Dr. Premal Thaker, MD provides education on a few types of cancer that impact women and the treatment options available.
Um Doctor Primo Factor earned her medical degree at Allegheny University Medical College of Pennsylvania and then her residency in obstetrics and Gynecology at the Hospital of the University of Pennsylvania. Then she went to Texas to complete her fellowship in gynecologic oncology at the University of Texas MD Anderson Cancer Center. Doctor Thacker is currently the Director of Gynecological Oncology Clinical Research in the Division of Gyno and a David G and Lynn Mutch, professor of obstetrics and gynecology with the washy physicians at Barnes Jewish Hospital. So, thank you so much. We appreciate you speaking for us today on ovarian cancer. Great. All right. Well, thank you everyone for having me. Um We're gonna dive right into this. So in 2023 there will be approximately 19,000 cases of ovarian cancer. Um So even though it accounts for about 2.1% of female cancers, and you can see that they are on the left hand side, that it's a small number in terms of the number of cases. It is unfortunately one of our deadly ca um cancers because we will have unfortunately to lose about 13,270 women uh to this disease. Uh The main reason we lose so many women is mainly we don't have a good screening test. Um There's definitely a holy grail to try to find screening mechanisms and modalities. A lot of you may be aware of trying to do ultrasounds, serial C A 120 fives. And there's been large um prospective trials that have gone over, over a decade trying to look for like serial changes in C A 120 fives, as well as um the ultrasounds in the general population. I'm talking about not a high risk uh genetic population, which is a very different um options that we can offer those women. But unfortunately, to date, we haven't found any sort of way to really predict who will develop ovarian cancer. And since overall the incidents are in a lifetime risk for a general population is one in 70 it's really hard to find a test that's very sensitive and has a positive predictive value. So a lot of these general large um studies that have been done in the past in both the UK as well as here in the United States, the plco uh trial, looking at another methodology of trying to detect ovarian cancer, found that you'd almost have to do about 1700 cases of ovarian masses to find an incidental ovarian cancer. So we still are looking, but unfortunately, we don't have that um to date. So I think that's why this is so relevant. Um for a P for speaking with you today because a lot of times the symptoms are vague and we find these women at an advanced stage. So hopefully to heighten awareness, um so that we can get these patients when they are symptomatic. Maybe to us sooner to be evaluated with that being said, ovarian cancer is a heterogeneous disease. So, when we do talk about ovarian cancer, the most common is epithelial cell carcinoma, um especially high grade serous carcinoma. And there are other ones that do affect women who are younger. Um And those are more of our sex cord stromal cell and germ cell tumors. And then there's also another etiology that is not considered to be a high grade ovarian cancer, like our typical serous carcinoma. But now it's called low grade. And that's really important for us to distinguish because of the fact that the treatment options and paradigms for that are changing quite a bit. So hopefully we will be able to maybe at some point um even forgo chemotherapy for low grade and have really targeted treatments in the future, then there's an entity called a borderline tumor, the ovary or low malignant potential. And it's really called that because most of the time those cancers really um are not truly invasive, they're almost like if you wanna think about it a preinvasive state. Um But they do have some capability of sort of metastasizing or spreading. So we do look, um if we recognize this um disease to say to take some additional sampling, make sure that there aren't any implants or any abnormalities that are noted. But these patients do not need chemotherapy. And this is usually found in women who are in their fertility in their twenties and thirties and forties. And so fortunately for them, we can usually offer them risk. Um I'm sorry, fertility preservation, which is nice cause the other cancers is really hard to offer sort of fertility sparing except for some of the germ cell and sex cord stromal cell tumors. So, um we're getting better in terms of understanding histology being diverse that they are not all the same cell type and based on what the cell type is, it also helps us um sort of tailor the treatments as well. So we talked about s cancer being the most common. I'm glad I'm after lunch and hopefully everyone's eaten lunch a long time ago because some of the pictures I have to share are probably not as nice as the psychiatrist uh of us who did. So um and then there's the mucinous tumors of the ovary. And that always is a little bit of a conundrum for us when we get an iIn ovarian cancer cause, those account for approximately only about 5% of ovarian cancers. And so we always wanna make sure it's not a metastatic site from another primary. So a lot of times they will get a co a colonoscopy, they'll get an upper endoscopy in order to ensure that it's not a me metastasis to the ovary. For some reason, the ovary is a very common site for metastasis, both for like lymphomas. Um G I cancers, as you