Welcome, all. My name is Dr. Tom Krivak. I'm a gynecologic oncologist and division director at the Western Pennsylvania Hospital in Pittsburgh, Pennsylvania in the United States. I'll be the moderator for today's webinar, a refresher on selecting genetic testing for ovarian cancer treatment decisions. This is sponsored by GSK, and we thank them. This webinar will be discussing the practice guidelines, as well as choosing available tumor testing, as well as germline treatment options for our patients with advanced stage ovarian cancer. Now, it's my pleasure to welcome certified genetic counselor, Dr. Leah Stender. Leah, please introduce yourself. Good morning. Thank you, Tom. My name is Leah. I am a cancer genetic counselor at the Ohio State University's Comprehensive Cancer Center in the United States. I'm happy to be here. Wonderful. So, some housekeeping items before we get started. Again, we want to try to keep this on time, and again, this will be available on the 360 IGCS learning webinar portal. We encourage you to submit questions via the Q&A, and we'll try to address as many questions as possible during this webinar. So, let's go ahead and get started. My name is Dr. Tom Krivac. These are my disclosures. I do speak for GSK, AstraZeneca, Immunogen, CGenG, GenMab, as well. I do consulting, as well as our division does get research funding, as well. So, those are my disclosures. Next slide. And really, what do we want to do today? We want to talk about germline testing, and really, there's been some, you know, I've finished fellowship in 2002. We really made great strides in genetic testing, germline testing, as well as tumor testing to help patients, to help their families, as well as to help develop treatment guidelines. Let's talk about HRD today. Let's talk about what it means clinically, as well as translational, and try to give everybody a good understanding of some of the tests available, and how to use these tests, and when to use these tests. And again, how are we going to utilize this testing in patients with advanced stage up front ovarian cancer to help develop treatment paradigms? And again, review some clinical insight with respect to HRD testing, PARP inhibition use up front, as well as in the recurrent setting. So, to me, I think these are nice four objectives that are very clinically relevant for our patients who come in and present with pelvic masses and advanced stage, or have recurrent ovarian cancer. So, ovarian cancer, you can see these are the top cancers in the United States. It did not meet the top cancers for females in the United States. It has decreased. And in fact, this year, we actually have under 20,000. So, for 2024, ovarian cancer has decreased to under 20,000. And to me, I think that that's tremendously important. Why? Probably utilization of genetic testing, panel testing, risk-reducing surgery. I think that has definitely helped, as well as potential increased use in OCPs. And again, what's the disappointing thing about this slide is we can see ovarian cancer is 4% of deaths, 12,740. What we can see is corpus cancer is now increased to over 13,000. So, I think in 2024, it's the first year that we've seen some changes in the number one cancer-related deaths from women with gynecologic cancer. So, I think that this is a good sign for women that we're decreasing the incidence, and we've gone under 20,000. We are slowly bringing down the death rate. However, it's still too high, 19,750 cases, roughly 12,750 deaths. And again, kind of highlights, not part of this webinar, but we still have a workout when we're caring for women in that endometrial cancer deaths are on the rise. Next slide. When we think about management of advanced ovarian cancer patients, again, a lot of us, myself, when I trained in 2002, it was primary debulking surgery followed by chemotherapy. There was no maintenance. Now we're looking at different tumor testing. We're looking at, are we going to utilize Bevacizumab? We're looking at clinical factors, as well as now we're looking at genetic factors. And I think what highlights this is, again, when we look at how we're going to do our maintenance strategy, you can see maintenance therapy can be based upon wild type or germline mutations or somatic mutations, BRCA1 and BRCA2. And that's kind of defined in here, as well as you can see homologous recombination, proficient or deficiency. So we're not just looking at what are the clinical factors. We're now looking at clinical factors. We're looking at molecular factors as well. So to me, I think this is a huge step forward for our patients. Again, you know, moving beyond carboplatin and paclitaxel, moving beyond carboplatin and paclitaxel, avastin, and trying to identify which patients are going to drive the most benefit from genetic testing, which patients are going to drive the most benefit from utilizing that genetic testing to come up with their maintenance therapy. So I think this slide kind of summarizes what's important clinically for our patients. The previous slide highlights what's important clinically for our patients, as well as their families in that we can identify patients with germline mutations and then utilize risk-reducing surgeries. And if we're fortunate, those patients who have germline mutations and have cancer, we're going to be able to utilize that information to try to help develop that personalized treatment plan. And again, with ongoing research studies, we're looking at how we're going to move these molecular medicines and targeted therapies into the frontline setting. So this slide, I think, kind of sets the stage of