We are very happy to welcome you to the master session dedicated to variant cancer. I'm Christina Fotopoulou from London. I'm a professor of Planning College and Imperial College. And I'm very honored. It's a great pleasure to be chairing this session with Dr. Angela Salvares and Dr. Claire Scott. You all know that this master sessions are always the most popular during our meeting. And the goal is practically to hear from leading key opinion leaders from all over the world. And we have today speakers from all over the world, really, from all continents, from many countries, so that they share with you their experience, their knowledge, discuss. You will be able and have the opportunity to present some questions and to submit these questions so that we can all discuss them together. There is a Q&A segment. So please, please take advantage of that and submit your questions. I'm very happy now to invite my co-chairs to join and to introduce themselves. Good morning. It's so exciting to be here with you, Christina and Claire. We're really excited about the master session in ovarian cancer. Our segment or the segment I'm doing will be about moving over chemotherapy. But we have a little bit of something for everyone. And it's a great pleasure to also be joining you. My name is Claire Scott and I'm from Melbourne, Australia. I will be chairing the part of the master session that deals with prognostic and predictive biomarkers. You'll hear more about that later, but it's an incredibly exciting time with one of the most exciting examples in ovarian cancer being that of PARP inhibitors. We have a lot to cover in terms of biomarkers and relating to PARP inhibitor therapy. So it's a great opportunity to be here and join you all today. Thank you. That's excellent. Thank you very, very much. So the first part of the session will be about surgery. What else? Surgery. Yeah, surgery will always remain a hot topic. And we will always try to catch up with the systemic advances that currently are happening in ovarian cancer. So we're just running behind currently. And it's very important that we discuss not just the advances in surgery, but also the challenges. Before I invite our first speaker, we have prepared a question for you. So we are very, very interested to see how your views are, how you would challenge a patient with primary ovarian cancer. How would you allocate her to which pathway? And we have a poll for that. So please go to the poll. And the question is, what factors would influence your decision making process to stratify a patient? Two-day adjuvant chemotherapy versus primary surgery. I know it's a very cliche question, but still, it's a question where the answers change every year according to new knowledge. So it's very interesting to see how our audience from all over the world would answer that. The first is the patient's performance status and nutritional status. Two patients, BRCA and HRT status, availability of theatre time, intensive care unit beds, oncology waiting lists, breaching times, as we have in the UK. Four, local philosophy, attitudes, tradition. There are some hospitals who would prefer a route more to another. Five, patient's wishes and preferences. And six, local infrastructural expertise. And if you don't have this expertise, whether you would refer the patient to another specialist centre. So it's not only one answer that is the correct one. You can take any that would apply. And we look forward to your answers. There's really a broad array of answers here in the poll. People are still answering. So it's very interesting to see how the bars are moving. But the top one remains what we would all expect it would be. I think also it's very interesting is you had the important questions there about availability of theatre time, ICU beds and oncology wait lists. And I suspect that this is probably a reflection of COVID. But, you know, right now it's trending at 45 percent. Yeah. Well, you know, something as sad as it sounds, it's not just within COVID times. There are countries who have a significant problem of waiting times, even in Europe. Yeah. So and even outside of COVID and just COVID has aggravated things. So waiting lists that were before weeks now are months. So it's amazing to see that. A few more last are answering, but I think we have the final answers. So I don't know if you can all see that, but we have number one, we have with 85 percent patient's performance and nutritional status. And second place is actually availability of theatre time, intensive care and oncology waiting lists. That's very, very important. And by the way, my question was outside of the pandemic. So I don't know if everybody saw that, but this is something that I'm sure does not apply just in the pandemic. Then local infrastructural expertise. And if not available, people would refer and are happy to refer the patient to a specialist centre with 38 percent. And then we have between 30 and 17 percent the rest around local philosophy, patient's wishes and patient's BRCA and HRD status. So actually very, very interesting, very interesting views. And this is how I would also vote, to be honest. Angela, Clare, any comments? Well, I'm not surprised at all with the top two. I think that we would have expected those to come through. And the second is absolutely that practical one. And even though we might think it doesn't need to feature, you know, there are just times when it inevitably will. And we hear that all the time in our MDMs. So I think that that is more a practical one. It may not impact that much on the timing as well, but just enough to, you know, to be the caller. So I think some of the others there are potentially more minor issues. Can I be the devil's advocate and say that would there be a day where you think the BRCA status might make an issue, might win the day? I think that's a great assessment, Clare, and especially about BRCA status. Who knows, that could be coming. But I do think the broad array of answers here that we saw probably reflect the international contingency of this meeting. And I wonder, you know, availability of OR time, access to providers. It's really important that we provide that internationally so that we can have health equity for all women. Exactly. And this is something that Professor Sundar is going to talk about. Coming back to the issue with the BRCA, that's why I extra put it in as an answer option. I have to discuss it. There are two ways to see it. Either you say these patients, they will do so well, you don't need to bother operating on them. Or you say these patients, they will do so well, so just give everything. Best surgery, best chemo, best everything. So these are the two main views on this. While we're here, can we comment on the fact that you need tissue? So if you are going to give new adjuvant chemotherapy, do you make sure that you take a biopsy before that? Always, always, always. We have now also Professor Charlie Goulet here. He will start a new trial and we will also participate where he will test, he will take samples at secondary debulking before PARP and after PARP. So there are window studies with PARPs before secondary debulking that we're also running. So the landscape is immense and many, many answers to come in the next years. So thank you all. Thank you for this very interesting poll answering. And then it's my great pleasure to introduce the first speaker of my session, who is Professor Jarlet Zichouli. Not just a great surgeon and a great gynecologist and a key opinion leader, but also a very close friend and colleague of mine. So I'm very happy to have him, that we have him on our meeting today. He's the director of gynecology and gynecology in the Charity University of Berlin. Jarlet. So, Christina, thank you. And I'm really missing, especially you and the community, because I think it's a wonderful time to evaluate even our milestones in gynecology, including ovarian cancer. And thanks to Claire and Angelus. And I do my best to be in 10 minutes and to give some feelings and maybe some hypotheses where we are and maybe where we have to go. So, again, thanks to the program committee for being part of this wonderful thing. And we always talk about medications and biomarkers, but surgery today is a different approach than surgery 10 years ago. And this is not homogeneous, but we have the wonderful time of collaboration. And that may be even the philosophy of IGCS and all the other cancer societies, to bring science together, because we want to change our best approach. And what is really new in ovarian cancer that we know that, again, surgery is not always the same surgery. And I will highlight some of the newer different trials. And that we have evolution even in the galvanic, and not only based on surgical approaches or block resection, even what our colleagues from the endotheliogist are doing and what is the perioperative and postoperative management. It's even part. It's like anti-emetics for chemotherapy. And we have to understand this. And we have to understand that surgery is a part of three elements of surgery, chemotherapy, and maybe maintenance approach. And we have to place it. And we have to understand what is the acute impact and what is the long-term outcome of these intervention. So what we have seen that surgery is based on many, many facts and maybe many, many eminence-based ideas, but what we have to discriminate, things what we believe is good for the patient, what is really evident for the patient. And that, I think, is one of the most challenging approaches in science for surgical aspects. And if you look on the evidence we have, everybody is reporting his own series. It's nice. It's good. Because it's quality insurance. But that's not enough to find a hypothesis. Therefore, we need this multi-center and multi-national approach to bring all the individual experience together and maybe to run in a prospective idea. And again, surgery in ovarian cancer is one of the backbone. And in general, the effect is so strong without any contact before chemotherapy and before PARP inhibition that surgery, it's a backbone for all things what subsequently happen. But surgery before chemotherapy is a different impact power than surgery after chemotherapy. That's very clear. And we have to discriminate patient where we want to cure and what we have to discriminate patient where we believe to relieve only symptoms. That's a different story. And I think this is a big fake news that surgeons are unable to do randomized trials. And we know from luck trials, it's not easy to do studies. Sometimes it's much more complicated to interpretate studies of surgical elements. But we can. And that's the reason why I want to highlight some clinical trials we did in our cancer community regarding lymph node dissection. It's wonderful. And my hospital has been paid 600,000 euros every year to do this lymph node dissection from the insurance company. But in the trial, the LION trial, you know, where we included patients with advanced diseases and we randomized patients without any macroscopic disease and even without any suspicion, the retroperitoneum, in the case of peritoneal-dominated ovarian cancer, to randomize them. And the complication rate was very low. I was really surprised. And I was happy that Christina and me have been the most enrollment center at this time. And we can say it's a very feasible, simple technique. 40 minutes without any complication regarding bleeding. But one hour in median longer surgery makes differences in complication. You will see it. There was no differences in ovarian survival, no differences in progression-free survival. And that's the reason why we deleted it. But again, I'm always shocked that patients, even in early stage, they don't do lymph node dissection because they find the arguments from the LION trial, but the LION trial was only for advanced disease. So science is important, but the interpretation of the right conclusion is much more important. And there's a current publication where you see that systematic lymph node dissection will influence quality of life issues, including sexuality. And that's the reason why we have to learn nerve-sparing lymph node dissection if it's indicated, for instance, in high-risk early stage ovarian cancer. So nevertheless, we did wonderful trials in Italy regarding sampling, regarding systematic lymph node dissection. If we see enlarged lymph nodes, we do systematic, but only in the compartment that can be a part of the discussion. So it's not a black and white discussion. And I think it's important to remind the previous trials. Timing, yes. Christine has said it's philosophic, it's emotional. What means radicality? I think we have to start with our vocabulary. And radicality, it's a nice title, but what is inside? It's not based on procedures, on number of surgeons, number of surgical complications. No, it's defined on morbidity and clinical outcome. This should be the story. And we know that complete resection is the most relevant prognostic factor. And that's the reason why I think we must be honest that we are unable today to select the right patients for complete resection or not. There are some ideas, some indications where we believe, yes, the chance is high. But similar to the BRCA and the subtypes, you cannot exclude a complete resection even in a patient with 5-liter ascites. That's even the interpretation of the current trials and even the PCI index or the Fagotti index, whatever you want. No, it's nice. But if you have a complete resection, still the most important overall survival element. And it doesn't matter if it comes from a PCI from 30, 20 or 15. At the end of the day, it's a complete resection. So, I know the arguments, you know the arguments for chemotherapy before surgery. And again, the story is, if you do a surgical trial, you must have the goal defined. And if you want complete resection, you must have at least 50% in it for the statistical calculation. And that was the limitation of all the trials we did in the wonderful community. It's wonderful, highly selected, some centers, one patient, two patients in 5 to 10 years enrollment. And then you want to translate these results to all the other patients. No, that's not science. That's nice, but that's not enough. And that's the reason why we have to fight much more in our community to increase the enrollment of these trials. And it was a superiority trial, to improve complete resection rate, to improve overall survival. This was the statistical assumption. And that is in the wonderful attachment, you see patients who have primary resection, ovarian cancer, have a better outcome than patients who have complete resection after three cycles of chemotherapy. That's always the same story. That's a Japanese trial recently presented at ASCO. And that's the reason why we did the TRUST trial. And we hope to see the results in two years. If patients were achievable, complete resectable, receive new adjuvant chemotherapy are really inferior or not, we have to wait for the studies. One sentence for the last two minutes for relapse. It's one of the most critical things. But based on PARP, we know we have many, many long-term survivors. And that's the reason even that surgery makes differences. There are some patients who benefit from it. This is a study from Tina Vinovich regarding hypertemia that was inferior in relapse ovarian cancer. I only touched it. And the DESTROP trial, you know, there were two trials from the GOG and from the NGOT and GCIG. And we have shown a superiority regarding ovarian survival for the patient who achieved complete resection in comparison to the GOG trial. But there was a different approach, different patient selection, and even a higher proportion of Asian patients. So it's not easy to estimate, in this case, the differences. Selection is the key point. I hope we can bring the biomarker into the story to add the clinical parameters like a situs, tumor-free interval, and all the other stories to be more efficant for our patient. And that's the reason why we established in the NGOT this helper