may remember from medical school, the famous Kueng tumors of the G I tract, you know, metastasizing to the ovary and then it's called a Kueng tumor. Um So it is very important that we always make sure that when we do find an ovarian cancer, that we really think it primarily started in the ovary, then there's the endometrioid type, which is basically it sort of replicates the tissue of the uterus. Um And so a lot of times this co commonly can be found, especially with patients who have um clear cell or, and excuse me, endometriosis, um it can lead into an endometrioid type. Uh cancer very rare. Is there a transformation of endometriosis, which is a benign etiology? It's probably thought to be an order of one to maybe 3%. Um but it is definitely something um that can over many years transition to a cancerous process. And then lastly is clear cell, which is also thought to be more endometriosis of an etiology of an origin. So, based on where the cell type is, a lot of it um depends also like I mentioned where it may arise from. So, the endometrioid type is thought to be from the endometrium. Um uh coming from there, we also a lot of times in women who have Lynch syndrome, um even though we think more commonly of them having colorectal cancers or uterine cancers, about 5% of them can have and um ovarian cancer as well. So sometimes in these women who are of young age, we wanna make sure that they're not having synchronous primary issues when they have Lynch syndrome. So if you see a mass on the ovary, a lot of times, we wanna make sure that it is not also uh second primary uh cancer as well or is it a metastatic uh component from the uterus itself? So that can be a little tricky um trying to understand that. But the majority of these cancers are really thought to arise from the ovarian surface epithelium. And now with a lot of pathology support, we really determined that there are precursors to the invasive serous carcinoma. And those are thought to be tubal intraepithelial carcinomas, otherwise known as stick tumors. And they're really thought to be originating from the FMRI of the fallopian tube. So there's been a huge push since I just told you, we don't have really good screening radiographic imaging um for patients or you know, blood sampling that if women are deciding to opt to have their, you know, forego their fertility and have some type of um sterilization techniques that really to opt for not a tubal ligation anymore, but really to do a self inject toy. So taking both tubes um in its entirety, um as opposed to just burning a portion of the tube is really the recommendation. And Canada has probably spearheaded it headed this initiative of the best of doing what we would consider a self inject toy as a modality of choice. Realizing that it doesn't really add much operative time, it adds about 10 minutes um to the operating room procedure, whether it be for a hysterectomy for some reason or um just being done at the time of uh you know, Cesarean section. Um So really trying to go ahead and taking those tubes since we think that's really where most of these cancers originate from. Um It did take a lot of, like I said, sleuth work by our pathologist to find this because most of the time the these cancers are found as a stage three or four. So they've already metastasized into the upper abdomen and there's large masses on the ovary. So it's really hard to sometimes find these small precursor lesions in the fallopian tube. But in Canada, like I mentioned, when they have actually implemented this, they have seen a reduction in ovarian cancer um by a 30%. Um So it really is maybe the best way for us to try to do a risk reduction for the general population. There's even initiatives to consider. Um Maybe if we can get our general surgery colleagues on board since there's, you know, several 100 thousands of cholecystectomy done every year, whether they should also women could get their uh tubes removed at that time, since they are taking the operative risk, anesthetic risk. And whether that would be also another way to capture more of these women. So I say stay tuned. But I think there is hope that there are ways that we will hopefully decrease um the number of cases and by in turn, improve also our um treatments that I hope to show you at the end part of this talk as well with all cancer. There's definitely been a huge push to do molecular characterization um for ovarian cancer knowing that it's a heterogeneous disease. As I showed you histologically under the microscope, it looks very different. Um but it also uh looks very different in terms of um the actual sort of tumor molecular profiles. So I think, you know, we're doing a good job in getting our women who are diagnosed with ovarian cancer to get genetic germline testing um performed so BRCA one, BRCA two are the main ones that most of the common population knows, but there are definitely other um minor components but still very important in what we call our homologous recombination uh repair sort of pathways um such as RD 51 cr A 51 D um that are equally important as well as pal B two BR one barred one. So it is a very complicated pathway. But so when they do get germline testing, they're not just getting tested for BRCA one and two, they usually are also getting tested for Lynch Syndrome as well as um some of these other um very important genes in the pathway to ensure that we can also impact families in addition to just um the patients. So if they are recognized