the importance of germline, as well as HRD testing. One very important study, again, going from carboplatin and paclitaxel, possibly carboplatin and paclitaxel bevacizumab, and looking at a targeted base therapy. You can see it was a study that basically looked at patients who had a germline, as well as somatic mutation. And we look at how this study was conducted. It wasn't an all-comers, high-grade serous histology, high-grade endometrial histology, two-to-one randomization, and having a deleterious tumor or germline mutation, randomized to a lap rib versus placebo. And again, if we go on to the next slide, we can see additional studies looking at PRIMA, upfront maintenance therapy, not looking not only at BRCA1, BRCA2 germline mutations, but looking at HRD. So again, looking at how we're going to go from germline to HRD testing, and how we're going to go ahead and utilize and see if these patients benefit from maintenance therapy. Again, moving on to biomarker-directed therapy, trying to increase the number of patients who could derive benefit from maintenance therapy with targeted therapy, such as a PARP inhibitor. Next slide. And this slide here highlighting another study looking at HRD, and not looking at only placebo as the control, utilize bevacizumab as the control. These patients were stratified by tumor mutation, so that would include germline and somatic. And then again, went back and retrospectively analyzed subgroups utilizing HRD testing. So again, looking at how we may go from utilizing maintenance therapy as single-agent PARP inhibition, whether it's a lap rib or a rap rib, for upfront BRCA mutations, upfront patients with HRD, and then another study looking at utilization of PARP inhibition with bevacizumab, and then comparing to bevacizumab maintenance. So again, these last three slides highlighting how we can go ahead and develop a treatment plan, looking at the different studies, and we'll go over some of these results later, on how we may develop an algorithm of how we want to treat our patients in the upfront setting. Next slide. When we think about HRD and we think about BRCA, again, this paper is probably 12, 13 years old at the time, but what it showed is the patients who have BRCA mutations, high response rates, longer PFS, high response rates when they recur, and those repetitive exposures to platinum. So really, when we think about BRCA, we think about these patients respond well, have good duration. They do have genetic alterations that help them respond to that. And again, when we think about BRCNS, then we went ahead and moved along to HRD testing. What are the other factors that may help these patients be susceptible to PARP inhibition? Have their tumors be susceptible to carboplatinum-based types of therapies? So again, I think as we looked at this phenomenon, now we've really brought it front line. And again, this is why I firmly believe in maintenance therapy for upfront patients. I firmly believe in genetic testing as well as tumor testing. And again, let's send it on over to Dr. Stenter so she can go ahead and talk about testing. Thank you. So these are my disclosures. I am a speaker for AstraZeneca and have done consulting and advising for the other companies listed here. So of course, we want to make sure that we're following the published guidelines and recommendations. But sometimes they're a little hard to discern because there are pieces and parts of genetic testing recommendations and multiple NCCN guidelines. And those are the ones that we rely on most heavily. But in the high-risk familial guideline, they do address the fact that all patients diagnosed with epithelial ovarian cancers, and of course, that includes those of the fallopian tube and peritoneum as well, should receive germline testing. And while BRCA1 and 2 are the most common causes of hereditary ovarian cancer, they're not the only ones. And so the guidelines now state that these genes listed here that include ATM, BRP1, PALB2, RAD51C and D, as well as the mismatch repair genes, should be considered in your germline testing approach. Most of these, with the exception of the mismatch repair genes, work alongside BRCA1 and 2 in the same molecular pathway. In the ovarian cancer treatment guidelines, which were referenced earlier, it expands beyond germline testing recommendations to give us some guidance around the somatic testing approach for patients with ovarian cancer. Of course, this also includes BRCA1 and 2, but taking a broader approach is usually recommended in this case as well. Of course, we want to assess for HRD, which we'll discuss in more detail, but then there's utility to looking at microsatellite instability, tumor mutation burden, and other factors as well. So I mentioned that BRCA1 and 2 are still known to be the most important players in the hereditary ovarian cancer space, but we do have a broader definition for hereditary predisposition, and much of this work was guided by Dr. Norquist's group. And there were some earlier papers, but this one sort of is what established the fact that 20% to 25% of patients with ovarian cancer are going to have an actionable or otherwise important germline mutation in one of these genes that could really impact not only their treatment decisions going forward, but also the anticipatory guidance we can provide them around other hereditary cancer risks and inform their family members as well. Here are the most commonly identified genes where we identify mutations in patients with ovarian cancer. And it's just important to sort of think about them in the context of the risk that they contribute. So