trial. So my last minute, I want only to underline that surgery is much more than to resect a tumor. That's the reason why we discuss ERAS Plus. And I am so proud to work with Christine and all the colleagues on this topic. And I just modified the definition from my perspective. The goal must be hasten recovery to improve the clinical outcome, to reduce mobility, and to preserve and to improve quality of life. And that's the reason why we just started in Germany a prospective trial to bring these elements into an algorithm. And complication management is the key point. And I congratulate Christina to this outstanding work because to identify risk factors is wonderful. But even this is science. Science is not always changing medical standards. Science has also the goal to bring experience in a script. And this is surgery. It's craft, but indication is science. And science can only mate as a team. Thank you very much. Thank you very much, Jalit. That was inspirational as always. And if anybody can talk about surgical trials, then that's you. I remind everybody to please, please submit your questions so that we can discuss at the end of the session. Then it's my great pleasure to introduce Sudha, Professor Sudha Sundar from the University of Birmingham, who is Professor of Gynecology. She's, again, not just a great friend and colleague, but she's a very inspirational woman. She's originally from India, is now the president of our British Gynecological Cancer Society and has changed massively the landscape of the quality of surgery, especially in ovarian cancer in the UK. So we're very, very grateful to her. So Sudha is going to talk about the global challenges of the implementation of surgery for advanced disease. That's a topic that is very close to my heart, because if you go to different countries, you see completely different things being done. So Sudha. Christina, thank you so much for this very, very kind invitation and for your very kind words, really. I think just to be in the same company as yourself Anjali Secod and Claire Scott is amazing. And to follow on from Riyalat Suhoori is a very unkind thing to do, because he's amazing at surgical trials. So unfortunately, my talk will not be quite as inspiring and as positive as Professor Suhoori's. Not so much. So my talk is going to be on the global challenges of implementation of surgery for advanced ovarian cancer. And I'm going to, I'm trying to move my slide, Guy. You need to make control, I sent you a request. Okay, so yeah, so the format of my talk is, what do we know about ovarian cancer globally? What do we not know? And what ongoing work we have to address the deficits. So let's start with what we do know. Next slide, please. So we're looking, when we look at the ovarian cancer worldwide incidence and mortality, we can see that the incidence of ovarian cancer is about 300,000 women in 2020, a mortality of 207,000, and five-year prevalence of about 823,000. It's interesting to see that Asia contributes about one in two women with ovarian cancer, Europe, about one in five, North America, about 8%, Africa and Latin America, about 15%. It's really important to keep that in mind, because much of our trial evidence and data that we use to manage our patients comes from Western Europe or North America, with of course other very important groups such as APCOT contributing hugely to trials, but at the moment our data does not reflect the prevalence of ovarian cancer across the world. Let's look at it visually, because I think this is a very powerful image, actually. So you see that ovarian cancer in the dark blue is very prevalent in Central Europe, a lot of Asia, in the Pacific Rim, Southeast Asian countries, and much lighter shades of blue outwith that, but still some dark blues in other parts of the world. So let's look at what we do not know for breast cancer, for ovarian cancer. And here, actually, our data is much behind breast cancer, which itself is not very brilliant when we talk about women of non-European ancestry. Let's talk about something that everybody thinks they know, which is what is the age of onset of ovarian cancer? We know that the age of onset of ovarian cancer is 60 to 70 for Western countries. Epidemiological data suggests that the peak age of diagnosis for breast cancer is 40 to 50. As I said, the data for ovarian cancer is a bit less robust as compared to breast cancer, but it's likely that this is also 10 years behind. What is not clear is whether this is an epidemiological artifact reflecting a younger patient population or whether there are genuine disease factors that are different between women across the world. Are there biological differences by ethnicity? In breast cancer, we know there is very good data that's been recently published by Tolga Tani in the British Journal of Cancer in 2021, that there's less favourable tumour characteristics, high stage, high grade, ER negative, HR2 positive, by ethnicity in both younger and older women. We don't have that data for ovarian cancer. Let's look at something that is so fantastic, PRCA, HRD prevalence, we've heard about this earlier in this panel. Tell me what the prevalence is in women of non-European ancestry. The answer is we don't know. We actually do not know. In the South Asian women, obviously, because I'm South Asian, we looked at the data. And so this data reflects about 1.6 billion population on this earth. We cannot know the mutation frequency reliably because we have very little information on matched survival, pathology or germline data on breast or ovarian cancer patients of South Asian origin. And this is data that we've published on, and it will be similar for black African women and probably for women of other ethnicities. Just putting that out there for you to reflect on. What do we know about ovarian cancer surgery and outcomes? Let's look at the lessons from breast and GI cancer. And so this study was published in The Lancet in 2021 and looked at variation in post-operative mortality and complications after cancer surgery in GI cancer and breast cancer. And essentially, patients in low and middle income countries present with more advanced disease and have a higher 30-day mortality for gastric cancer and for colorectal cancer, not so for breast cancer. And the absence of consistently available post-operative care facilities was associated with 7 to 10 more deaths per 100 major complications in their mix. So that's what we don't know. What are we doing to address the unknowns? So certainly for the BRCA, we are setting up match studies between the West Midlands, which is a very, very diverse population and the population that I work in, and looking at studies that recruit both patients in the UK as well as patients in India to assess BRCA and high-risk susceptibility genes in ovarian cancer patients along with survival and pathology data. And we hope to recreate this across the world and be very happy to hear of any collaborative efforts in this space. But this is a study, this is a session on surgery. And so for the next little while, I'm going to concentrate on the work that we've done on surgical studies internationally and surgical trials in low and middle income countries evaluating perioperative interventions. So for this study, for the COVID surge gynae cancer, full credit must go to Christina Fotopoulou, who established this huge, big collaborative network across Latin America, the South America, APGOT with the Asia Pacific region, and across the world. And this study is probably one of the largest studies we have on gynae cancer outcomes. But essentially, we recruited, we accrued data for three months in any hospital performing elective cancer surgery, where patients, so this is all first-line patients, mostly first-line patients, I should say, so planned for curative or significantly life-prolonging cancer surgery that have surgery completed in the three months since the first COVID patient started in their hospitals. And we collected this data in RedCap and analyzed this. We had population, we had participating countries across Europe and Central Asia, Latin America and Caribbean. So it's a start of a gynae cancer collaborative network. Obviously, we have more high-income countries and low and middle-income countries, very few low-income countries. Nevertheless, it's a start at a international collaborative network. We recruited 4,722 patients over three months. In terms of the participating countries by income categories, as you can see, we have some low- and middle-income patients, low-middle- and upper-middle-income patients, and very few low-income patients. And the intention of surgery, we have about 1,350 patients with ovarian cancer. And the intention of surgery was down as curative, palliative, or life-prolonging in the majority of patients. Median post-operative stay in this international study of 4,347 patients was 6.93 days, which is actually remarkably good. And the 30-day mortality for ovarian cancer is 1.4% of patients. Nevertheless, I'm trying to move to the next slide. In terms of the impact on treatment by cancer site, nearly one in five women for ovarian cancer had an impact and change in treatment. This included patients who had either a change to neoadjuvant chemotherapy or longer neoadjuvant chemotherapy. Next slide, please. Either delay in surgery, change in choice of surgery, patients who received neoadjuvant chemotherapy, longer neoadjuvant chemotherapy, or patients who were not operated at all. Although this study was performed during COVID times, I think it also gives us an opportunity to look at outcomes per se in gynecancer internationally. So in summary, the largest multicenter analysis of gynecancer surgery during COVID pandemic has demonstrated adjustments of timing, indication, and radicality of surgery. Perioperative complications were low. We're currently looking at what the extent of ovarian cancer surgery is and cleaning up the codes that have been used. And so hopefully, in the next week or so, we will have data on the kinds of ovarian cancer surgery that have been performed. Okay, so how do we make surgery safer? How do we generate evidence that is relevant to low- and middle-income countries? And let's start from patient selection, risk prediction models, perioperative care. So in that regard, we've been working with the Global Search Collaborative in Birmingham, which is funded by the UK National Institute of Health Research. Next slide, please. And this is a large collaborative network that is funded by the MRC, Wellcome Trust, the NIHR. It's led from the University of Birmingham, University of Warwick, and the University of Edinburgh. And this is basically an international collaborative network that focuses on surgical care in low- and middle-income countries. So this is pan-surgery. It's not just gynecology, for that matter, and it's heavily weighted towards general surgery. Nevertheless, there's a small proportion of patients who are gynecancer, and we can expand that. And the trials that we have been doing include trials that have been generated as ideas from collaborative networks across the world. So this is not a high-income country takeover of the space. And the plan is that priorities are set by people practicing on the ground. This is then converted into, is supported to build up into randomized trials that then run across the world. And we support this by trials unit support and information exchange and knowledge exchange. Next slide, please. So CRANE, for instance, is a nutritional intervention that I'm involved in. And this is basically a trial that is running across Ghana, India, Philippines, and Malawi. And we look to see whether we can identify low-cost, sustainable nutritional supplements. So we have first identified whether we can implement nutritional screening tools in low- and middle-income countries. Secondly, we've identified that we can collect data on 30-day mortality. And now we are going to, we've identified low-cost, sustainable nutritional interventions across all of these four sites. And we're now moving to pilot to see whether implementing these nutritional interventions can result in an impact on 30-day mortality. This is a study that, this is a trial that I'm involved in. But there are also trials that are running from the unit, such as, next slide, please, such as the Falcon and the Cheetah trials, which are pragmatic trials on the use of chlorhexidine, betadine, coated sutures, non-coated sutures, changing equipment and instruments before and after surgery, once you open the abdomen and then when you close the abdomen. So relatively pragmatic interventions that may make an impact on 30-day mortality from surgery in these settings. Next slide, please. So in summary, can we address the evidence gaps in gynae cancer care? I believe that we can work with existing trial groups. We can expand our current gynae collaborator networks if we work together. Working with international societies will be key to success and sustainability. I'm very keen for people who have ideas or who have, who want to work collaboratively to get in touch. I don't have the, I don't have the solutions. I don't know the solutions, but I think working together and brainstorming, we may get to a point where we can actually stop this current inequity where we have enormous data on a very small group of people. Thank you. Thank you very much, Jutta. That is so very true. And I was very impressed with your statistics about one in two of ovarian cancer patients are from Asia. I only saw that today, actually. I mean, it didn't, you know, you have to look at numerically and visually for you to see it. I mean, we see it in the systemic trials that there, I mean, the carbotaxel weekly, one of the most that was done in the Japanese population then did not get confirmed in the Caucasian population. So there are differences that we really cannot explain. So thank you very much. Again, I encourage you to please, please send the questions and take advantage of the expertise of our speakers. And then the last speaker of the first surgical session is Professor Marcella Del Carmen, who is an amazing surgeon, who I was so much looking forward to seeing her today. She's a professor of gynecology at Harvard, who I don't see as often as the others, just because she's in the US and I hope to meet in Rome. So Marcella, I really hope we can welcome you in Europe very, very soon again. She will talk about the fertility-sparing surgery. So how do we do, how do we operate patients with fertility-sparing wishes? Marcella. Thank you, Cristina. And I want to also extend my thanks to you and to Dr. Angeles Secord and Dr. Scott for this wonderful opportunity. I wish that we could be in person, but nonetheless, it's wonderful to be with you. And I just want to, again, give you my deepest gratitude for letting me be part of this wonderful panel and experience. So as you said, I'm going to talk a little bit about both the oncologic and the reproductive aspects of fertility-sparing surgery in the management of women with epithelial and non-epithelial ovarian cancers. What we'll share over the next few minutes is basically, the theme is going to be the lack of data, but we'll go over the data that we have and we'll address the quality of those data and what the challenges remain moving forward and the answers that remain, the questions that remain unanswered. I have no conflicts. So just in terms of setting the stage and background, we know that there are over 113,000 women who are diagnosed with gynecological cancers in the US, as an example, in this year, and 21% of those women will be women under the age of 40. ASCO has defined fertility as a key survivorship issue going back to 2006. However, despite that definition and that statement, about 5.5% of women who are reproductive in age that present with either long breast, colorectal, or cervical cancer are evaluated for fertility preservation, and of those women, only fewer than 5% of them will undergo fertility-sparing procedures. We know from the data that are available that there are challenges that affect