to have a genetic mutation, we really are trying to do a better job with what we call cascade genetics, getting the family um tested, you know, ha providing letters. So uh patients could provide that to their families since a lot of times, some families are not as open to these dialogues or conversations. Um because that's another mechanism for us to hopefully reduce the incidence of this disease. The nice thing about knowing all these sort of targets or potential pathways is the fact that there's always constant drug development. Um And so hopefully with um improved drug development, patients won't have to always get chemotherapy as their first line or if they do when they recur, there should be other options that are more quote targeted and getting us that precision um medicine that we all strive to offer our patients. So I, as I was mentioning before most of the time, unfortunately, we find our women at an advanced stage. So about 85% of ovarian cancer patients are found with a stage three or four. So meaning that it has metastasized to the upper abdomen diffusely throughout the abdomen with studying on the intestines. Um, and has left the pelvic area. Um, and the reason it's so critical is because it's really not something we can cure unless they have a hopefully a BRCA mutation. But, um, if we could sort of recognize these symptoms earlier and find them as a stage one, then we definitely, um, believe that with our current treatments that we could cure 85% of women. Um and stage two does drop down a little bit to about 65% but much better than stage three and four where we're curing about 15 to 20%. We have patients who definitely live longer for sure because of the advance uh advances in um medicines and sort of new medications coming um almost now every year, which is very exciting for our patients. However, you know, really, we still need to achieve that C word, the cure word. So we're, we still are fighting to try to find out how to maintain those remissions that we ultimately get. But the reason it's so hard to detect is that the symptoms are very non-specific. So, you know, they have pelvic abdominal or back pain. If I talk to my, if I even think of myself, I have back pain in the morning, I don't have ovarian cancer. But, you know, when you put all of these constellations together, it's really important to maybe think about it, especially in a woman who's in their fifties or that this could be symptoms of an ovarian cancer. Mainly they have bloating. A lot of times you'll hear these women say, oh, my abdominal size just blew up over the last two weeks. Um because they're filling up with ascites. So they usually will also describe early satiety due to the fact that they have this stunning of their tumors on a lot of the sur surfaces of the intestines, as well as the heavy mental cake, which makes it harder on the stomach for digestion. So that's why they will say my appetite has been declining over the last several weeks. Sometimes they'll have urinary or bowel symptoms in terms of having difficulty, either having diarrhea or constipation because these masses are pushing on their bladder or rectum. And a lot of times it's just as non-specific as I'm just really tired all the time and I don't know why and then they'll start developing these other symptoms. So it really is imperative that our primary care physicians or obgyns or family practice physicians. You know, sometimes think about these non-specific symptoms being maybe signs of ovarian cancer, even though it's rare, you'll make a huge difference by getting them evaluated. Um, so that we can hopefully get them intervened sooner and maybe hopefully find them at an earlier stage. So really, um the treatment of choice for ovarian cancer, even in early stage. Um One c is still chemotherapy and surgery, the extent of surgery really is dependent on the stage. So, if it is thought to be an isolated ovarian mass, there are times where you can just remove the ovarian mass, especially depending on the um histology of it and just also take lymph nodes and do staging biopsies to ensure that it hasn't spread as. Um and these are options really for the women who with high grade serous carcinoma who wanna maintain their fertility. Um And that's what we're sort of emphasizing today, are those women with high grade serous cancer. If they have a stage one B, you can still take out both ovaries if they have ovarian masses. Cause now with reproductive technology, um women who don't have their ovaries can still use their own uterus um to carry Children. So this really requires a multidisciplinary approach um for discussion. And so we're very fortunate here at Wash U to have great colleagues and reproductive endocrinology and infertility who help us and get um these patients in very quickly to be, you know, have a consultation and a discussion about what their wishes are. Um Because really until they know all their potential options of, you know, adoption surrogacy, um potentially being their own uterine carrier, they really um can't even fathom. I mean, it almost seems like it's a movie that's come to life because there are so many options. Um And so I do really, I'm very grateful for re I colleagues who are able to help us since we don't have time to really wait and say, oh, we'll wait for your appointment in a month. Uh We can call them and they can get them in very quickly so we can make the best decisions uh for these women. Um And then if fertility is not desired or