again, BRCA1 and 2 contribute the highest level of risk for patients, but these other genes also significantly increase risk, just not to the same degree. So if you have the opportunity to cascade test in a family where you've identified a mutation in an ovarian cancer patient, you can intervene with family members and potentially lower that ovarian cancer risk, which is really what we're all trying to do anyway. So homologous recombination deficiency is essentially what has become one of the most important things, of course, for ovarian cancer patients. But HRD can be caused by multiple mechanisms. So of course, if you have a germline variant in BRCA1 or 2, that seems to lead to HRD. We're starting to understand more the role of a germline mutation in some of those other genes that work in the HRD pathway, but we're not entirely clear whether or not those other genes contribute in the same way. A somatic variant in BRCA1 or 2 or one of these other genes can also lead to HRD. But then this idea of genomic instability, which is measured differently by different laboratories and laboratory products, but loss of heterozygosity, large state transitions, and allelic imbalance are also biomarkers of HRD. This is not an all-inclusive picture here, but I think the reason why I like to present it in this way is that when we're thinking about looking at HRD and the trials, each different trial used a different product for measuring HRD. And so not to go into the weeds here, but when you're sort of comparing them across, you can see that there are subtle differences, even when using the same test, about the cutoffs for LOH, for instance, or the HRD score. So it's just important to sort of keep in mind when treatment decisions are being made reflecting back on what was used in the clinical trial. So assessing for HRD and BRCA mutations and others has potential for major impact. This is a very simplistic view, but essentially half of your patients with ovarian cancer are going to have meaningful results, either a germline mutation or a somatic mutation in BRCA, or perhaps their genetic testing is normal, but they still demonstrate HRD. And so that means that their potential for decision-making and outcomes are going to be quite different. So from a practical standpoint, what are we going to do? Somatic, germline testing, both, ideally both of these tests would be feasible for all ovarian cancer patients. But it is really difficult to have a standardized approach. And some of the reason behind that difficulty is deciding timing. So are you going to do these tests together at diagnosis, or are you staggering and doing one test or the other at diagnosis and another at recurrence? Do you have archival tissue to use? I think sometimes patients don't necessarily have a pretreatment biopsy specimen, so do you need to acquire a new one? And the guidelines are now, they do recommend consideration of circulating tumor DNA, which is a brand new frontier if no tissue is available. We also have a bit of a burden around the idea that there's no single comprehensive testing option where you're sort of have one test and you're checking all of the boxes. So it can be logistically difficult for your care teams. The billing and reimbursement rules are very tricky. In the United States, there are lots of different programs where people can apply for financial assistance, but not every insurance company covers testing in the same way. So you sort of have to have some understanding of that. And the laboratories vary, both in the assays that they provide and the reporting practices. So it's very difficult to sort of streamline all of that. But if we think about timing, this is from a recent paper that actually was just published in the last month or so, where we review different approaches to testing in this patient population. But essentially, at the time of diagnosis, germline testing should be offered. And there are two major branch points that you could take at that point. So you could either also do somatic testing at the time of the germline testing, or somatic testing at the time of diagnosis for patients who test negative. So you're either doing them concurrently or waiting to see that germline test result and then ordering somatic testing at that time. And then some practices hold on doing somatic testing until the time of recurrence, although I think that's becoming a little less common. And, you know, I don't know that there's an exact right or wrong answer to that question of when the tests need to be completed, except that what I've circled here in red, this should be your sort of deadline. So a lot of these decisions are happening post-primary treatment. So sometime in that early period, ideally is when you would have those test results for making next step decisions. There's a ton of variability in germline panel testing options. I've just listed some of the companies here. This is not exhaustive. You know, the list price is different for each of these. And of course, if you're dealing with insurance reimbursement, the cost is gonna be even more variable. But the number of genes included, you can range anywhere from two to roughly 100 genes with everything in between. Some of the laboratories allow you to sort of pick and choose which genes you're gonna include on the panel. But again, they should at minimum include those HRD related genes, but you may even choose a germline panel that's telling you about completely different hereditary predisposition syndromes. And we know that sometimes we're surprised. So we may be very surprised if a person with ovarian cancer