women's access to fertility-sparing surgery. So this is not only a survivorship issue, it's become an issue of disparities and equity because factors that have to do with geography, socioeconomic status, race, ethnicity, age, insurance, and education also impact the patient's ability to engage in a conversation regarding the appropriateness or not of undergoing fertility-sparing surgery for a primary ovarian cancer. We know that approximately 12% of women will be diagnosed with ovarian cancer at some point during their reproductive years. Reproductive-age women that develop epithelial carcinoma of the ovary are more likely to present with early-stage disease. We also know that there are non-epithelial ovarian cancers, including germ cell tumors, that commonly occur in this age group. Approximately 60% of germ cell tumors will be stage one. Most of them, as we all know, tend to be unilateral and affect only one ovary. Fertility-sparing surgery is the standard, given that these tumors tend to be very sensitive to chemotherapy. We also know that about 57% of sex-borne stromal tumors will also be diagnosed at a stage 1A. Most of these tumors, as we all know, are seen in women who are postmenopausal. One third, however, are gandulosa cell tumors, and they're diagnosed in women of reproductive age. And again, similar to germ cell tumors, they're not only stage one, but they also oftentimes are unilateral. The National Comprehensive Cancer has put out a statement in their guidelines about how to best manage women that want to seek fertility-sparing surgical approaches. And as you can see, for epithelial carcinomas of the ovary, the recommendation is that for women with a well-staged 1A or 1C, as long as it is not clear cell histology, you can actually embark on a unilaterals or pingual ophrectomy and comprehensive surgical staging. That remains a critical piece of the equation. As one of my colleagues stated earlier, a lymphadenectomy should not be omitted in patients where you're trying to do the lymph dissection to ascertain staging information. For malignant sex-borne stromal tumors, the recommendation is that for tumors that are 1A and 1C, you can actually proceed with a unilaterals or pingual ophrectomy and comprehensive staging, and then move to completion surgery after childbearing is finished. And for malignant germ cell tumors, irrespective of stage, it appears reasonable to embark on unilaterals or pingual ophrectomy, as well as comprehensive staging. For epithelial carcinomas of the ovary, let me share with you some of the data that are available. This is a study that came out of Italy, retrospective study, including 240 women with stage one treated by either cystectomy or unilaterals or pingual ophrectomy with or without adjuvant chemotherapy. The study included all grades and histologic subtypes of epithelial cancer of the ovary. It had a nine-year follow-up data by the time that it was published, with the median age of patients at 32. Cystectomy was carried out in 26% of the study population, with a relapse rate of 17%, and a mortality rate of 6% in those patients. Unilaterals or pingual ophrectomy was more often the procedure carried out in almost two-thirds of patients, with a relapse rate of 9%, and a mortality rate of approximately 4%. They reported a pregnancy rate of 80%, 65% of these patients had one or more children. Grade three importantly was associated with the worst progression-free survival and overall survival, so caution there that the study highlighted some features that may be concerning and may be something to entertain, and grade three was one of them. PMP, interestingly, did not affect pregnancy outcomes. This is another study done by Alex Malamat, when he was a fellow at Mass General, and he looked at the National Cancer Database to actually address all-cause survival in patients with early-stage ovarian cancer who underwent fertility-sparing versus conventional surgery. He looked at data from 2002 until 2014, included over 1,700 women, 48% of them, or a little bit over 800 of them, underwent fertility-sparing surgery. These patients tended to be younger, they were more likely to reside in the West or in the Northeast part of the United States, and they were also more likely to have either tumors that had serums or mucin assistologies. He then conducted a propensity score matching, where he included 452 patients in each arm, the fertility-sparing and the conventional surgery control arm, and you can see in the table that 10-year survival was very comparable in all patients, as well as in patients that had high-grade tumor features, including stage 1c, grade 3, or clear cell histology. These are the Kepler-Meier curves that he presented in his paper. Under the section on the graph in the A graphic, we see that these are all patients. You can see that the lines are very similar to each other. And then under B, the second part of the graphic, he was able to show the same, essentially no difference in 10-year, all-comer mortality between patients and controls, looking only at the subset of women that had high-risk tumor histology, again, stage 1c, grade 3, or clear cell. This is a study that was also done by one of our fellows and led by Alejandro Raujain, who's now at MD Anderson, this is fertility, fresh pregnancy outcomes in women with early stage ovarian cancer. This is a retrospective study that looked at women between the ages of 18 to 45. It actually looked at the California Cancer Registry and included women with stage 1A or 1C epithelial cancer of the ovary. And they actually linked the data. These data from the California Cancer Registry were linked to California Office of Statewide Planning and Development Birth and Discharge Data Set. The primary outcome was preterm birth at less than 37 weeks. They had 153 cases that were propensity matched to 206 controls. They noted that the treatment for ovarian cancer was not associated with preterm birth, small for gestational age, neonates, or severe maternal morbidity or mortality. You can see that the outcomes across multiple domains, including preterm birth at less than 37 or 32 weeks, small for gestational age, fetus, fetal demise, cesarean delivery, neonatal morbidity, no difference between the ovarian cancer cases or the matched controls. Systematic review of the literature. This was done by currently our first year fellow. This is a PubMed search that included the years in parentheses between 1995 and 2020, included studies that had women between the ages of 18 and 50 that reported both oncologic and or reproductive outcomes after fertility sparing surgery for ovarian cancer. The study to be included in the review had to have at least 20 patients. They were included 117 studies, and you can see the breakdown 44 were studies of women with epithelial cancer of the ovary, 42 of women with borderline tumors, and 31 studies of non-epithelial ovarian cancers. Overall survival was not compromising. Patients who underwent fertility sparing surgery. However, the review found that there was controversy in the included retrospective studies around the safety of fertility sparing surgery in patients that had high risk tumor factors, including grade three or clear set of histology or stage one C tumor. This is basically a table that's included in the paper that addresses the size of each of the studies included. And you can see that the problem in trying to understand how to put together these data is that the studies include not only different time ranges where adjuvant therapy changed, but also different numbers of patients and surgical staging was either performed comprehensively or not. So very difficult data to interpret in terms of being able to ascertain the best way to manage a patient in front of us. With regards to obstetrical outcome, we have to remember that that's the other part of the equation. You should be offering fertility sparing surgery only to women who are able to achieve the pregnancy beyond cancer therapy. The estimated rate of successful conception in these patients is approximately 30%. When you actually adjust the data, and Christina has done a lot of the work here, you can actually see that if you include only women of reproductive age, the successful conception rate actually is much higher, maybe closer to 60 to 100%. In a review of 440 women who underwent fertility sparing surgery for early stage ovarian cancer, about a third of them were able to achieve conception and that 70% of those or 90 were able to have a pregnancy with an reported miscarriage rate of approximately 17%. The second review that included over 300 women, they reported 119 pregnancies with a 96% life birth rate. Another review of 711 patients, again, 37% reported rate of successful conception. I just want to leave you with some thoughts and conclusions in terms of our review and what we understand from this literature. Remember that we don't have any randomized control data and in the absence of that, we have to lean on observational studies that actually inform on whether fertility sparing surgery is appropriate in the selected group of women with early stage ovarian cancer. We just want to give a note of caution that high risk disease is controversial and that requires an even more guarded conversation with patients, especially those presenting with stage 1C, comprehensively staged tumors, grade three or clear cell tumors. Pregnancy rates among cancer survivors may be lower than those of age match controls and that may be confounded by higher rates of infertility in cancer patients or also reduced attempts at conception in cancer survivors. Pregnancy outcomes in the data that we have appeared to be similar, there are limited data on whether and when completion surgery should be performed and that should be part of the discussion. There are largely non-existent data on the use and success of assistive reproductive technologies in this patient, so that also should be part of the conversation. And I cannot emphasize enough that this patient should be carefully counseled. This should be an interdisciplinary conversation, not only with oncology, but with reproductive medicine and maternal field of medicine if appropriate. And it is critical to integrate the patient as part of the conversation to optimize cancer care as the priority, but also look for options when available to provide fertility-sparing surgery and hopefully achieve a pregnancy. We will need further studies to elucidate on what are the best patients to be selected for fertility-sparing surgery that will also hopefully answer some of these questions that remain yet unanswered. And those studies should be inclusive of patients who never achieve a pregnancy. Again, I wanna thank you for your time and I wanna thank again the program committee and the chairs of this panel for the opportunity to be able to speak with you this morning about this topic. Excellent, Marcella, thank you very much. A very good overview. So we have a few minutes for questions that I'm going to read from our poll. Please, still you have chance to submit your questions, so just go ahead. So we have a very, very interesting question. First of all, to all of you, but especially to Jalit, whether any of the surgical trials, Jalit, are especially addressing patients with a BRCA status. So whether there will be any stratification for patients, especially with BRCA patients. Yes, I think it's very important. And if you look on the data from ZSOLO and even from the new PARP trials, I think we will address that later. And the subgroup analyzes, we see the most relevant benefit in maintenance is in patients who achieve complete resection. And this is independent from the age and even from the BRCA status. And we did, Christina, you remember with Ioner, a publication several years ago with low grade and high grade, and we have seen no differences in relapse if you compare both groups. So if you have complete resection, then the additional benefit potentially for chemo resistance, whatever, will add. So I totally against. What I like that we think, do we really need six cycles chemotherapy if we have a patient who achieved complete resection? And this, Christina, I can announce, will be the next trial we will do in MGOT. Three cycles after complete resection, again, six cycles followed in both arms with maintenance approach. Because the six cycles have been developed in a time we have done no marginal surgery. So I think we should not separate BRCA from non-BRCA. We should try to identify patient who achieve, who are able to achieve a three milestone treatment and can be a potential long-term survivor. That should be the idea. And if you look on long-term survivor, it's not only BRCA positive patients. That's, I think, the key point. Yeah. Very interesting. Very interesting views, but I think it's very interesting too and very important to emphasize that we need, we need a translational aspect of any of those studies. And in trust, we have a very big translational aspect where we are going to collect tumors, assess also the somatic BRCA status. So there is a lot to come. A question about minimal invasive surgery and ovarian cancer to all of you. Marcella, a minimal invasive ovarian cancer and fertility sparing approach. How would you see it? Again, we don't like, we don't have randomized control data between minimally invasive and open surgery, but I think in patients that are appropriately undergone preoperative imaging, I think that we can lean heavily on good imaging of the chest, abdomen, and pelvis. I think, and also based on surgical proficiency of the operator. Then I think that if you can do a comprehensive no dissection laparoscopically and get to the notes that you need, both pelvic and periodic lymph node dissection, I think it's a reasonable approach to offer patients to spare them the morbidity of an open surgery. I think in the absence of that, as I always say to our fellows in laparotomy, there's still an indication for that. And so I think in patients that may not be candidates for a great surgical evaluation laparoscopically because of things that have to do with BMI or anything else, then I think an open procedure would be more indicated, but I think it's very appropriate to consider a laparoscopic or minimally invasive approach under the right hands, right surgical expertise and with good preoperative imaging. Preoperative imaging. There were some questions about how do you define really the high-risk patients grade three? What do you mean by grade three? What histology and what is early stage? Is it stage one? Is it stage one and two? There were many questions around that. Can you please elaborate? Sure. So, yeah. So thank you for the question. So I think early stage in the literature that is available is defined as stage one. So stage two are not included in most of these retrospective series. So stage one, most of these patients underwent some kind of surgical staging procedure and they had either stage 1A, stage 1B or 1C. The studies that look at high-risk features define those as grade three. So as opposed to grade one or two tumors. And then they also categorically look at clear cell histology as a different high-risk subtype that actually can in some studies has been shown to demonstrate a worse outcome when treated in a... And again, they're treated in fertility sparing ways but some of that I think in clear cell histology specifically may have to do with the chemosensitivity of these tumors. And the fact that they just purport a worse prognosis in general from more chemosensitive cell types like serous. Excellent. Thank you very much. I have a last question before we go to the next session to Sudha. Sudha, these were very impressive data that you have presented and we always have to think and come all of us out of our little box and little space of thinking and see that the problem of disparity is much more extensive than we think. How do you think we can in the future try as an oncology community to equalize differences in care, in access of care, in expertise? How do you think we should address that? So