cautiously, I know, you know, not to point fingers at a pathologist, but you know, it is not as common. And so if people are not seeing it, it may not be made on the endometrial sampling before the surgery is done where more tissue can be given. And I think that's the other thing is that, you know, we all have to be understanding that giving the pathologist sample means giving them enough of a sample to be able to make an accurate diagnosis. And there was one study that showed 67 patients with a final postoperative diagnosis of uterine serous carcinoma, you know, 17 reported as endometrioid beforehand. So not an uncommon thing. If you do get a diagnosis of serous carcinoma on your initial sampling, then CA-125 should definitely be done and imaging should be done right away to look for any subtle distant disease that may be there that is not causing symptoms for the patient that then may dictate what you're, how you're going to approach because it's, you know, when you see patients in, when I see a patient in my office who has advanced disease, my first question is surgery or no surgery? That is the question, right? Are they resectable? Are they not resectable? And then once I have that decision made, then I can, you know, work through the rest of the plan for the patient. So if the disease is confined to the uterus, then surgical staging is performed and surgical staging for endometrial cancer, taking out the uterus, taking out the adnexa, assessing for adjacent spread, doing a potal hysterectomy, taking out the uterus and the cervix with the uterus, taking out the adnexa, doing pelvic and periortic lymph node. And for uterine staging, you know, I do take out the omentum as well and peritoneal biopsies. And I think you may get, you could have a quote unquote argument in the room of is that helpful in uterine cirrus, but I think for comprehensive surgical staging, definitely taking out the omentum and doing the pelvic and periortic lymph nodes. So advanced disease, if the patient is resectable, surgical optimal cytoreduction is what's, if it's feasible, that's what we like to do for the patient. And we know through multiple prior studies that, you know, surgical cytoreduction, if we are able to get the patient to no gross disease, that is the strongest predictor for the best outcome. You know, where do we hear that? We hear that all the time in ovarian cirrus cancer treatment outcome. And so same here. And again, data has shown that. And then how do we treat them? What is the adjuvant treatment? And, you know, we have many options, but which is the best? And therein lies another question, which is the best? So just to kind of look of where we are today, you know, I think Ortec3 was a study that we did, that was done looking at chemo RT, specifically pelvic RT with two cycles of cisplatin, followed by four cycles of carbotaxel versus pelvic RT alone. And you can see there that chemo RT had a five-year overall survival of 81% versus 76% of the pelvic RT alone. So not a huge difference. Although when they went into further, you know, dissection of the data that the stage three patients actually did a little bit better with the chemo RT. And also the uterine cirrus cancer patients did it better with the chemo RT. And if you take a step back and say, well, if I'm going to think of uterine cirrus carcinoma more like ovary cancer, then adding the chemo sort of makes common sense to me since it is a more chemo sensitive at the get-go, which is a good thing for our patients that initially, if they get diagnosed, even at advanced stage, vast, vast majority will respond. Obviously we know it most likely will come back and there is the challenge, but at the initial diagnosis, the chemo sensitivity is definitely there. And then GRD258 was a chemo RT here. It was cyst with volume directed RT followed by carbotaxel again, four cycles versus carbotaxel by six, carbotaxel now six cycles. So, you know, now comparing it to chemo alone versus RT alone, and there was really no difference in overall survival. And so, you know, I think we have many patients that get diagnosed with uterine cancer, less with cirrus cancer in the high grade and really the treatment option, which is the best, I think really still is a question, but the way I kind of spin this and look at it is that they all seem to work pretty good. So I think sitting down and kind of seeing which is going to be the best for your patient in terms of outcome, but also least amount of toxicity. But really the recommendation, you know, for the stage three is after they're surgically resected to hopefully no gross adjuvant chemotherapy is sort of the preferred where most of us default to plus minus vaginal brachytherapy, which is really just for local control. And recurrences at the cuff or in the pelvis can be challenging for the patient in terms of symptom-wise. So if we can give something early in their treatment that may decrease the chances of them getting a local recurrence, then I think it's well worth it. And that chemotherapy is, you know, carbo-taxol as we saw in the first presentation by Julius that that's what she got and responded nicely. And initially until then she had meds to the spleen and the brain. And if a patient is not a candidate for chemotherapy, then, you know, whole pelvic RT is another option with good outcomes. So I think it's nice to be able to tell patients that there are options that have good response rates and good outcomes. So the stage four patients, I think, you know, again, the surgeon always asks, is the patient surgically receptible? And some stage fours definitely are. And the case that I presented had meds to her omentum and was able to have a nice optimal surgical cytoreduction. And then after surgery, follow it by, again, the chemotherapy with vaginal brachytherapy. And if a patient is not a candidate for surgery, or you feel that the disease is not receptible, then starting with chemotherapy, as we saw in your case. So chemotherapy, initial treatment, what do we choose? We choose carbotaxel. Where did that come from? GOG 209 looked at carbotaxel or compared carbotaxel to TAP, which would, what had been the standard of care up until GOG 209 and tapasysplatin, doxorubicin and paclitaxel. And we came to that, again, by many previous trials, kept adding drugs on top, starting with doxorubicin, adding cysts, then adding taxol. And by adding more drugs, we saw patients did better and did okay in terms of outcomes, in terms of toxicity. But patient, we sort of started to turn to dropping the doxorubicin and just doing carbotaxel. And finally, we did a study that said, you know what? The outcomes