turns out to have a mutation in a gene that is usually associated with colon cancer, but that could be equally important information to know. We usually have our results back in about two or three weeks. There are differences, you know, we can use saliva or blood in doing this kind of testing. And the need to have testing sooner than two or three weeks does sometimes arise. And we, you know, can rush testing on some of the results, but usually not all of them. So with all of these options, how do you choose? And, you know, we are lucky that we have a lot of really good options to choose from, but the things that we need to pay the most attention to are that the testing should be performed in a CAP and CLIA certified lab, if done in the United States or the non-US equivalent. You know, there are standard recommendations for variant interpretation, and that's really important because labs can't really be making this up as they go. We want some standard across laboratories for interpreting a variant of uncertain significance for example, from a pathogenic variant. And then of course, we want to make sure that they're including that minimum list of genes. Certainly more could be included, but we wouldn't want fewer. You know, there are reasons where you may want to access a genetic counselor specifically when interpreting these results. You know, variants of uncertain significance can be complicated. We are seeing more possible mosaic results being reported with better technology. So sometimes that represents clonal hematopoiesis of indeterminate potential, and that can have implications going forward too. But beyond, you know, these sort of basic analytic details where we want to set a standard, we want to make sure that the laboratories that we're using are limiting financial toxicities for patients, so do they have an assistance program for those that don't have full coverage? And are they detecting all of the kinds of variants that we may find, including large deletions and rearrangements? That's usually the differential. So I mentioned variants of uncertain significance. Depending on the size of the panel, the rate of receiving these sort of inconclusive results varies. But for ovarian cancer patients, it's close, it's, you know, 8% to 28%. But if you're doing a very large panel, that number can go up significantly to almost 50%. Most of these eventually are downgraded, meaning they're reported as uncertain significance, but over time they're reclassified as being benign or likely benign. So thinking about how your practice is going to manage that communication, you know, is this information that you will receive and then pass on to the patient, or will you only contact them if it's an upgrade, meaning it goes from uncertain to pathogenic? It's really important that when we receive these results, we manage the patient and their family's risk based on the family history and not the VUS, unless it's proven to be pathogenic. We do sometimes use this publicly available database. This one is ClinVar. There are other similar databases. And, you know, I still think you manage based on what the report shows, but it is helpful sometimes to look the variants up in ClinVar just for perspective of whether or not other laboratories would interpret that variant differently. And it's really important to keep in mind that the classification systems are not exactly the same between somatic labs and germline labs. So you may have variation in a somatic report reported as pathogenic, let's say, but the germline laboratories would call that a variant of uncertain significance. So you just really sort of have to be critical when reviewing those reports and using them accordingly. There's variation in tumor testing options too. Again, this is not an exhaustive list. There are additional details in this recently published SGO statement. So that would be a great resource in addition to today's discussion. But again, you can see the difference in number of genes, the types of variations that they can identify, some of the other molecular markers that might be important as you're thinking about treatment decisions are offered, some are not. So really just taking a look at what options are available to you, comparing them against each other, and then making a decision forward. And I think we can skip this one. Back to you, Tom. Thank you so much. I'm just answering a question here real quick. I like how they're coming over the chat here. It's like, would you test the primary or the metastatic tumor? I would say I would test what's the easiest accessible tumor, whether it's a CT guided biopsy, or if you have done a primary debulking, I would probably most likely send the metastatic disease to be assessed for somatic mutations. I do agree that it can affect what we see. I mean, tumors are heterogeneous, and so we're always gonna have that heterogeneity when we look at different portions of the tumor. So we have about 15 minutes, and I wanted to try to get through a case here real quick. 