I think there's an issue around, first of all, data really, in the sense that we, I think we do have the ability to establish wide collaborator networks to pool data and to value, first of all, to recognize that the data that we're seeing is not extrapolatable to the patient that we see in front of us. And I think in the UK, for instance, not all the patients that we see are of European ancestry. So we do need to recognize that it's what we see and believe to be true, may not be true for the patient in front of us. That's point one. Second, I do think we can establish collaborator networks across the world to try and address some of these evidence gaps. And the reason why it will matter is that as universal health coverage comes in, I think this evidence will start getting more and more important because I think most countries have committed to UHC in the next 10 years or so. And so filling these gaps becomes quite important. So I am a great believer in collecting data, running trials. These are the things really. And actually thinking about low cost alternatives, do we need to do, can we use Plumpy Nut rather than the Kwashiorkor Nutritional Supplement? That's what they're going to use in CRIN. So I think treating people with mutual respect where we can learn as well as we can teach, I think is also a good point. And with these excellent words and inspirational words, I give the voice to the next session to Dr. Tangellis to start and introduce our speakers. Thank you very much all. Thank you. And what an excellent discussion. And I'm just inspired by the sense of shared purpose that we all have to help women with ovarian cancer, not just ovarian cancers, but certainly gynecologic cancers across the world. Let's go ahead and get our next poll launched because I know that takes some time as we move into this next segment titled, Move Over Chemotherapy, Exploring Systemic Therapeutic Options in Ovarian Cancer. So our poll question as they launched that is quite extensive, but essentially it's trying to capture what is happening globally regarding the use of PARP inhibitor maintenance. And our question is, which of the following best describes your choice for frontline PARP inhibitor maintenance in stage three and four, newly diagnosed epithelial ovarian cancer after cytoreductive surgery and response to platinum-based therapy? Is it a PARP inhibitor strategy for all? PARP inhibitor for those with BRCA mutations only? PARP inhibitor for those with BRCA mutations and or HRD, otherwise known as genomic instability tumors? PARP inhibitor in BEV for these patients? I do not recommend frontline maintenance or I do not have access to PARP inhibitors because they're not available or I do not prescribe PARP inhibitors because they're not covered by insurance and are too expensive. And we're hoping that with this question, we'll be able to get a sense of what is going on globally. It looks like at the top of the leaderboard right now, 40% is the use for patients with BRCA mutations or those with tumors that have genomic instability or also known as HRD. But we do see that about 20% are not prescribing them because they're not covered by insurance and it's just too expensive. There's also a PARP inhibitor for all strategy in about 15%. 12% don't even have access to PARP inhibitors because they're not available. Things are shifting a little bit here. Some individuals incorporate bevacizumab into the strategy with PARP inhibitors for maintenance in select patients. And that's essentially where it lines up. There's no one that does not recommend it. So it really looks like as if they're not being utilized. It's because of lack of access. So to go ahead and start us off here, and we really have an international contingency of speakers, but to start us off is Dr. Rebecca Crystalite. I'm so pleased to have her speak with us today regarding beyond PARP progression, what now? And Dr. Crystalite is from the United Kingdom and a medical oncologist. So thank you so much, Dr. Crystalite. Thank you very much, Ankeles. So good afternoon, everyone. I'd like to thank very much our three session chairs for extending an invitation to discuss this question of how we can best manage our patients who progress in a PARP inhibitor, focusing on the current evidence for mechanisms of PARP inhibitor resistance that are clinically validated and potential strategies likely to be clinically important available now and in the future. These are my disclosures. As PARP inhibitors are now established as a standard of care in first and subsequent lines of ovarian cancer treatment, and patients are usually treated to progression, we have an urgent need to understand the clinically relevant mechanisms of PARP inhibitor resistance in order to develop and adapt treatment paradigms for these patients. PARP inhibitor resistance can be primary, meaning it's present before treatment with a PARP inhibitor and inherent to the tumor, or is acquired during the course of treatment with a PARP inhibitor due to treatment pressure selecting for resistant clones, as predicted by preclinical data shown here, where continuous treatment with a laparib in vitro selects for mutant BRCA-reverting clones over time. Mechanistically, five distinct classes of PARP inhibitor resistance have been described, but not all have been clinically validated. There's a case report by Pettit et al. describing a patient with primary resistance to a laparib found to have a PARP1 mutation affecting DNA binding, thought to be the underlying cause. But really, the PARP inhibitor resistance mechanism that's best clinically characterized is restoration of homologous recombination. But there is also emerging evidence that targeting replication for protection and cell cycle control in situations of replication stress will be an important therapeutic strategy to overcome PARP inhibitor resistance. So focusing first on restoration of homologous recombination as a mechanism of resistance to PARP inhibition. This has been described both as a cause of primary and secondary PARP inhibitor resistance. And the mechanisms of homologous recombinant restoration that have been identified clinically include BRCA reversion mutations first described in 2008 and depicted here on the right showing an intragenic deletion that developed following a laparib exposure in a BRCA2 mutant cell line that restores the open reading frame and results in PARP inhibitor resistance. In addition, in ovarian cancer, RAD51C and D reversion mutations have been identified as well as loss of methylation of BRCA1 and RAD51C as alternative mechanisms restoring homologous recombination function and PARP inhibitor resistance. And I'll be discussing those in detail. Reversion mutations can be detected in tumor but also in circulating cell-free DNA. It's currently estimated that BRCA reversion mutations occur in approximately 15% of ovarian cancer enriched in platinum refractory and resistant disease. Much of the clinical data for restoration of homologous recombination comes from the ARIEL2 diagram in the top left study. This was a two-part open-label single-arm trial of recaparative monotherapy treatment for patients with relapsed platinum sensitive, resistant or refractory ovarian cancer across both parts of the trial. NGS was used to define patients prospectively as BRCA mutated, BRCA wild type and LOH high or BRCA wild type and LOH low. The clinical benefit of recaparib represented by progression-free survival, top right, response rate, waterfall plot and duration of response, swimmer's plot was greatest in BRCA mutated patients, the blue line of the PFS, followed by BRCA wild type LOH high patients in orange and least beneficial for BRCA wild type and LOH low. And this has been validated in several trials subsequently. So blood samples were taken from patients in ARIEL2 during recaparib and on progression to determine whether BRCA reversion mutations could be detected in circulating free DNA and correlated with response. Data from this analysis was clear that the presence of a BRCA reversion mutation predicted for primary and secondary resistance to recaparib. This is illustrated by the waterfall plot in the bottom right, and where asterisks represent patients with a BRCA reversion mutation. These patients are congregating to the left of the plot indicating least response or progression on recaparib. These analysis also showed very clearly that BRCA reversion mutations were associated with platinum resistant or refractory disease shown in the top right diagram. And the bottom two rows of dark green lines are more frequent on the left in platinum refractory and resistant disease. Progression-free survival without a BRCA reversion mutation was nine months compared to only 1.8 if a BRCA reversion mutation was present on recaparib. And interestingly, 10% of post-progression samples harbored secondary BRCA reversion mutations that were not found at baseline. So further tumor sample analysis, this time not blood tests, from parts one and two of Arial 2 has given us a very rich evidence source for the mechanisms of PARP inhibitor resistance that are emerging during treatment with recaparib. Shown on the left is progression-free survival in four different patient subgroups of Arial 2 combining platinum status in addition to LOH status in BRCA wild-type patients. This shows that BRCA wild-type patients who are platinum sensitive, even if LOH low 5.3 month PFS did better on recaparib than patients who are platinum resistant or refractory, even if they were LOH high, they only had a 1.9 month PFS. This suggests platinum sensitivity is an important discriminator for benefit of recaparib and the LOH status should not be considered a predictor of PARP inhibitor benefit in platinum resistant patients. Although archival BRCA1 methylation levels were not associated with differential progression-free survival with recaparib, PFS was better in patients with wild-type ovarian cancer, BRCA wild-type ovarian cancer, containing high BRCA1 methylation immediately prior to initiating treatment. The overall response rate was 43.8% in patients with high methylation ovarian cancer, but only 5.3% in patients with low methylation high-grade ovarian cancer and 10.1% in those with unmethylated high-grade ovarian cancer. This difference in response indicates that decreased BRCA1 methylation may be an acquired resistance mechanism to root caparib. High-grade ovarian cancers that maintained high methylation across archival and screening biopsies were enriched for platinum-sensitive disease, 6 out of 8, while those with a decrease or loss in methylation were predominantly platinum-resistant or refractory, again suggesting a possible mechanism of cross-resistance for platinum and PARP inhibitors. Analysis of other molecular factors using targeted NGS of 315 genes from 482 areal 2 tumor samples revealed alterations in other pathways such as homologous recombinant, non-HRR DNA repair, cell cycle regulation, PI3K signaling, RAS pathway, and various receptor tyrosine kinase signaling pathways as shown here. CCNE1 amplification of microplatinum resistance and refractoriness is associated with HR proficiency was mutually exclusive with the presence of a BRCA mutation. These pathways and genes have all previously been associated with resistance to PARP inhibition pre-clinically, so it is highly significant that these alterations are observed in the tumor biopsies and correlate with response. AREAL4 is the confirmatory phase 3 trial of root caparib monotherapy when compared to standard-of-care chemo across all platinum-sensitivity subgroups, and root caparib was confirmed as an effective treatment option across all subgroups. It was also confirmed for the first time in a randomized phase 3 trial that the presence of a BRCA reversion mutation predicted for worse outcome from root caparib. Replication stress is an increase in DNA damage either exogenous with chemo or endogenous such as reduction in nucleotide pools that increases pressure on requirement for DNA replication. In a situation of replication stress, DNA synthesis slows and replication forks stall and it's a primary cause of genomic instability. Important drug targets of replication stress are ATR, CHECK1 and WE1 as they coordinate the DNA damage response which is mediated through activated ATR. Inhibiting components of this pathway as their function is to stabilize replication forks causing resistance to PARP inhibition is likely to be an important therapeutic maneuver and clinical data for this is beginning to emerge. ATR inhibition in ovarian cancer induces replication stress, promotion of entry into M phase resulting in mitotic catastrophe and cell death. There are defined preclinical biomarkers of sensitivity for ATR inhibition including ARID1A loss of function, ATM loss of function or mutation and CCNE1 overexpression, several of which are being incorporated into early phase trial evaluation of this drug class. There is little clinical data on ATR inhibition in PARP inhibitor resistant ovarian cancer however one abstract was reported at ASCO this year combining an ATR inhibitor with a laparib in BRCA mutated or HRD positive platinum sensitive but PARP inhibitor resistant ovarian cancer showing an encouraging overall response rate of 46% but in only a 13 patient sample size. There is therefore an early suggestion that this might be an approach we could take in PARP inhibitor resistance. CHECK1 inhibition remains under investigation clinically for platinum and PARP inhibitor resistant ovarian cancer and there are two monotherapy trials of Prexacetib shown on this slide in BRCA mutated population on the left and a BRCA wild type population on the right. They're small studies but show a modest benefit of a response rate between 11 and 29% for CHECK1 inhibition in ovarian cancer. Many of these patients had received prior PARP inhibitor and biomarker analyses are ongoing to help guide molecular selection. The phase 2 trial of inhibition of cell cycle target WE1 combined with a laparib and PARP inhibitor resistant mainly BRCA wild type ovarian cancer also a platinum resistant population shows again a modest improvement in clinical benefit with an increase in overall response rate and PFS in the sample of 80 patients. This again may be an avenue to investigate further and sequential schedules of WE1 and PARP inhibitors might be appropriate as suggested by preclinical data. This shows a combination of an AKT inhibitor and a laparib given the preclinical data suggesting this is a synergistic combination. This showed 11 out of 25 ovarian cancer patients experienced clinical benefit despite four of them being PARP inhibitor resistant and is an interesting approach that we might want to take further forward. On to, there are three novel, completely novel drug targets that I just wanted to mention before I finish. The first is PARP inhibitors, a novel class of drugs with the ability to increase replication stress that are in preclinical development. A further promising drug target is DNAPK for PARP inhibitor resistant and it is a component of the NHEJ pathway. And finally, possibly most excitingly, is Pol-Theta inhibition that is capable of inducing BRCA gene synthetic lethality and targets PARP inhibitor resistance and for which there is a defined predictive biomarker identified. So in conclusion, I would consider that we should be including methylation status circulating pre-DNA BRCA and tumor reversion mutations into our biomarker assessment of patients eligible for a PARP inhibitor. That markers of PARP inhibitor resistance are dynamic and our therapeutic response needs to be, so translational research is key. I think we really need to understand more the interaction overlap with platinum resistance. Can this be used as a marker of needing, you know, not needing a PARP inhibitor and needing these alternative approaches instead? And inhibitors of targets within the replication stress response pathway are the most promising agents currently with novel agents emerging. Many thanks for your attention. Thank you so much, Dr. Kristolai. That was