not an issue, uh then really it's a hysterectomy. Um And then we say into bulking cause it's really challenging to know exactly um how much we'll need to remove. Sometimes this requires splenectomy, sometimes it requires colon resections. Um So it's much more than just a hysterectomy. So it does require a lot of counseling uh for these patients. And you can imagine they're quite overwhelmed uh with just the thought of it being a cancer its um and then hopefully, you can still see my screen. Um The stages as, as I mentioned um before, are that you can see that with the invasive epithelial cancers, like we're talking about stage one, we really have a very high cure rate of about 78 to 93%. Stage two, it can be up to 82%. And then it's stage three and four is where we start dropping quite a bit. I would say most patients are actually found as a stage three B where there are cancer in the upper abdomen is either less than two centimeters, but the majority are found as stage three C, um, or a four A where they'll actually just come in with shortness of breath and be found to have a large pleural effusion. Um, so that's how they can sometimes be diagnosed as well. So you can see that the relative five year survival rate does, unfortunately, uh, drop with the more advanced stage it's happening. All right. So the goal of surgery is, um, really to go to no gross residual tumor. So this definition has been changing throughout our, um, throughout the sort of decades. Um I would say in the nineties, it was that if you got a tumor down to less than two centimeters, and that means studying anywhere up to that size, that was considered optimal, then it was like, that's not good enough, it needs to be less than one centimeter. And now the actual real definition is complete tumor resection, meaning that there's no microscopic, I'm sorry, no gross residual disease. So that's really hard to achieve when I'm telling you a lot of these little nodules or implants are like five millimeters or even smaller to really go throughout the whole abdomen and pelvis and really try to find everything. But it's very key and important because you can see when they did compare these sort of differing definitions in the sort of peach line you with it where you have greater than a centimeter of disease, you can see your median overall survival is about 17 months and if you are in that middle category where it's less than one centimeter, it's improved to 32. But if you're really in that complete resection, you're at 56 months. So it makes a huge difference um for patients to have this maximum cy of reduction. And that's why it's so key that we talk about all these sort of debulking procedures that patients may need. Um because it can take a lot of different complex surgical procedures to get them to this complete uh resection. So based on this, we've been really trying to figure out how to predict who can actually even get an optimal resection cause we would like to minimize, you know, harm to patients. And so I put some pictures of CT scans on the right hand side and also like an intraoperative picture where you can sort of see this is the studying you see in ovarian cancer, a lot of these sort of white little um areas on the surface. So this is looking at the diaphragm, this is the liver below and you can see how it's just studded. It's not necessarily making a large mass, but these masses. Excuse me, the studying is throughout the abdomen and pelvis and trying to strip all of this takes a lot of um surgical time and effort. Luckily, we have other lasers and other things to help us besides quote, cutting it out only. But regardless, you can imagine that that's why these surgeries can take 67 hours at times. So we have looked at C A 125 to see if you have a higher C A one 45 level. Cause remember that usually the common cut off for AC A 125 is about 35. Um And so if you use 500 or something large, would that tell you that you could not have an optimal resection, then should we use that? And we found that uh it's actually uh has a false positive um prediction of about 22 to 31% of cases. So, really not very good in telling us what, how much disease is actually in sight to. Then we looked at imaging because of course, there's CT there's MRI dynamic MRI. Um And even though there's been still multiple different criteria proposed, different sort of um you know, protocols of how to actually section these type of uh cases, they really still have a very false, high, false positive um rate as well. So then we came to looking at maybe diagnostic surgery. And so we're gonna talk about how laparoscopy can actually help us to do a couple of things, one to assess receptivity, um which is really key uh for this as well as hopefully um empowering us to get better tissue samples so that we're able to go ahead and actually learn more about this disease. Um So, you know, when we take these laparoscopic biopsies they're much bigger than what we can get with, you know, CT guided biopsies. Um So we do get much more tissue, we're able to access the site more easily. So it is very helpful. Um There's also been looked at before um combining some of these factors like your C A 125 with AC T scan um to see if the combination would improve, um you know, the ability to optimally resect And all of this has struggled with external validation and uh reproducibility. Mhm. Um So then actually in Italy, they really developed something that we actually utilize here at wash U as well. It's