64 year young patient who presents with basically signs and symptoms consistent with high grade ovarian cancer, and she undergoes a CT guided biopsy. Next slide. And so she gets referred to GYN oncology. She gets panel testing, gets treated with carboplatin and paclitaxel, undergoes interval debulking after three cycles of chemotherapy, has an excellent response. She needs a THBSO, rectosigmoid-collecting omatectomy, and she has no gross residual disease, and additional tumor was sent for tumor testing. Next slide. She recovers from her surgery. She gets three additional cycles of chemotherapy. She has no BRCA mutation tumor in the tumor, so germline and somatic negative, but she does have a GIS score over 42, and she's HRD positive. So she goes through neoadjuvant chemotherapy, interval debulking, no gross residual, was on carboplatin and paclitaxel. What are her options at this time? Next slide. So this patient doesn't necessarily fall into SOLON1, but I come back to SOLON1. I think all of us on this call are very familiar with this data, but I think it's important to show what we're starting to see with these maintenance strategies. Let's go to the next line. And what I think is important when we're looking at some of our maintenance strategies, we're seeing a significant improvement in PFS, but let's go on to the next slide. Next slide. We're starting to see overall survival benefit. So BRCA mutations, overall survival benefit, statistically significant. BRCA mutations. Let's go on to the next slide. And again, what else are we gonna do? We're looking for tumor testing. So if they're BRCA negative, let's test the tumor. And this patient was homologous recombination deficient, genomic instability score of greater than 42. So again, how I look at utilizing maintenance therapy, I look at BRCA mutations, HRD, HRD test negative, HRD test positive to help formulate how I may wanna go ahead and utilize maintenance therapy in the upfront setting. And again, I think everybody's gonna do this differently, and that's how you're gonna base upon how you wanna develop your testing paradigm. I personally believe that everyone with advanced stage ovarian cancer should read some form of maintenance therapy, whether it's single agent Naraparib, whether it's combination PARP with Bevacizumab, single agent Bevacizumab. To me, I think all women should be recommended or offered some form of maintenance therapy. And that's just based off myself training 20, 25 years ago and knowing the second look data being positive for a high percentage of patients who are considered to be in remission. Next slide. So what are the HRD tests available? And again, Leah, you did a great job. And I think what this slide kinda highlights is you talked about Foundation One and Marriott. Again, those are the two FDA approved, but you can see folks will utilize Keras, Tempest. And again, we saw how that Foundation was kinda set based off the aerial data, how they move the LOH score. And Marriott was set by looking at the three parameters, trying to get that HRD similar to BRCA phenotype. And then they went back and looked clinically at how they're going to develop that score. And again, I'm sure the company has messed with looking at scores of 40, 38 and things of that. But the cutoff of 42 generally captures about 95% of the patients who have a BRCA mutation. Next slide. And again, there's in-house kits. I think at West Penn Wormat in the States, we're thinking about trying to team up with Illumina so we can go ahead and do this in-house. And again, I think this was developed along with Marriott, but you can see there's other additional assays that can be done in-house. So if you're a pathologist and you're genetic testing folks, we're gonna bring it in-house. Or you can see we have at least four clinical cases that you can send out each testing, as well as you can get next-generation sequencing with these additional, with these other tests. Next slide. So looking, coming back to why is this important? Are we getting a test just to know? Are we getting a test to try to make some treatment decision points? And again, Prima upfront study, we all know this looking at advanced stage of brain cancer, stage three, stage four, it was at all comers. They wanted to go back and look at HRD and looking at the different subgroups. You can see it was a two-to-one randomization of Naraparin versus placebo, progression-free survival by Bikker, overall survival, and hopefully we'll start to see some overall survival reports here soon at the upcoming meetings. And you can see how they kind of stratified the weight and platelet-based dosing for this group. Next slide. And again, tumor HRD testing was important. So looking at the overall population, you can see that patients who were treated with single-agent Naraparib derived benefits. So not looking at biomarkers, but looking at the patients all comers enrolled, because that's what the study did. All patients benefit from maintenance therapy. And again, or at least the all comers did. And again, this is why I've always kind of firmly believed in maintenance therapy. Next slide. And looking at the HRD deficient. So again, the patients who have a BRCA mutation, germline, somatic, or BRCA wild type, but have an HRD test, and this was the genomic instability score greater than 42, you can see derived the most benefit. Then improvement of progression-free survival of roughly 11 to 12 months, hazard ratio of 0.43. So if you're taking Naraparib, you have an HR deficient tumor, whether it's a germline mutation, a somatic mutation, or genomic instability score of greater than 42, you derived significant benefit, 57% decreased risk of recurrence, as well as an improvement in PFS by 12 months. And so to me, I think, again, looking at how we would utilize this information and how the clinicians are gonna develop their maintenance strategy. Again, to me, I think HR deficient, very, very important to kind of set point as to how we're gonna treat these patients with respect to maintenance therapy. Next slide. Again, there's the hazard ratio and PFS. Excellent. And again, looking at how can we say, well, HR deficient is being driven by the BRCA mutations, but