outstanding. I loved all the translational science. I think that the data that you presented is so rich and it really informs us of the next steps from a research perspective, both preclinical as well as clinical trials that we need to take over this next decade. So very exciting. Next, we're going to hear from Dr. David Tan about non-conventional therapeutic options. Dr. David Tan is from Singapore and from the Asian continent, and I'm so excited that he'll be able to present with us today. Thank you, Dr. Tan. Hello, right, and thank you very much for inviting me and giving me this opportunity to talk about non-conventional therapeutic options in ovarian cancer. These are my disclosures. So I think we all realize that ovarian cancer is a heterogeneous collection of diseases and different subtypes of ovarian cancer have different molecular abnormalities and therefore potential therapeutic targets. We've learned a lot by how we can target homologous recombination and that precision therapy can work if you select the right biomarker and the right drug. In this discussion, I'm going to talk about these non-chemotherapy, non-conventional options that may change the way we treat ovarian cancers in the future. I'm going to talk a bit about replicative stress response that Rebecca has really mentioned earlier, and then the all-important immune checkpoint inhibitors and the challenges we have with ovarian cancer and how approaches to modify the tumor microenvironment might help to improve responses with this particular therapeutic modality. Then finally, I'm going to talk a bit about antibody drug conjugates before we refer to some of the new mutations that may be targetable, especially in non-serious ovarian cancer. So the replicative stress response is a key node in the DNA repair pathway. Essentially, when you've got DNA damage, what you need to do is to get the cell to slow down so that you can repair your damage and then get it to go again. And if you can't slow the cell down and there's damage that's unrepaired, then the cell eventually goes to mitotic catastrophe. And that's why throughout the cell cycle, you'll see that there are multiple proteins, cell cycle checkpoint proteins that are crucial to try and control the progression of cell replication in order to enable the cancer cell to survive. And we know that there are ATR inhibitors, V1 inhibitors, CDK2 inhibitors, as well as DNAPK. And we know already about how PARP inhibitors may also contribute to the overall stress within the replication process leading to mitotic catastrophe. Of course, the mitigation of replication stress has already been highlighted by Rebecca as a potential mode of PARP inhibitor resistance. And hence, this potentially is of interest in the HRP phenotype as well, which as we all know, is less likely to be responding to PARP inhibitors as well. And we've seen data of V1 inhibitors, kinase inhibitors being combined with chemotherapy showing improved progression-free survival in this study that was published by Ozar and colleagues. And we've also seen the recent data that was presented by Rebecca as well that Shannon Westin showed us in ASCO this year, where patients with BRCA wild-type ovarian cancer, platinum-resistant and PARP-resistant ovarian cancer seem to respond better than the BRCA mutant patients who were treated with adivacetib or adivacetib plus olacrip. ATR inhibitors are now being developed, and we have single-agent activity being demonstrated in specific biomarker-selected cohorts of ATM loss and ATM mutant tumors. In this particular Bayer compound, which is adimersitib, there has also been prolonged disease control seen in some patients with ovarian cancer that were BRCA mutant and had progressed on PARP inhibitors as well. And Panos and colleagues from Dana-Farber showed us that the combination of the ATR inhibitor basositib plus gemcitabine showed a significant prolongation of progression-free survival in the context of platinum-resistant ovarian cancer versus gemcitabine alone. And interestingly, there was more progression. The progression-free survival seemed to be more pronounced when the progression-free interval was less than three months. So how about immunotherapy? Right, we've done really badly with immunotherapy in ovarian cancer, and we can say that, you know, the responses here really only been in the single digits, or in some cases, maybe up to 15%. And there was two randomized phase three trials of immune checkpoint inhibitors in the first line of ovarian cancer showing no benefit. That was the JAVELIN study, which was chemo plus a valumet versus chemo, and imagine O5O as well. And in both of these studies, there was no difference in the immunotherapy plus chemo arms. However, I think we can say, in terms of the retrospective data that we've seen from these studies, that there are probably specific subgroups of ovarian cancer that do benefit from immunotherapy. If you look at Keynote 100, which was the Pembrolizumab in patients with recurrent ovarian cancer, you can see that CPS score, the PD-L1 CPS score, seem to predict better responses to Pembrolizumab as a single agent, in terms of the CPS more than 10 versus those that have CPS one or less than 10. And likewise, histologically, we see that the claisel ovarian cancers had a response rate of about 16% versus high-grade serous, which was only about 8%. And if you go back to the imagine O5O, and when they did a subgroup analysis of a small population of the patients that had a PD-L1 positivity of more than 5%, there was a hint that there could be a difference in the progression-free survival. And it could be that in the future with immunotherapy, we will have to think about selecting patients with a higher level of PD-L1 expression in order to see whether or not there'll be more significant benefit to be gained when using checkpoint inhibitors. Of course, MSI-high tumors are a known and bona fide biomarker for response, and in the Keynote 158, ovarian cancers had a 33% response to Pembrolizumab if they were MSI-high. And likewise, if you have a TMB-high tumor, then you are more likely to respond to immunotherapy as well. And in that context, if you look at the different histological subtypes, it could very well be that for immunotherapy, we need to be start thinking about specific histological types of cancers that we try and target with immunotherapy, because you can see clear cell endometrioid, endometrioid cancers tend to have a higher prevalence of increased mutational burden and higher prevalence of MSI-high tumors. In the gene expression profiles of ovarian clear cell cast numbers, we do see very consistent immunogenic signatures across different ethnic populations, and this was recently published by Hong and colleagues, where we did an initial analysis on the Singapore samples, and subsequently in Japan and the UK, and you see quite consistently that you get these T-cell antigen presenting subgroups with T-rate upregulation in certain groups. And certainly, it does appear that the PD-1 high and CTLA-4 subgroups of these cancers appear to have a worse prognosis than the proangiogenic subtypes. So, it's a good question to ask, I think, about whether clear cell cancers are more likely to respond to immunotherapy, and there are three studies that are ongoing, the MOCA study, which is DERVA versus key positions choice chemotherapy, which is completed and should read out towards the end of the year or early next year. There's the ongoing LARA study, which is combining limbatinib plus pembro and recurring gynecological clear cell carcinomas, and the PCOP study, pembrolizumab in the UK, for clear cell carcinomas. We are, of course, very interested in making cold tumors hot, and this has been approached in different ways in ovarian cancer. There's been interesting responses seen when niraparibs have been combined with pembrolizumab and recurring ovarian cancer, with response rates of about 18% being described, and likewise, anti-VEGF therapy may lead to maturation of dendritic cells, increased antigen presentation and T cell infiltration and trafficking, and so this combination of anti-VEGF and immunocheckpoint inhibitors may also be extremely relevant in treating recurrent ovarian cancer. And finally, adoptive T cell therapy has also been looked at in the context of small pilot studies showing quite prolonged disease control in some patients. There are studies looking at combining AKT-PI-PIC3CA pathway inhibitors with PARP inhibitors, as well as with now immune checkpoint inhibitors, seeing that there could be a biological rationale for synergistic effects when you can inhibit the T cells with PIC3CA inhibitors and then subsequently enhance the effect of the PARP inhibitors by down-regulating BRCA expression with PIC3CA inhibition as well. TGF-beta is a protein which is involved in cell proliferation and switching of a microenvironment to a more immunosuppressive environment by enhancing up regulation of Th2 and M2-type macrophages, and there are multiple approaches to now try and inhibit TGF-beta, including a vaccine strategy with gemogenovitussil, which is an autologous cell vaccine from harvested tumors that reduces the expression of furin in downstream TGF-beta1 and 2. And this was presented this year in ASCO showing that in the HRP population, there appeared to be a significant improvement in relapsed resurvival and overall survival in the HRP population patients that were treated with this vaccine. Beta-catenin and Wnt has been up-regulated in immune-depleted cancers, and there are studies now targeting porcupine, which basically palmitolates Wnt to allow it to be secreted into the tumor microenvironment, and if you can inhibit porcupine with porcupine inhibitors, you might then be able to convert a cold tumor microenvironment into a hot environment, as seen here in this cholangiocarcinoma patient that was treated with ETC159, this porcupine inhibitor. And there's an ongoing phase one study combining PEMBRO with ETC159 and recruiting ovarian cancer patients as well. And finally, we have therapeutic vaccines like dendritic cells, adjuvants, and bio-vectors, and we look forward to more and more of these readouts in the future. Antibody drug candidates include an antibody that will bind to a selective protein expressed on a cancer cell that's linked to a cytotoxic drug, and there are now many ADCs that are in development in various phases in ovarian cancer. One that is now in quite advanced development is tissue factor ADC-tisotamide vedotin. There is an ongoing study of weekly TV for patients with platinum-resistant ovarian cancer, and there's also the mervetoximab soraftazine, which is a folic alpha ADC, receptor alpha ADC, which is a folic alpha receptor is expressed in about 60-100% of ovarian cancers, and we see here that folic receptor alpha expression high platinum agnostic cancers had a longer median duration of response, and also quite significant and deep responses when given this combination. Of course, apart from high-grade serous ovarian cancer, we do need to start turning our attention to clear cell and endometriotic cancers, which do have a larger prevalence in Asian populations, and we know that ARID1A is a frequently mutated tumor in clear cell and endometriotic ovarian cancer, and there are now various strategies that have suggested that ATR inhibitors may be effective in targeting tumors deficient in ARID1A and their ATR and PARP inhibitor combinations that are ongoing at the moment in phase one trials, and it appears that ARID1A deficient tumors may also be more sensitive to inhibition of the glutamine and glutamate synthesis as well, and more recently BET inhibitors have also preclinically been shown to be a potential drug to target tumors with ARID1A mutations. And finally, we need to look at low-grade serous ovarian cancer, a rare subtype, but hard to treat and very challenging in the advanced setting, but we do know that most of these tumors are associated with KRAS and BRAF and mutations, and there have been studies looking at targeting the RAS pathway with MEK inhibitors, and this is a Trematinib study showing improvement in the progression pre-survival of Trematinib versus control, but in the overall survival there was crossover and there was no significant benefits in here, but there was still a trend towards the benefit of Trematinib being used in these cancers versus a physician's choice treatment, and Brett Monk and colleagues also published this randomized study of Binimatinib in the context of recurrent slow-grade serous ovarian cancer, and in the KRAS mutant population you saw a much higher complete and partial response rate, suggesting that a KRAS mutant selection may be important in this tumor as well. So in conclusion, I think we can look forward to multiple new targets and agents emerging for ovarian cancer, and one-size-certainly-does-not-fit-all. Molecular profiling is really going to be important to identify the right therapy for the right patients. We do need to address efficacy and toxicity across various ethnic subgroups, and I think translational studies will be the key to understand our reasons for success and failure, and finally, we do have to address the big elephant in the room, which is drug and clinical trial accessibility. Thank you very much. Thank you, Dr. Tan. That was so insightful. I'd like to introduce Dr. Angelica Noriega-Rodriguez from Brazil and South America. Thank you so much. She's going to be presenting Real-World Challenging Accessing Novel Therapeutics. Thank you, Dr. Angeliz. Hello, everyone. On behalf of the low- and middle-income countries community, I'd like to express my gratitude to IGCS for including this necessary discussion, Real-World Challenging Accessing Novel Therapeutics. Please pay attention to my conflicts of interest. According to the GlobalCAN, over 300,000 women are diagnosed with ovarian cancer, and more than two-thirds of them die globally from the disease, and the relevant information for this discussion is that, according to the World Bank, only 16% of the world population live in high-income countries, while 84% live in low- and middle-income areas. Focusing on GlobalCAN projections, by the year 2040, ovarian cancer incidence should rise by 47%, with an even larger increase in mortality, nearly 59%. And working with these numbers, we are able to calculate a global increase in the mortality to incidence. Despite all ongoing medical advances in ovarian cancer, its mortality to incidence ratio is expected to increase within 20 years, from 62 to 67 percent. And these numbers are boosted by the much concerning African scenario where ovarian cancer, when ovarian cancer mortality to incidence is expected to reach 78 percent by the year 2040. The aim of this presentation is challenge success in novel therapeutics. These include PARP inhibitors, genetic support, which have become game changers. However, for properly tackling an adequate systemic treatment, it may be important to take a step back as basic support still may be the most relevant barrier to improve ovarian cancer mortality. This is Brazilian data from 45,000 ovarian cancer patients published by our group last year. And according to it, almost one third of the patients take more than 60 days to start their treatment after having a biopsy. And around 20 percent of them die after one single treatment modality. For example, just one surgery or one chemotherapy. Numbers which probably mirror other low and middle income countries. What's more, Brazil is an upper middle income country, not a low income country. An overview of resources in Africa was published at JCO Global Oncology. And the authors reported a total number of only 102 cancer treatment centers, not sufficient to cover the increasing needs of the African population affected by cancer. Essential medications in the whole list were shown to cover only half of the demand. Buying drugs privately costs an amount equivalent to between one and seven months of income. And believe it or not, prices of magazine in Africa were between two and six times higher in Africa than