called the foti score, the laparoscopic predictive index uh to help determine disease distribution. So they made it um a scoring system. So really trying to make it more validated as opposed to just oh this is what I think and hence, we're not gonna proceed. So they actually call it uh have a scoring system where they look at peritoneal carcinomatosis and look at that miliary pattern of distribution, which was like the picture I showed you before. It's miliary cause it's so small. Um versus is it Carma tosis just involving one section, like just the diaphragm and not studying on bilateral diaphragms or um all over the abdomen, they look at diaphragmatic disease. They also look at the mesentery, especially the root of the mesentery. Um And if you really talk with your uh radiographic uh colleagues, even though they really try their best to help us ascertain. If there's Mesenteric disease, it's really challenging for them. And you can see why cause these nodules are pretty small and sometimes it's all hidden because the, you know, I tell every patient the same thing that your CT is one snapshot in time. So if the mass is sort of covering things in that picture, you may not be able to see it. Additionally. if there's a lot of ascites, it's very hard to see through all that fluid, all of the small uh little areas. Additionally that we look at a mental disease, we look at um bowel infiltration, um stomach infiltration as well as is there any uh liver metastasis um that potentially um can be seen. So based on this, you get two points. Um So you either get zero or two depending on what it is and they actually did a triage system. So this was the first sort of look by these investigators in Italy to actually try to figure out what is the positive predictive value for having um a laparoscopic evaluation that would not allow you to have an optimal tumor reduction. Um And this was really cha sort of very game changing. It took a while to adopt here in the United States. But I will say, I definitely feel like we can try to give our patients the best opportunity um for us to make sure that we're not missing somebody who may benefit from as an upfront surgery. So you can see if you have, um, when you start having more than six points, then you have about 10% of the time and inappropriate surgical debulking. Um, so, you know, a lot of centers will use eight, as a cut off. Um, and because they did a secondary trial where they looked, um, to do this prospectively using this and if you look at the cut off that if you have greater than or equal to eight is where you sort of start getting into more, um, a potential for having, um, inappropriately uh explored patients. So it's really important that if it's in eight or 10 to make that decision, but if it's greater than 10 points, you really should go ahead and not, um, go put the patient through a large debulking. Um, because remember then what you're doing is delaying them from starting their chemotherapy. And why is this, you know, now looking backwards, this looks like, oh, we all should have been doing this all this time. But remember that we're surgical oncologist and when you think the sur that surgery is gonna win, you always wanna give patients the op opportunity to actually have surgery first. But then for we were able to do a prospective trials looking at um, neoadjuvant um, and surgery and upfront and seeing head to head, do they actually have equivalent outcomes? Um, because before there had been lots of retrospective data, but there had never been a prospective trial, randomizing patients to upfront to bulking versus neoadjuvant chemotherapy. Um And of course, as you can imagine, this disease is here in the United States treated by a lot of gyn oncologists. However, you know, in our community, we have lots of medical oncologists and even some OBGYNS and surgical oncologist um attempting or getting caught with ovarian cancer. So it's not always a disease that gets to AAA Center of Excellence. So it is nice to sort of have a trial to show that there's equivalent outcomes. Um If you actually do either upfront debulking surgery or neoadjuvant uh chemotherapy. So this was first time level three, I'm sorry, level one evidence um for us that we could really hang our hats on and say, oh, this is um still a very appropriate care. Having said that this is a, the trials that have been done to date are very, are all European trials. And the training for a GWN oncologist is very different than here in the United States where it's a separate fellowship. Um And so there is some concern still about maybe the maximal radical surgical interventions were not um done. But I think having said that it's still the best evidence we have to help reassure all of us that we're doing the best thing because really it is you need both. It's a matter of which sequence is important. Doctor Parker it looks like they're saying that the slides, it's still on the heterogeneous disease. Oh, no. Ok, Andrew. Do you have any suggestions for? Ok. Try to just move it that way. Ok. Sorry, I can't see. Can you not see your slides? No, I'm seeing because I do two things. I apologize. Ok. Ok. Sorry about that. All right. Ok. Here now we are and I can't see the chat, so I apologize. So they're the guidelines. Hopefully we can get the slides to people since I've been so off. Um because I came running, you send it to me. I can, I can forward them right after. OK. That's fine. I can do that. Um So really, we've done guidelines