you can see here in the subgroups of HR deficient with BRCA wild type, you can see the hazard ratio is 0.5. So again, you're still seeing an improvement in progression-free survival. You're still seeing a difference in the hazard ratio, 50% decrease in risk of recurrence in the patients who are BRCA wild type, but genomic instability score greater than 20, or an LOH greater than 14 or 16, depending upon what type you're gonna do. And again, you can, as well as in the HR test deficient or HRD test negative or HR proficient, you still did derive benefit, but not as great as a benefit as you saw in the HRD test. So to me, I think as we think about how we're gonna utilize these medications, how we're gonna utilize the combination of these medications to me, this is why testing is important, germline testing is important, tumor testing is important of how we're gonna kind of not just look at our patients with respect to medications and delivery medications, but it's predictive and prognostic for these folks. Next slide. And again, looking at PALA, PALA was a two-in-one randomization, Bevacizumab versus Bevacizumab plus Olaparib, stratified by BRCA mutation status, but also went back and retrospectively analyzed the HRD test. If we could go on to the next slide. And again, stratified by BRCA mutation. Next slide. Looking at HRD test positive, excluding tumor BRCA, you can see again here, these patients, HRD positive with BRCA, HRD positive without BRCA, these patients derive benefit. You can see a HAZ ratio of 0.43 in the HRD test positive group. And again, there was no benefit with respect to addition of Olaparib with Bevacizumab in the HRD test negative or HR proficient. So this is important because again, these trials are showing very similar results with germline HRD test positive or HRD test, the deficient patients. And again, trying to show that there's select groups that we need to use PARP or combinations of PARP to help improve their benefit with PFS. If we can go to the next slide. Next slide. Next slide. There was an overall survival benefit. There was an overall survival benefit in SOLO and there was an overall survival benefit in PALA. And so what we need is we need those overall survival results for PREMA. So to me, I think when we say, why aren't we using these medications? Sometimes we hear the argument that we may not be seeing a true benefit. Should we use it later lines of therapy? I think that when you're starting to see PFS1, PFS2, an overall survival benefit in these groups. And again, we need to see the PREMA data and hopefully we'll be seeing that soon. To me, this is very exciting that we're starting to see a trigger with respect to these patients having an overall survival improvement, utilizing maintenance therapy in a very directed way. Okay, next slide. So let's take another look at another patient. I think that with PARP inhibition and everything, there's been some changes with respect to recurrent ovarian cancer. Patient who's 54 years young, has high-grade serous cancer, diagnosed age 46. She gets treated with upfront debulking surgery. She has a high-grade serous ovarian cancer and a right over-floating tube, as well as metastases to the pelvic peritoneum. She had a THBSO resection of pelvic mass and pelvic peritoneum. She had lymph nodes removed, as well as biopsies of the upper abdomen, omentectomy. So basically a thorough staging procedure. Next slide. Again, she was treated with six cycles of chemotherapy. She did not want streamline testing, no tumor testing was sent. She basically wanted to be treated to get her chemotherapy and move on. She was NED for eight years, and then she had pelvic pain, had blood in the stools, and was noted having elevated CLN25. Next slide. She has a CT scan showing a complex pelvic mass, no ascites, no upper abdominal disease. She undergoes exploratory laparotomy, tumor debulking, refractive sigmoid colectomy. She does have a small nodule in the upper abdomen in the residual omentum. At this point, she does undergo germline testing and tumor testing for HRD as well, and she was found to have a BRC2 mutation. Next slide. So in the recurrent setting, we've had the dear doctor letters. And again, what I wanted to highlight is platinum-sensitive disease. Unfortunately, this patient offered genetic testing, did not want to go it. Some patients, I think it's pretty rare. I'd love to hear what Leah has to say if she gets a lot of counseling and then they don't want the genetic testing. But to me, we are gonna run into some of these patients that had surgery, may have not undergone testing, tumor testing, or germline testing, and then they're found to have a genetic abnormality. Again, looking at the utility of PARPs in these patients, there's been a number of dear doctor letters that we looked at how we were gonna use PARP in the recurrent setting. But again, looking at where the NCCN guidelines and the FDA labels, we're looking at utilization of PARP maintenance in this patient due to the fact she didn't have PARP maintenance, she has recurrent disease, and she has a BRC2 mutation. And again, the NCCN guidelines highlight this. And again, we as clinicians may go by the incidence and guidelines in the FDA label. We as clinicians may utilize these medications a little more liberally. Next slide. So again, the patient's treated chemotherapy. She's then placed on PARP maintenance, cascade treatment for family members. And again, really for these patients, who should be getting PARP? Which patients? BRCA1, BRCA2 mutations, HRD patients, all comers, and what's the length of therapy? You know, a lot of