international reference prices. Now moving our focus to Asia, according to asthma data, cancer drugs availability is heterogeneous in the region, as you can see by the colors. And some essential medications as carboplatin and patrotexel, nibs and mabs are only available at full cost or not available at all in low income countries as Afghanistan, Cambodia, and Nepal. In fact, globally, low and middle income countries have significant lack of availability and high out of pocket expenditures for both essential medicines and recently approved, still not on the whole list. But also high income countries struggle with inequities. This meta-analysis founded higher mortality among U.S. ovarian cancer patients who are Black and have low socioeconomic status. Women access to clinical trials is also harder for those in low and middle income countries. Number of recruiting sites for ovarian cancer trials is higher than in the U.S. And the number of ovarian cancer trials is currently 25 times higher in the U.S. compared to Asia. A recent publication, a gem on time to drug approval, has shown that it's faster in high income countries, median eight months, compared to 11 months in upper middle and 17 in the lower middle tier. And it's the slowest in the African continent, again. There is a great need to expand genetic testing and counseling for ovarian cancer globally, but there are peculiarities. Like here in Brazil, we currently have access to the expensive HRD tests supported by the industry, but PARP inhibitors are still out of reach for the majority of the population. A real world challenge to access novel therapeutics in ovarian cancer are multiple, but may be grouped into the following five main categories. Lack of epidemiological data. Currently, only one in five low and middle income countries have the necessary data to drive policies. Geographic barriers explained by distances and insufficient number of centers per country. Limited access to genetic testing and counseling. Costs to health systems and to patients as out of pocket payment is a common practice in poorer areas. And long time for drugs approval. We are still far from a magic solution for these problems, but the following should be the focus of our immediate focus. Data reflecting the diversity of local populations, shortening the time for approval and registration of cancer medicines. Access to appropriate and timely genetic testing and counseling. Increasing the budget allocation for effective medicine. Increasing the budget allocation for effective medicines and improving affordability. I'd like to bring this presentation to an end by highlighting that despite the advances we have been witnessing in ovarian cancer, its mortality to incidence is expected to increase. And if we really want to call ourselves the generation of game changers, we must strive for equity. Thank you very much for your attention. Wow, I just, I feel like I've been on a roller coaster ride here. I'd like to join all our speakers, or ask all our speakers to join us on this panel and I want to introduce Dr. Lisa Bezet Marabella from Botswana in Africa. You know, I was, you see Dr. Chris Light's presentation, Dr. Tan's presentation, all this amazing translational research, the science, novel therapies, and then Dr. Noguera-Rodriguez brought us back to the harsh reality that a lot of these medications are just not available for most women with these cancers. And Dr. Bezet Marabella, you know, you're from Africa and just really boots on the ground trying to treat women with these cancers. Can you describe the experience in Africa and the availabilities of some of these drugs we're talking about, such as PARP inhibitors and just as Dr. Noguera-Rodriguez brought up the access to chemotherapies? You're on mute, Dr. Bezet Marabella, you're on mute. Thank you, thank you. I appreciate you giving me the opportunity to represent some of the countries in Africa that I've worked in. I spent four years in Rwanda and now the last two in Botswana after practicing 15 years in the U.S. So I have quite an interesting perspective, but we can talk all day about PARP inhibitors and all different types of novel therapeutics when we struggle to get basic chemotherapy much of the time. Botswana is a middle-income country and we typically have carboplatin and Taxol available, but beyond that, if a patient has a recurrence, we don't really have access to many other drugs in the public sector. And many low-income countries are often still stockouts of the basic chemotherapy drugs where we can go weeks and months without having just access to the essentials. Yeah, that's absolutely sobering and incredibly sad. You know, one of the questions in the chat is how do you even begin to handle these high cost of drug prices in Africa? And not just Africa, but I would say other countries as well, as brought forward in the presentation we just heard. I know that's a big ask of this panel, but we thought that they were happy we drive those prices down. I mean, I was going to add that, you know, even within Asia, there's a lot of disparity and, you know, in terms of, you know, various economic statuses in various countries, right? I mean, there are some places where, as you have the same problem, just, you know, getting patients to cover the cost of chemotherapy is going to be a real challenge, let alone when you start talking about PARP inhibitors and immunotherapy. Where I think it has been quite useful is that increasingly we see a lot of companies recognizing that there is a problem with getting access for patients and not just, you know, get drug access, but even biomarker access, right? If you can't even test whether a patient has got a BRCA mutation or HRD positivity, I mean, how do you even stratify whether these patients will benefit from that treatment or not? And in a way we've seen, and certainly in my country, you know, not everyone can afford all the treatments we put down, but we've worked with certain companies to come up with patient access schemes, compassionate access schemes. And I think perhaps we do as a group have to lobby with, you know, with the companies that we work with and with the pharma industry to see how we can improve that equity, perhaps with sort of compassionate access. And also I think trial access, because I think the one thing we can say is that, you know, when you look at disparity that Angelica demonstrated between the US and Asia, I think, you know, even the rest of the world, you know, there's so many women and so many ethnic groups that just don't get a chance to participate in studies that potentially could be, you know, life-saving for some of these patients. And so one of the other questions in the chat was directed toward Dr. McGarrick-Rodriguez regarding, well, you know, how do you bring about equity? And I think you gave us a roadmap. Your one slide absolutely did that. And I think that our challenge as part of the society is to take that roadmap and really make it into actionable items and develop some metrics around that. So any other thoughts that you would like to present on that, Angelica? I tried to resume something that is very difficult, but first of all, I think that we need data. We need to show to the countries that it's possible to do different. Then we work on that. And as an international society, to clinical trials would be very important when we participate. Doctors start using the drug. They know how to test patients and they start working, striving for changing this situation. And I think that this kind of discussion in international societies, they are very important for us. Thank you for bringing the topic. One of the items that Dr. Coleman said in his presidential address is the I in IGCS, right, the international component. And I think that from these presentations that you all have given us, it's just been incredibly insightful. So I'm hopeful that we can use this to launch this initiative to provide equitable care for not just ovarian cancer, but all gynecologic cancers across the globe. But we can certainly start with ovarian cancer. And there are several presentations already given today to try to launch this purpose. So maybe something to talk to Dr. Coleman and to Mary Eichen about in terms of some new projects within IGCS. I just want to touch forward on Dr. Kristolite's presentation. You gave a whole bunch of different ideas about translational research. What do you think are the next critical agents to explore in patients with PARP-resistant disease? Oh, that's the million-dollar question, isn't it, Angeles? I mean, I think each one is probably a bit different. You know, I don't think you could pin me down and say it has to be this drug and has to be that drug. I do think where we are from today, the replication stress response is the one where there's most ability to target. I think ATR and ATM inhibitors are very interesting drugs. Obviously, there's much more data out there for ATR inhibitors. We've got an indication of possible sensitizing biomarkers. So that would probably, if you had to pin me down to one, it would be the ATR inhibitor group as the next wave coming through. But I think there's a lot coming behind, and I can't stress enough how important it is to be continuing to collect all that molecular data to understand what the dynamics are of everything we're doing. Although, you know, I do hear the issues with, you know, getting access to treatment per se, but we need to know. I think maybe that's another angle of access to treatment is if there is difficulty and there is rationing, it's so important to get it right. It's so important not to waste time with the wrong drug. So, you know, it's a full circle here. Absolutely. Great. There are some other questions in the chat, if you all can turn to that. In the interest of time, we really have to move forward with our next session. So I'd like to thank you all for your insightful presentations. Dr. Brissette Mirabelli, I hope we can do another session, just so you can focus and give us more information on the situation in Africa at some time point. And with this, I'd like to send this back to Dr. Claire Scott. Great. Thank you very much. And look, it has just been so inspiring so far with such a great pace set as well. And I'm sure we're going to be able to continue that because we have some fabulous speakers coming up. So it's a great pleasure to be chairing this particular part of the Ovarian Cancer Master Session. I'd just like to begin by saying that thanks to the extraordinary results of PARP inhibitor therapy, we now know that treating ovarian cancer will thankfully never be the same as it was in the past. However, apart from women with ovarian cancer, which is mutated for BRCA1 and 2 and a few related genes, it's not entirely clear who else should receive PARP inhibitor therapy and when. So for this first example of a treatment for which we need biomarkers, two major issues come to mind to me, something we've already discussed tonight. Not all countries in the world have equal access beyond BRCA1 and 2, in my country included in Australia. So select groups of patients need to be targeted for therapy, and we don't quite know how to do that. We don't know how to make all ovarian cancers as responsive to PARP inhibitors as are some, for example, BRCA2 mutant cancers, some of which seem to be able to be cured almost with single-agent PARP inhibitor first-line maintenance therapy. So we clearly need biomarkers to identify women with ovarian cancer suitable for certain combination PARP inhibitor therapies, and we've heard a lot already tonight about potential combinations that would aid in that direction. So this session you're about to hear will go some way to addressing this exciting example of the importance of the role of prognostic and predictive biomarkers in ovarian cancer, and will also address other important examples of sorely needed prognostic and predictive biomarkers. So as I said, we will have three superb speakers who've each made significant contributions in different areas of biomarkers in ovarian cancer. So I'd like to start by introducing Charlie Gouley, who needs no introduction to many of you, as you will have heard him speak before, but for some of you, you may not have heard him speak and is going to be an absolute treat to listen to. He trained in Glasgow at Edinburgh University and was appointed Senior Lecturer in Medical Oncology at University of Edinburgh back in 2005, but has been a professor for a very long time, nearly 10 years, and is the current chair of the Gynecological Cancer Intergroup at GCIG in terms of the Translational Committee as well. So we've been fortunate enough to have Charlie direct a lot of our action in ovarian cancer over the last number of years. He's also active in a lot of ovarian cancer clinical trials and was indeed the UK lead for SOLO1. But more than that, he also has been a heavy contributor to our translational research, both in terms of expression analyses, but more recently on genomic characterization, including whole genome sequencing of ovarian cancer. And this really has been to try to discover novel biomarkers of ovarian cancer, drug sensitivity and resistance. So over to you, Charlie. I'm really looking forward to this. Thanks very much. Thanks for the introduction. Can you see my slides OK? Yep, they look great. Thank you. Thanks. So these are my disclosures. So first of all, a warning. I'm a medical oncologist. I'm not a surgeon. And I'm going to talk about biomarkers, which I think currently impact the surgical decision making in our multidisciplinary team. And, you know, thanks to Claire and Christina and Andres for the invitation. This wasn't an easy talk to write, I have to say, because the truth of the matter regarding molecular surgical biomarkers is that we would love to have true molecular biomarkers that tell us which patients could be developed to zero and which could not. That would really help us. And I could easily go through a list of studies that have proposed and even published about biomarkers in surgery. But unfortunately, none of these have really survived attempts at validation. And because of that, none are really incorporated into routine standard of care decision making. But what we do have is a growing understanding of the biology of ovarian cancer. And some of these understandings do feed into our surgical decision making, at least as I see it as a medical oncologist contributing to that discussion of who should have an operation and who shouldn't. And so I'm just going to go through it in that sort of context. So it was really a thought exercise. So I was thinking about what could you regard as biomarkers that currently feed into our decision making? And I could only really think of three things. Histological subtype, AGO score by virtue of the imaging component, which I think is possibly could be regarded as a biomarker. And then in brackets, BRCA and HRD status. I mean, I'll explain the reason why that's in brackets later. So if we talk about histological subtype, and it's already been mentioned today, and all of you be aware, ovarian cancer is a number of diseases in terms of cell of origin, in terms of molecular biology, in terms of response to therapy. But in terms of the surgical decision, I think histological subtype is really important for the primary debulking versus neoadjuvant chemo decision, because you cannot regard all these cancers as the same. For the same reason, in the decision making around about secondary debulking, histological subtype is really important. And then also, if we were ever to be in a position where we thought there were surgical biomarkers, then histological subtype is really important in terms of interpreting those biomarkers, and I'll explain that. And the last thing I'm just going to say with regards to this slide is that if you're in doubt about the histological subtype, p53 sequencing can really help. In our MDM, it was only very recently we've had access to that, and we used to sometimes have difficulty discriminating high grade and low grade series on the