are the same. Equivalent overall response rates, progression-free and overall survival, but with less toxicity. So now the standard of care is carbotaxel. And then now we have targeted therapy. So we test our serous tumors and our high-grade tumors for, you know, for HER2. And if positive, then trastuzumab we add to our chemotherapy and we see really nice changes in outcome and improvement in outcome. So that has been a new finding that has really improved outcome for patients with advanced serous. Trastuzumab requires getting an echo before and during. So don't forget that and getting that baseline echo to make sure the patient is a candidate for Herceptin is important and then following it. And I've had many patients now on the combination of the carbotaxel with the Herceptin and have done very nicely in terms of cancer outcome but also in terms of minimal toxicity. So what do we do once a patient has been treated already and they come back with a recurrence? And with our ovarian serous, it's all about when did they recur? So progression on or after a platinum-based chemotherapy. You know, I think it also depends now on what does the tumor look like, a high tumor mutational burden. We can treat with our PD-1 antibody Pembrolizumab which Pembro has really shown some nice, very nice response rates to, in patients with recurrence or progression on frontline therapy. And then of course, looking at our mismatch repair and Pembro and now Darstolomab has been, which is another PD-1 antibody that has been tested and has been shown to have nice response rates as well with minimal, or I shouldn't say minimal, with not as bad toxicity. And I think the important thing to remember is the toxicity of these, you know, of these anti-programmed cell death protein-1 antibodies are very different than our chemotherapy. And we see lots of itises, thyroiditis, pulmonitis, colitis. And so just kind of being aware that the toxicities are different, but treatable. And so just being aware and having patients report symptoms to us and then, you know, responding to them appropriately. But I think this is a really exciting movement towards this new targeted therapy away from chemotherapy or in conjunction with chemotherapy that is giving patients with more aggressive tumors really nice options. And once the patient recurs and is on another line of therapy, you know, the general plan is to continue treatment until they progress or until unacceptable toxicity. And, you know, progression of disease in patients who don't, you know, who aren't deficient or have MSI high tumors. Again, we look at the treatment-free interval in choosing the next line therapy. So if they're less than six months, sorry, if they're greater than six months away from having carbotaxel, well, then we give them carbotaxel again. And I put in there or endocrine therapy. And I, you know, when I started looking at these, I was less thinking of the serous. So for the serous tumors, we really don't do endocrine therapy. And we'll look at a final slide at the end here. But so if they progress within greater than six months of having carbotaxel, then going back to carbotaxel again is completely reasonable. If they progress less than six months, then using Pembro and, oh, sorry for that typo there, Pembro and lenvatinib. And that is a really nice combination that has been showing really good response rates. I will say it can be a bit toxic for patients. And so we started the lenvatinib or lenvima is the other name. We started at really high doses. And over the years, we've like, we started to lower those doses and trialed them on lower doses. So initially we saw a very overwhelming amount of toxicity that was disruptive to the patients, no doubt, but we are changing doses and seeing a difference in toxicities, fortunately. And so lenvatinib is actually a vascular endothelial growth factor receptor inhibitor. And together the combination of Pembro and lenvima, like I said, has really shown nice response rates and progression-free survival numbers. And you can see here, there was one trial looking at Pembro and lenvatinib versus whatever the physician choice was. And that, you know, there was a whole host of things from doxorubicin and doxil and the median progression-free survival was 7.2 with the targeted agents versus 3.8. Low numbers all around. When I look at those numbers, sometimes I think, wow, this is not much of a gain in terms of long-term, but we are seeing some improvements. And then I realized it's a median, so some people are doing much better than that too. So chemotherapy options, single agents that have been tested and tried and true, doxorubicin has a pretty decent response rate as a single agent. You know, again, cumulatively has some cardiotoxicity, so have to be cautious of that and monitoring that. Paclitaxel on its own. Liposoprotein doxorubicin or doxil can also be used as a single agent. And then targeted agents, bevazizumab or Avastin, which, you know, when at the end of the presentation about the brain med, you know, Avastin has been shown to work for many solid tumor brain meds. They use Avastin for primary brain disease, but for many solid tumor studies, Avastin has been nice. So perhaps that will come up in our next lecture, but for endometrial cancer, it has been tested as a single agent and has some nice response rate. I think it was 22 or 25% as a single. And now mTOR inhibitors, temsorolimus and iverolimus are being investigated right now and hopefully will show some, based on understanding what we know about advanced endometrial cancer and serous cancer, perhaps the mTOR inhibitors will show some promise there and changes. And again, our endocrine therapy, which is a really great therapy, and I use it a lot when I have patients who are in need of a chemo break or just kind of are not ready to take on the potential toxicity of chemo, using endocrine therapy is a really nice option, but unfortunately in serous cancers where estrogen is not a driver and not estrogen related, then really we cannot use endocrine therapies. And we've tried and we've actually done multiple trials and really have not had any positive trials. So unfortunately that's not an option, but hopefully again with some of these more targeted agents as we study them, we'll have different options for patients as they continue to live longer with advanced disease, probably with active recurrence, but getting treatment and hopefully living a good quality of life. And I think that is it. I appreciate.

postmenopausal spotting

adenocarcinoma

advanced stage uterine serous carcinoma

surgical staging

chemotherapy

targeted therapies