these studies, again, utilized PARP until progression. And again, PARP plus Bevacizumab, whether it's Olaparib, Naraparib, combinations of these medications. Again, we had the Mediolo study. We had numerous trials looking at combinations of these medications. Next slide. And again, so go ahead, next slide. So what we can see in the NOVA trial, which was really, really important in my mind, is this is a recurrent ovarian cancer trial, platinum sensitive, BRCA mutations, BRCA wild type, HRD. And we looked at utilization in Naraparib, and we got, you know, benefit across all boards. And so across all treatment groups, whether it's HRD test negative or HR proficient. And again, the FDA gave approval originally for these patients. However, if we can go to the next slide. The FDA has made some modifications, again, in looking at germline versus non-germline. And you can see here the follow-up data. And again, there's many issues with this. There's many issues, non-analytic endpoints, patients lost to follow-up crossover. The bottom line is that we still saw a benefit in the patients who had germline mutations, and the patients who did not have germline mutations, we did not see that benefit anymore. So there's been a change, and you can see where the FDA had pulled back some of these guidelines with respect to PARP utilization and the maintenance treatment. And again, I think that that's very important as we show the upfront data, the PRIMA data showing tremendous benefit, SOLA and PALA, and again, starting to see overall survival that really should focus our shift to upfront testing and upfront treatment. Next slide. And again, I think, you know, talking about recurrent ovarian cancer and utilization of PARP, study 19, I think, was a randomized phase two trial that really kind of highlighted, I appreciate the authors, how they took all comers high grade, serious high grade, endometrial. Go ahead and next slide. And it showed a benefit across these patients, whether they had germline mutations, HRD, and this led to the approval of all comers. However, that's been modified through AstraZeneca as well. So again, I think when we think about recurrent ovarian cancer we think about patients who have a BRCA mutations who may have not received upfront PARP maintenance, you know, PARP after PARP's been investigated, not FDA labeled, but we look at, there was a benefit for these patients in the recurrent setting. And again, when we think about norepirib, it really brought the all comers in the recurrent setting. Olaparib was utilized to treat patients, you know, with the Kaufman data upfront. So these medications went through the development and where we're at right now is it really, it seems like the greatest benefit is gonna be derived upfront with looking at the BRCA mutated patients, the HRD patients as well. Let's go ahead onto the next slide. And so really, you know, to me, the utility of germline testing, just like, you know, Leah chime in here at any time. I mean, it's really, really important. I think we opened up by showing some of the epidemiology and the fact that I think three or four years ago we were still in the 21,500, 22,000 cases of ovarian cancer. Now we're under 20,000. So that panel testing, that risk reducing testing, risk reducing surgery, operatism to stop inject me being performed, I think has really helped decrease the number of patients we're seeing with ovarian cancer. And again, my personal opinion is, again, I think the panel test adds additional information. Again, germline testing, who's gonna benefit from PARP therapy upfront. You know, my algorithm generally is patients who have a BRC mutation, they're gonna get a single agent therapy, whether it's an Arab rib, whether it's elaborate, but they're gonna get a single agent therapy upfront. If they're HRD positive, tumor test positive, combination, either PARP with Bevacizumab, again, you can use single agent and Arab rib and there's data with an Arab rib with Avast and the ovary trial. So again, we can use that. And again, looking at germline testing, it may identify patients in the recurrent setting who weren't treated upfront. HRD testing, HRD testing is gonna expand that. You know, we saw that, you know, 15 to 20% of patients are gonna have a germline mutation, 5 to 10% are gonna have a somatic mutation, an additional, you know, 20 to 30% of patients may be detected having some type of HRD test positive, whether it's an LOH test with foundation, whether it's a Karest test or whether it's a Marriott test utilizing LOH, large-scale state transitions and telolytic imbalance. And again, you may utilize single agent PARP or combination PARP with anti-angiogenic therapy. Next slide. And again, looking at PARP therapy upfront, BRCA germline somatic mutations, HRD test positive, it's gonna help delineate our therapy, recurrent ovarian cancer, maintenance therapy. I don't know what others are doing, but I also think that, you know, plant sensitivity is important as is HRD positive, with plant sensitivity. And they need maintenance therapy because I personally leave a maintenance therapy upfront as well as in the recurrent setting. So, you know, I may not go with a label, I may go against the FDA guidelines or at least talk with my patient about that, trying to utilize a maintenance therapy in that setting. And then again, I think germline and HRD test gives predictive and prognostic information for our patients, maintenance therapy, cascade testing with risk-reducing surgery. So to me, I think that those are all very, very important. Next slide. Well, I think that's all we have today. I