basis of morphology. And, you know, I would say to our pathologists, I really need to know, because it really helps us in our decision making, surgical and systemic therapy, and thankfully now we've got p53 sequencing available, which really makes things a lot easier. So, in terms of the primary debulking versus neoadjuvant decision, for high grade series and high grade endometrioid, there are algorithms that are well published that help you decide whether a patient should have an upfront operation or should have chemo first, then an operation, and that's fine. I wouldn't argue with that. But for clear cell, low grade series, mucinous, and low grade endometrioid, the response rate to primary chemotherapy is extremely low, and so neoadjuvant chemo is not a good choice unless there's no alternative, I would say. And so I think the decision making point, a balance point, is different in these histologies than it is in high grade series and high grade endometrioid, where you know the response to neoadjuvant chemo may be decent. Examples are clear cell, chemo response 32%, low grade series, platinum response about 8%, non-platinum response somewhere between 0 and 15%, depending on what study you look at. Interestingly, aromatase inhibitor response about 14%, and in the relapsed disease setting, the trimetanib response rate is 26%, so there is discussion in some truly non-debulkable cases of perhaps doing studies of aromatase inhibitors or MEK inhibitors. And then in the secondary debulking setting, it's a similar story. So for high-grade serous and high-grade endometrioid, I think the decision-making can be largely based around the AGO score. Again, for clear cell, low-grade serous, mucinous, and low-grade endometrioid, the response rate to chemo is very low, but durable survival is possible. So for that reason, in selected cases, secondary debulking should maybe be considered outside of the AGO score, which I would reckon probably doesn't apply because there won't have been many of those histologies in the desktop studies. And of course, this has been looked at in retrospective series. So in low-grade serous, there seems to be a benefit from secondary debulking in terms of progression-free and overall survival. Although, of course, these studies are always criticized because there will be strong selection bias in terms of the patients who were operated on. And then this is the study that I was mentioning with regards to interpreting surgical biomarkers and needing to think about histological subtype. And it's a study from a long time ago by Martin Kobel, but it really was very informative. It took 500 ovarian cancer patients. It looked at 21 tissue-based protein biomarkers. So fairly basic from that perspective, but what they showed was that 20 out of 21 biomarkers differed significantly between subtypes, but they didn't differ between stages within the same subtype. And when they looked at prognostic biomarkers, which of these were prognostic, nine of them were prognostic. But once you've corrected for histological subtype, only three were prognostic. And the reason for that is you can sometimes, if you take the whole of ovarian cancer and you find the biomarker that you think is prognostic, it's often prognostic because it's associated with a bagged risk histological subtype. And so you must correct for histological subtype in all of these analyses. So biomarker two, the AGO score, you'll all know about the AGO score. This Kaplan-Meier curve is from the DESKTOP3 study, which is a great study showing an overall survival benefit for patients who were operated on if they met the AGO criteria, which is performance status zero, complete resection at the time of primary surgery, and less than 500 mils of ascites. And then the last potential biomarker I was going to mention is BRCA or HRD status. So Jalad spoke earlier about the LION study, which showed that if lymph nodes aren't enlarged, there isn't an outcome benefit in terms of resecting them. But we now live in a world where our stage 3 and stage 4 patients can get PARP inhibitors if they've got a BRCA mutation, or depending on your local licensing, or if they're HRD, or if they're HR deficient. So we went from a stage where maybe 10 years ago, we asked our surgeons to always take the lymph nodes, to a situation where if the lymph nodes are not enlarged, we don't ask them to take them. But if I've got a stage 2 patient with high-grade serosevere in cancer, I find myself asking, could they have covert stage 3 disease? And if they've got a BRCA mutation, I really, really want to know if they've got covert stage 3 disease, because I really want to know if I should be giving them a PARP inhibitor. So I have on occasion asked our surgeons to take lymph nodes in order to determine that. And that's perhaps a controversial thing to suggest, and obviously it would need to be discussed with your local surgeons. But when you see the long-term benefit, this is the five-year follow-up from the SOLO1 study, from patients getting a laparib compared to placebo, I don't want to have patients who appear to be stage 2, but actually stage 3 missing that opportunity. And then the very last thing to say about this is the issue of PARP inhibitor resistance. And Rebecca spoke very well about this, and there's not enough time to go into the mechanisms, but whatever resistance mechanism there is, there is overlap between platinum and PARP inhibitor resistance mechanisms. And one can't help feeling that an upfront operation that minimizes the number of cells that may contain resistant clones before exposing to chemo and then to PARP inhibitors might be better than exposing a huge bulk of cells to chemo, allowing resistance to be selected for early in the patient journey. And maybe we need to look at ctDNA to look for whether there's pre-existing resistance mechanisms. Maybe we need to be more sophisticated about this, but I think we need some sort of way to feed that into the surgical decision. So in summary, unfortunately, there are few biomarkers to direct surgical decision making, and it's a major area of need. It's great to hear Christina say that the trust study is going to incorporate a lot of molecular analysis. Histological subtype is key in the first line and relapse disease setting in terms of the surgical decision making. And a greater understanding of the underlying biology and evolution of the various ovarian cancer subtypes may help the future development of surgical biomarkers. So thank you very much for your attention. Thank you very much, Charlie. Look, it's a really great, I think it's really great to hear a medical oncologist speak about surgical aspects. And, you know, it has to be a combined approach to understanding really what we're going to do with our patients, and particularly when we have such critical questions about impacting on our therapies. But for now, we'll continue to move on. And I'm delighted to introduce Dr. Rowan Miller, who is a consultant medical oncologist specializing in gynecological oncology and early phase clinical trials at University College London and St Bartholomew's Hospitals in London. She completed her undergraduate training at University of Oxford and then trained at Guy's and St Thomas', and trained also at UCL, and then went on and obtained her PhD from the Institute of Cancer Research. Then she did a fellowship at the Dana-Farber in Boston. So Rowan has been involved in a series of clinical trials, but also in basic research projects. And she's a member of the ESMO Personalized Medicine and Translational Research Committee. And really notably for me, she was the first author on the ESMO Recommendations on Predictive Biomarker Testing for Homologous Recombination Deficiency and PARP Inhibitor Benefit in ovarian cancer just recently, which I think is really important for many of us in the field. So I'm really looking forward to her talk today, where she's going to cover off on a lot of those relevant issues. Welcome. Thank you, Claire, and thank you for inviting me to speak today. I'm sorry if I can't share my video, it's seeing the host is not allowing me. So today I'm talking about biomarkers to direct systemic therapy, and particularly with a focus on the ESMO ovarian cancer guidelines. These are my disclosures. And as an introduction, when we talk about biomarkers to direct systemic therapy, we really mean predictive biomarkers. That is tests that can be done to select patients for a specific treatment, which has been known to improve outcome. And when we think about the ESMO guidelines, there are a number of criteria or scales that are considered before a recommendation is made to ensure that there's high quality recommendation and there's consensus across the different guidelines. So we consider the level of evidence whereby clinical trial data is graded from one to five, with level one being high quality, randomized, prospective clinical trials that are suitably powered to answer the question of interest, down to level five, whereby these are often a retrospective or cohort studies, not statistically powered. Any recommendation is graded whereby grade A is a strong recommendation with good evidence to support it and is highly recommended, down to E whereby we don't recommend this indication because either there's no evidence of benefit or indeed there's harm associated with this treatment. And then finally, more recently, ESMO has been incorporating this magnitude of clinical benefit scale to all their guidelines. And this is a way of trying to compare different studies with lots of different treatment intentions in order to provide a rational, structured and consistent approach to derive a relative ranking of the degree of benefit. And things that are taken in consideration when providing this ranking is, is this a curative study? Is it given for palliative? What's the overall survival, progression-free survival, hazard ratio, etc.? And when we take in these three scales of benefit that need to be considered and adopt this to ovarian cancer, particularly with regards to predictive biomarkers, really the only ones of which there's good evidence, enough to be incorporated in the guidelines, is the use of biomarkers to select PARP inhibitor therapy in high-grade, predominantly high-grade, serious ovarian cancer. And here we're talking about BRCA mutation status and homologous recombination deficiency. So you'll all be very familiar with this pie chart, which is now a decade old. It's from the Cancer Genome Atlas, whereby they screened a number of ovarian cancers. And here we plot the recurrent mutations in high-grade ovarian cancer. And by far the most common recurring mutations, as we're all aware, is those in BRCA1 and BRCA2. And about 20 to 25% of our patients will have a hereditary or somatic mutation in BRCA1 or BRCA2. And the prognostic and predictive role of this biomarker is well established. This Kaplan-Meier curve is actually from 2012, and it shows a five-year survival advantage for BRCA mutant cancers compared to BRCA wild-type. And it's worth noting that this is prior to the widespread introduction of PARP inhibitor use. We know that BRCA mutation status is a strong predictive biomarker of superior response to PARP inhibitor therapy. You know, indeed, PARP inhibitors were developed as a synthetic lethal approach for BRCA mutant cancers, and all the early phase trials were enriched for patients with the BRCA mutation. And so even in the dose-finding studies, superior responses and prolonged duration of responses were seen in the BRCA mutant patients versus their wild-type cohorts. And when we apply this to ovarian cancer, this is one of the first randomized trials, which you'll all be familiar with, Study 19, which looked at maintenance of laparib or placebo for patients with recurrent ovarian cancer who'd responded to platinum. And the top Kaplan-Meier curve, you can see there's a benefit for the population as a whole, but when the authors retrospectively apply BRCA status, there's a significant increase in benefit in the BRCA mutant population with a really highly significant hazard ratio compared to a much more modest improvement in BRCA wild-type cancers. And this pattern of shift-wide drop in benefit when you move from BRCA mutant to wild-type is something we can see consistently regardless of the type of trial, the setting, is it first line, is it recurrent disease, is it being given as maintenance, or is it being given as therapy? So as a result, BRCA testing has really been incorporated into our guidelines for many years now. And as long ago as 2013, the ESMO guidelines recommended that all patients with high grade ovarian cancer should be tested for BRCA1 and BRCA2 at diagnosis with high level of evidence and strength of recommendation. Now, based on all the recent first-line PARP inhibitor studies, an update for the ESMO guidelines was recently released. And here they've stated that patients with a BRCA mutation who've responded to first-line chemotherapy should receive maintenance treatment with a PARP inhibitor. And that can either be two years of elapra based on the SOLO1 data, nerapra based on the PRIMA data, or for those patients already receiving bevacuzumab, elapra can be added. And we know that each of these studies is a high level of evidence with strong recommendation. Now, we know that BRCA only represents about a quarter of the patients, and this original TCGA data suggested that about half of patients with ovarian cancer had a mutation or abnormality in one or more gene-controlling homologous recombination, which is this highly conserved means of double-strand DNA repair. But despite this knowledge being present for a decade or so, really, it's not been clear until recently how we should be measuring these cancers for homologous recombination deficiency, who we should be testing when, and what's the benefit of testing HRD in the cohort of ovarian cancer patients. And based on these uncertainties in 2019, the ESMO Translational Research and Precision Medicine group really identified a big need for a better understanding of HRD, and really the need to develop some consensus statements, particularly when it comes to the role of it as a predictive biomarker for PARP inhibitor benefit in ovarian cancer. And a collaborative project was launched, but really, the three main aims were, firstly, to define what do we mean by HRD test, and how can the HRD test validity be best assessed in the context of high-grade ovarian cancer, to provide an overview of the rationale for each of the different tests and the level of evidence to support them, because we know that there are lots of different ways of examining for HRD. And then finally, and probably most importantly for us clinicians, is to provide some recommendations on the clinical utility of HRD testing, particularly with regards to the management of high-grade serous ovarian cancer. Now, there are a number of ways of looking for HRD, and I don't really have time to go through these in great detail, but to summarise, most fall into one of three categories. We can look at the etiology or the cause of HRD by screening for individual mutations or methylation in different HR genes. The problem with this is that with the exception of BRCA1 and BRCA2, mutation in other homologous recombination genes are present at low frequency, and actually the individual effect on each of these genes in terms of PARP inhibitor response is not well described. Ideally, we'd love to have a functional assay which provides a real-time readout of homologous recombination, but as yet these assays are not yet ready for clinical prime time, and often they're highly reliant on fresh tumour samples, which are probably not practical to apply at scale to all ovarian cancer population. So increasingly, we become reliant on these genomic scar assays, and that's because a cancer that is defective in BRCA1 or another homologous recombination gene is more reliant on error-formed means of DNA repair, so over time you get this accumulation of DNA damage across the genome, which can be viewed either using copy