for neoadjuvant chemotherapy and advanced ovarian cancer. And this really um is mainly to help, especially our community colleagues um to, to really know that this is a joint decision making. So we really partner with a lot of our um community medical oncologists um to try to make the best decision and we appreciate that opportunity. Um So that patients can hear from both sides what their options are. Um And there really is. So if you are suspected to have an ovarian cancer, you know, and you think it's a high risk for perioperative morbidity cause we do look at sort of frailty of patients. Um You know, a lot of patients are frail because of the fact, like I said, they have had abdominal bloating they've had changes in, in their eating habits and so their albumin levels can be quite low, um, as well as their, their ability to sort of, um, walk and move because of the extra fluid or the fatigue. Um, so we do have to also take that into account cause it's not also disease distribution. But how are you going to sort of um, recover from a surgery as well? Cause we wanna minimize your risk of pe s and complications. So you can uh start your chemotherapy. So if we do think that you're either too frail, um and you need that time to, you know, it sounds sometimes contra intuitive that chemotherapy would make you have time to get your body better in shape. But with the shrinkage of the disease, hopefully you can um improve like your nutrition, your stamina in order that when you finally do get um your surgery after three or four cycles of neoadjuvant chemotherapy that you're in better physical shape. Um And also, as we mentioned, if there, if you have a laparoscopy and you don't think a cyto reduction is um uh gonna be likely to occur, um then, you know, to less than one centimeter of microscopic, then we really should go ahead and um also a advocate for new avant chemotherapy. Um So, systemic treatment strategies for epidural ovarian cancer, this is what a mental cake looks like. So this is the large intestine here. Um And so you can really get a graphic idea as to why this is, you know, sort of pounds of tumor in a sense hanging in, draping off your colon. And that's why you can imagine that you don't have the transit times in your intestines to allow things to go move through as well as that. You do have that pressure on your stomach that makes it very challenging um to eat and have a full, you know, nutritional status. Um So chemotherapy is really given um after surgery in order to improve uh survival for a while, we had been giving the chemotherapy intraperitoneally that has sort of been abandoned. Um But we are re looking at that and I have a slide a little later about looking at hich um giving being given sort of in the neoadjuvant setting at that interval, debulking. So giving sort of a heated uh intraperitoneal uh chemotherapy like they do for colon cancers, like appendiceal cancers or mucinous colon cancers um to see if we can actually still improve outcomes. Um So that's a stay tuned. We'll be participating in a clinical trial that's being done nationally to offer our patients hype. Um We're very encouraged by it because of how the distribution of the disease is that we do think that hopefully that could benefit patients um as well. So chemotherapy has sort of come, oh come an advanced. Um Now we're able to give our chemotherapy all as outpatients. Um you don't need to be hospitalized. And really the standard of care is what we consider carboplatin and paclitaxel. So a Taxane and a platinum agent. Um We were talking earlier, I caught the tail end of the last um presenter that you know about drug shortages. Unfortunately, some of you may have heard about the platinum shortages uh which definitely uh had affected us here at wash U but also nationally that there really was a shortage of carboplatin and CISplatin, which are really key backbone uh treatments that we utilize all the time for our patients. Um So I'm glad to say that that has resolved, but we did have to look for other sister agents like oxaliplatin to use um for patients. But it's a very hard to practice oncology, thinking of drug shortages just like it is to practice any part of medicine. Um But it definitely uh was eye opening to have to put that into our discussion as well. Cause I think patients were rightfully worried as we are too, that we could be compromising care since you know that these sister agents of Oxaliplatin had not been really utilized in the upfront setting for patients that we're hoping we could still cure. Um So it really was a hard time in um counseling and seeing patients. Um But what is really revolutionized? Um Ovarian cancer treatment is the whole concept of maintenance therapy. Um you know, maintenance therapy has been around forever in breast cancer that you finish your chemotherapy and then you go on to some type of maintenance uh therapy. And that actually had not really been the norm in ovarian cancer, but a lot of our patients now are really eligible for maintenance therapy, um which is great cause as I said, as I may not have mentioned, is that usually 90 to uh 95% of our patients will go into remission with a combination of chemotherapy and surgery. So we get a remission, but then we're always waiting for the other shoe to drop quote unquote. So if we can try to maintain their responses, hopefully we can also end up curing uh these patients. So one of the first trials to look at this was actually using um Avastin in