kind of skimmed through those slides really quick. I think myself and Dr. Stenter, we got through about 68, 69 slides today. I wanna thank everybody for being on the webinar. Lee, I thank you for your time and insight and expertise. I thank GSK for supporting this webinar as well as the IGCS in doing these webinars for education. Most of all, I thank all the participants for your great care that you give the patients and for listening today. And again, this can be reviewed on the IGCS Education 360 web portal by the end of the week. If there's any additional questions, I had that question about somatic testing. Should we test the tumor or should we test the primary tumor? I think there's another question coming in over here. After two or three years apart maintenance, if any, when do you stop? How do you patients react when you do that decision? I think that's a great question in that you're looking at ML and there's certain subgroups in looking at two to three years upfront. And then obviously the GOG energy study that's being thought about, about de-escalation of PARP upfront. I would say if somebody's NAD for two to three years, I would probably use right around two years and stop them in the recurrent setting. In the upfront setting, two to three years as well, if they're doing well and they have no side effects and they wanna stay on for a third year, there'll be a kind of a shared decision-making and allow them to stay on for the third year. Some patients are very nervous about coming off. They're very smart. I think all of us that meet with these patients know they follow their CM125 very carefully. They're bright. They know that the cancer is a virulent cancer and wants to recur. So some people are eager to come off because they don't want the side effects. Some people don't wanna come off. And to me, I think that comes into the counseling. It was easy when we had patients on ovaria or we had them on the clinical trials because you gotta come off at this time. I think in clinical practice, I have a lot of patients who are like, we know this disease is bad. And to me, I think it's tough, but some patients don't wanna come off. Some patients do have some of the side effects, the fatigue, the nausea, and they do wanna do that. It looks like there's another question for you. NCCN recommends considering PARP inhibitors for stage two plus, but major prospective trials included only stage three, four. Can you elaborate on the use in stage two patients? Do you have enough data to do this routinely? I don't think we have enough data. That's a great question. We kind of lumped stage two through four. We used to do stage one, stage two, stage three, stage four. I like that the NCCN gave us that latitude that if somebody has a BRCA mutation and an HRD that you can use them in the upfront setting because patients with stage two disease still have a high risk of recurrence. I usually quote right around a 30 to 40% risk of recurrence. So if somebody is HRD positive or it definitely has a BRCA mutation, I will discuss it with them. I think it's completely reasonable since it's on the NCCN guidelines. But if the patients do not wanna come on, then I think that's fine. But do I recommend it for the patient who has a stage two BRCA1 mutated cancer? Yes, I would do that. So going back to that recurrent ovarian cancer, that was a stage two. If I would have known that, I probably would have said, do you wanna go on single agent therapy for two to three years? There's no data. However, we kind of consider stage two as an advanced stage and say that we're extrapolating that information. But it's always a risk benefit. You always have to worry about MDS-AML. MDS-AML is about 1.5% in that upfront setting. And unfortunately, it seems like when patients develop MDS-AML, that is a lethal side effect. So I think it's a difficult question to answer. I think it's a great question. It's gonna be individualized. But I would review with the patients, we should consider this. If they were HRD test, negative, or homologous reprimandation proficient, I don't think I would. I would just give them chemotherapy. Those are really good. Two really, three really good questions from the group. Leah, do you have any insight or any final comments? I really appreciate your talk was outstanding. Any thoughts on why patients may not get tested like in the case? Yeah, you mentioned that in that case example, the patient declined testing initially. And I would just say that it's pretty uncommon. I think most patients are very much in favor of doing testing, but not all of them are. And I always encourage my colleagues to revisit the discussion. Sometimes it's information overload. It just wasn't the right day to bring up testing, but it's usually based in some sort of misunderstanding or lack of information, the reason why they may be against it. So I think with appropriate counseling and conversation, most patients see the utility of it. Wonderful. Well, it was great working with you on this webinar. It's great to see how many people signed in this morning. I hope this gets everybody's week off to a great start. I think we're all done here. And again, I thank everybody for being on. I thank GSK for sponsoring this. And again, thank everybody for participating in these clinical trials. It's really changed the standard of care over these last few years and improve the care for our patients with gynecologic malignancies. So thanks so much. Thank you.

genetic testing

ovarian cancer

treatment decisions

HRD testing

maintenance therapy

PARP inhibitors

germline BRCA mutations

recurrent setting