combination with our chemotherapy of Taxol and carboplatin. So you we were using it, one arm was looking at just the single um of standard of care of Taxol carboplatin. The other was looking at Taxol carboplatin and Bevacizumab just during those six cycles of treatment. And then the other was looking at Taxol carboplatin and Bevacizumab followed by Bevacizumab maintenance. So, Bevacizumab uh maintenance is intravenously given every three weeks. Um It does have some side effects of, you know, hypertension proton nia um but overall manageable side effects. Um but we did learn in COVID, obviously, people did not wanna come to the med center. So intravenous is not always the best, but it definitely was our first trials looking at the use of maintenance. So there was no overall survival benefit with the use of um adding maintenance, bevacizumab. And this was given for about 15 months after the completion of your upfront chemotherapy um which takes about 4.5 months. Um So there were some subset analysis of who may have done better and those were the stage four patients. Um So Avastin gave us our first inkling about how we maybe should be offering maintenance therapy for patients. And this is probably where we made. The biggest uh difference is the solo one trial. So the solo one trial was looking at patients who had a BRCA mutation, the majority of patients on this trial. Um and there's about 400 patients who are on this trial um had a BRCA germline mutation and they were put on chemotherapy. I'm sorry, after they finished their chemotherapy, they were put on a P inhibitor which has made its way into breast and prostate and other cancers as well. But it all started really with ovarian cancer and they were put on a P inhibitor one pill twice a day uh for two years after the completion of their chemotherapy. And this was presented in 2018. And you can see on the left hand side, the progression free survival is, you know, a home run um that your hazard ratio is 0.3. So you decrease the risk of pro progression by 70%. I mean, when I show our fellows this, I'm like, this is like you could drive a Mack truck through the how the curve separate and stay separated. So it's really impressive that we're very optimistic that we're hopefully curing patients um based on the fact that they are able to stay on this treatment uh for very long periods of time and then show a sustained benefit. So this was also looked at by the blinded um independent Central Review. So it's not just based on investigators and then this was all updated uh most recently in 2022 with seven years of now follow up of these women. And you can see in the olaparib arm uh that the median overall survival still hasn't been reached. And that for the placebo, the patients um were at 75.2 months. So we really have made an impact in terms of curing patients um because about 44% of patients um in the placebo group did switch over to receiving a P inhibitor cause once this was thought to be such a breakthrough, you can imagine women obviously wanted to be on this. So there is a little bit of confound confounding of crossover um in the overall survival. But I hope by showing you the progression free survival, you can see those cars really separating apart and showing that we are impacting uh these women. So what happens if you don't have a germline uh mutation. Then we look at what we consider your hr D score, your homologous recombination score. And that is a talk in and of itself because there's lots of different uh companies that provide these scores um based on the tumor microenvironment. Um And then based on that score, we consider you to be somebody who is um homologous recombination deficient, which makes you more amenable to having benefit from a P inhibitor. But this trial, which is called the Paola trial looked at using a LA rib, the P inhibitor like we just saw in solo one, but adding a vast into it as well. And what you can see is they actually sort of subdivided our hr D groups of positivity to include patients who have tumor BRCA mutations. And tumor BRCA is actually thought to be up to 40% of actually, tumors have a BRCA BRCA ness or BRCA signature. So a substantial amount of patients, even if they don't have a germline mutation will have this somatic mutation that will make them more susceptible to the benefit of um parp inhibitors. So you can see that in the patients who got a parp inhibitor plus bevacizumab, that um the median progression free survival is 37.2 months versus if they got a placebo with a par, I'm sorry, with bevacizumab only, it was about 17.7 months. So a hazard ratio of 0.3. So very similar to the hazard ratio. Uh that I just showed you with a perp alone in a different sort of molecular signature. Then moving to the other side, if you take out the tumor BRCA mutated patients, which you would suspect would do better and just look at other um uh pathway abnormalities in the homologous recombination pathway. And they are still considered deficient. Like we talked about uh 51 C or having an abnormality in BR one. Then they do still derive benefit from the combination, but their benefit is a little bit less with the hazard ratio of 0.43. And then our real issue of trying to find a good maintenance therapy for patients is hr D negative. Those are patients that we really don't have good maintenance cause you can actually see these are almost overlapping curves. Um And that's where the majority of our patients do fall into at least 50 to 60%. Um So we really are working hard to try to figure out how can we impact these patients um more than we have to date. So this is also the updated OS subgroup analysis and you can see that um some of it does get affected by downstream fac factors such as what other treatments they've had. But in the BR commutate group, there still is a substantial hazard ratio of 0.6 and the HR D positive excluding BRCA mu, it's 0.71. And then uh for the HR D negative, there really is not a benefit that seen. So then a LA rib is not our only perp inhibitor. We also have something called Nora and this is the prima trial and this was actually a trial that is a nested cohort trial that looked at the BRCA mutated population, um looked at the BRCA wild type population, but we're still had an HR D signature and then sort of those really hard to treat. Like I just showed you the HR D true negatives, they have no signature. And what you can see is the mutated patients did similarly with the hazard ratio of 0.4 cause it's always nice to see confirmatory large phase three studies um confirming the results of other trials. And then looking at the BRCA wild type hr D positive, there's noted to be a hazard ratio 0.5 and then the negative really, the hazard ratio is significant with 0.68. But if you look at sort of the differential in terms of benefit for the patient, it's about 3.5 months or so. So not something that's as significant of getting like, you know, 18 months or 16 months like we do in the other categories. So it does tell us that we still have work to do there, but we're making incremental uh progress. Um So based on that, there's lots of ongoing trials, there's looking at immunotherapy as well. Um In combination with um I uh Carp inhibitors, which you can look at the Athena trial. So, trying to see if we can augment the immune system with the use of another part called rap with that would be beneficial. We've also looked at adding um PDL one inhibitors with a Vastin Bevacizumab along with a Laib. Um And there was significance with a progression free survival um in patients who received this triplet combination of Derval maab Bevacizumab and a lab. Um I can't say that it's been widely um taken up this because I didn't, I would argue that triplet um maintenance therapy sounds almost like real treatment uh for these patients. And on top of it, looking at cost effectiveness is we have to look at that as well. Um Parp inhibitors overall have been very well tolerated in the sense that they do cause fatigue. Um and you do have to monitor blood counts uh for them because they do have a lot of anemia thrombocytopenia. But the one thing that makes us uh a little wary is we always have to be on the lookout for myelodysplastic syndrome. The rate is about 1 to 1.2% of developing myelodysplastic syndrome. But anyone who's ever had a patient with M DS knows that it's a, a really tough uh disease. So patients are warned about this um as a really major side effect that could pop up. So we do talk about that um as well cause part of maintenance therapy should be having a good quality of life, which all these trials did show that the quality of life of patients are not impaired by using such long term maintenance of two years. And then the prima trial I did mention is three years of maintenance. So it's a long amount of time that you're asking patients to take these oral drugs, which of course we do for a breast cancer population, but it is a paradigm shift for ovarian cancer. And we're very fortunate to be able to see results from all the trials that we've done uh to date. Um And then we can look at there's been different ways to give chemotherapy, but that's not as exciting anymore with all these targeted uh therapies and then IP therapy, as I mentioned, um has gone away. Um But I think my main thing I wanted to sort of say is how do we follow up these women? Cause we get them through, they go into remission. And a lot of times we share survivorship plans um with primary care physicians and obgyns and internists. But really what are we doing? We're looking um to really see the patient every three months. Um Typically for the first two years with C A 120 fives, we really image mainly at least once a year, sometimes every six months, but we don't really do it every three months. Um because we do have data that just looking um for an elevated, I'm sorry, doing CT scans, doesn't end up detecting disease in a way meaningfully that we impact their survival. So it does cause obviously a lot of anxiety for patients. Um So we do try to empower them to listen to their body by us doing physical exams, doing the C A 125 which typically um has been elevated, especially when they've been just newly diagnosed, imaging them as needed. And then also focusing on, you know, learning the same symptoms that sort of they did not realize was the cause of their disease, but noting that that are high risk sort of factors that could cause their disease to return. Um So with that, I will end and take some questions. So if anybody has any questions, please feel free to put it in the Q and A or chat and, uh, you know, maybe sometimes questions come up down the road, feel free to go ahead and email those to me. Um I can always get those to Doctor Thacker or Laurie and we can, uh, get those answered for you. Well, thank you so much for your time. I really appreciate it. Thank you. Enjoy the rest of the afternoon. Ok. Thanks so much. Have a great day, Doctor Becker. All right. Thank you.