number assays where you see typical changes in chromosomes, such as loss of heterozygosity, telomeric imbalance, large-scale transition, and these can be measured and combined together to form a GIS or genomic instability score, or we can use whole genome sequencing looking at various signatures, of which particularly signature 3 is associated with homologous recombination deficiency. There are two commercial assays currently available which use a composite test, including both BRCA mutation status and either GIS or LOH score, and to date these are really the only assays that have been applied at scale to clinical trial data. So on that basis, with regards to the recommendations from ESMO with which testing we should be doing, when we look at HR gene level tests, we already know that BRCA mutation testing should be done, it identifies these patients who have the greatest magnitude of benefit, but as it stands there's not enough evidence to support using panels of non-BRCA genes to predict PAR-penetrator response. Although in theory functional assays are great, there's not enough evidence to support their use currently, but there is evidence to support the use of genomic scar assays, particularly those that incorporate either genomic instability or loss of heterozygosity, to identify the subgroup of BRCA patients who derive the greatest magnitude of benefit from PAR-penetrators. And where did that data come from? Well, we know that many of the trials involving PAR-penetrators, particularly all the recent first line trials, have incorporated HRD testing with a view to seeing whether it can be used as a predictor for PAR-penetrator benefit, and particularly here I'm talking about the PILO-1, the PRIMA, and the VELIA trial. Now some caution needs to be taken when looking at this data because none of these trials were actually prospectively designed to evaluate the role of HRD tests in all of the subgroups, particularly the HR-proficient tests, and although it was a pre-planned analysis, it was an exploratory analysis. However, despite that, these are large trials involving lots of patients with good quality data, so we can derive a number of conclusions from them. Here we have a forest plot. It's not designed to compare all the different trials, but merely to show that the benefit of PAR-penetrator versus control in all the different biomarker subgroups across all the different trials. And as you would imagine, the patients with a BRCA mutation have the greatest degree of benefit, the lowest hazard ratio, and that's consistent, and there's actually fairly consistent value across all the trials. But not far behind them is this group of patients that are BRCA wild type and HRD, who have a highly significant hazard ratio and a great benefit from PAR-penetrators. And then the least benefit is seen in this group, the HR-proficient, or sometimes called HRD-negative group, who have only a small magnitude of benefit. And indeed, although many of the hazard lines cross one, there is a trend towards benefit even in this group of patients, which probably suggests that the assays that we're currently using are not good enough to reliably identify all the patients who do benefit from this treatment. So taking these results into consideration and the ESMO consensus statement on HRD testing, this has now been incorporated into the ovarian cancer ESMO guidelines, which have just recently been published, but what state that we should now be testing for genomic instability or homologous recombination for all patients with ovarian cancer, because it does identify the subgroup of BRCA wild type patients who derive the greatest benefit. This is supported by high quality evidence and it's a strong recommendation. Following on from that, they state that patients with a positive HRD test who've responded to chemotherapy with or without bevacuzumab should receive maintenance therapy with PAR-penetrator, and that can either be a laparib in addition to bevacuzumab if they're already on bevacuzumab, or noreparib monotherapy. And again, supported by high level evidence, strong recommendation, and a high magnitude of clinical benefit score. On the flip side, patients who are on bevacuzumab and turn out to be HRD negative have no benefit from the addition of a laparib, and therefore this is not recommended, and indeed it's not licensed. And then finally, we know that noreparib monotherapy is available for all patients with advanced ovarian cancer, and the long-term data from this is not yet available, and therefore the recommendation is that decisions about using this drug, particularly in the HRD negative or unknown population, really needs to be made on a case-by-case basis, so there's not enough data to either support or refute this indication. So in summary, ESMO guidelines now recommend incorporation of HRD or GIS testing in addition to bracket testing for all women with newly diagnosed advanced ovarian cancer. And with this information, it really does help us determine the optimal maintenance treatment for our patients, and importantly gives some predictive information on the expected degree of benefit from this treatment, so we can counsel patients appropriately when they start. I think despite these recommendations, we have to take them with some caution. The negative predictive values of the current commercial assays is not great, and there are, we will miss some patients who benefit from PARC. And then we know that these don't provide a contemporaneous HRD readout, so for example the BRCA reversion mutations that we've heard about, which would restore HR function, because these tests are historic reading, these patients would still come out as HR deficient, despite no longer meeting that phenotype. So thank you for your time and opportunity to share my slides. Thank you very much, Rowan. I think that that was an excellent example of where we are at this point in time. It's a complicated field, it's taken a huge amount of data to be able to produce these guidelines, and at least it shows us where some people in the world are at. I'd definitely wish I was in the position of being able to take advantage of these guidelines, and like many in the world, there are many countries who aren't yet able to take advantage of those guidelines in terms of not having access to the drugs, but at least we can see where we would like to be, and certainly knowing where the data is at is incredibly important. So our last speaker for the session is Dr. Alexandra Leary. She's an oncologist within the Gustave Roussi Department of Oncological Medicine in Paris and has been involved in many clinical trials. She was senior author on the cervical keynote 158 study and has also been involved in many translational analyses of gynecological cancer. And so because of her broad experience, I'm confident that she'll be very well-placed to provide us with future directions. So Alex, we're really looking forward to what you have to tell us. Thank you. Hello, and thank you for the invitation. These are my disclosures. So what is the future? Well, I guess one of the questions we have is what do we know about biomarkers of PARP-I benefit beyond BRCA mutation, which remains our best biomarker? And these GIS scores that have been very nicely presented by my colleague, is this good enough? Do we want more than that? And I think that's a bit what I'll be discussing today. Now, why would we bother? Why do we need other biomarkers for PARP-I benefit, especially probably in our BRCA wild-type patients? Well, maybe because what we have currently is not good enough. One is these scar assays, they're commercially available, but actually they might not be available around the world. I know that in my country next year, I don't know how we're gonna do it. That speaks, if we talk about Africa, South America, how are all of our patients gonna be having access to this? So can we find tests that might be more feasible locally in academic laboratories? Second point is that 15 to 18% of the tumors analyzed for these genomic instability tests are actually non-contributive. We don't have the information. That's actually the same proportion as those that we identify that are BRCA wild-type genomic, genomically unstable. So we have an equal amount for which we do not have the information. And we do have some BRCA mutated that have primary resistance. Luckily, the number is low, but if we could identify those, that could be useful. So what do we know today about biomarkers beyond BRCA mutation and beyond these scores? Now I'll go over this briefly because I actually thought it was gonna be discussed, but one is how about BRCA promoter hypermethylation? So there are patients do not have the mutation, but they lose the gene expression because of hypermethylation of the promoter. For a long time, we didn't have much data to suggest this would predict PARP benefit, but actually there's some nice data that has come a lot from Liz Swisher and colleagues showing that actually some BRCA hypermethylated tumors are probably very sensitive as long as they're very hypermethylated and it's basically a homozygous event. So perhaps. Alterations in non-BRCA HR genes. Again, not much data to support that. And although I'm not presenting the data, it was very nice data presented by Éric Pujet-Lorraine recently that showed that actually in the Paola study, mutations in non-BRCA HR genes were rare. First of all, 5%, depending on your panel, and it did not seem to predict any benefit from the addition of elaporate to bevacizumab, at least in the Paola study. So for now, really, we can't use this either. So I thought I'd present a couple of other approaches. They're not here yet, but we're hoping maybe they would provide some data. So how about whole genome sequencing signatures as predictors? We actually have data that goes back to 2017. This is in breast cancer, but where by doing whole genome sequencing, you can see if you look at sporadic breast cancer compared to BRCA mutated, that they have very different complex patterns of genomic alterations. When you take into account the type of translocation patterns, the type of mutations, they're very unique. It's like a thumbprint almost, okay? And so although this was done in breast cancer, these authors showed very nice data showing that if you took into account all of the types of alterations they have, the types of signatures they have, you could construct almost like a formula that was very sensitive to predict BRCA mutation with an AUC that's great. So that was very, very interesting, but they did not provide the data to suggest that these signatures are useful in identifying benefit from a PARP inhibitor, especially in BRCA wild type, okay? Now, since then, there's been a lot of other elegant work actually by Charlie Gouley and some of his colleagues using shallow whole genome, which is much more feasible and routine. And there's a big collaborative effort within Europe to identify novel markers. And some people are looking at shallow whole genome to see if we can identify biomarkers of benefit using the samples that were in the Paola study. What other approaches are there? The other approaches are some of these functional tests that were mentioned during Rauhan's presentation. And here there's a big effort, again, a nice academic collaboration in Europe looking to see if we can develop a functional predictor. And here this is RAD51 predict. So what is this based on? Well, we've known for a long time that if you take fresh tumor cells, you irradiate them to induce DNA damage. And then you see if they're capable of repairing their double-strand break and to show evidence of repair of double-strand break, they should be able to recruit RAD51 foci, which are one of the most downstream effectors of homologous recombination. If they can, you induce DNA damage that can recruit RAD51 foci, these are proficient. You induce DNA damage, they can't recruit RAD51 foci to the nuclei, they are HR deficient. This is great, but as was said by my colleague, it requires fresh tissue. However, actually in some types of cancers, you might not need to induce extrinsic DNA damage because actually these tumors are so genomically unstable in a basal state that maybe you could just look at in a basal state their capacity to repair damaged DNA. Okay, and this is sort of the requirement to look at a functional test of double-strand break repair and fixed, formal and fixed paraffin-embedded tissue, okay? So you need to look at these tissues, see if they're incapable of recruiting RAD51, you've seen no RAD51 foci in cells that have to be in S phase, because that's the phase of the cycle where you use homologous recombination. And obviously you need to demonstrate that they have high level of double-strand breaks. And using this sort of triple staining, you might be able to identify HR deficient tumors. Now this is a collaboration with a number of great investigators. One is Julieta Serra in Val-de-Bron. Now she does these in breast cancers and she's shown in PDXs that these are all PDX models of breast cancer that you see over here, these are the RAD51 low tumors. So we suppose HRD and sure enough, those are the only tumors that responded to a PARP inhibitor in PDX models. These were all RAD51 high, HR proficient, they did not respond. And interestingly, this assay identifies BRCA mutated tumors that are HR proficient and do not respond to a PARP inhibitor. So we are doing the work in the ovarian cancer, which we presented at ASCO this year, which showed first of all, that all high-grade serious ovarian cancer has very high levels of DNA damage in a basal state with high gamma H2AX, that if the RAD51, they respond to platinum better, they have a better PFS. And importantly, among the BRCA mutated, we were able to identify a small set of BRCA mutated ovarian cancer that were essentially resistant to platinum. So this is obviously not validated and work is ongoing, but that's the second approach. Third approach is how about using artificial intelligence? Now here, our pathologists have told us for a long time, if you look at a tumor in the microscope, we can almost identify whether or not they're BRCA mutated. Why? Because BRCA mutated tumors on an HNA slide, so just one slide, have certain features such as TILs, more necrosis, that tend to predict that they have a BRCA mutation. Now this is useful, but it's not perfect. As you can see here, some of the BRCA associated tumors have none of these features. But although the eye is good, could we perfect the use of features, morphological features in an HNA to predict BRCA? Maybe we could if we used machine learning, so artificial intelligence. So we're not there yet with ovarian cancer, but we've proven it in other tumor types, okay? Using just artificial intelligence on a single HNA slide, you can predict mutations in non-small cell cancer, you can predict microsatellite instability in GI cancers. So could we predict HRD or PARP E-benefit in ovarian cancer? And I know a lot of us are working on this, and that only uses one HNA slide. In terms of biomarkers resistance, I won't go over this in detail because Rebecca Crystalite has talked about this, but we've known for a long time about BRCA reversions in patients after a platinum or after PARP inhibitors. In this publication, there was 14 different BRCA reversion mutations in a post-mortem analysis in a patient who was resistant to PARP. Do we have prospective data that reversion mutations are associated with primary PARP inhibitor resistance? So yes, this is Rebecca Crystalite's data from Ariel 4 that showed that if you have a reversion mutation at the time you introduce the PARP inhibitor, the blue line, you do worse than with standard chemotherapy, okay? The good news is these reversion mutations at relapsed disease are relatively rare. This is only 6% of BRCA mutated patients in Ariel 4. So in conclusion today, I think our best predictive biomarker for PARP benefit remains BRCA mutations, whether they're somatic or germline. Mutations in non-BRCA genes have not been proven to be useful, and for now we can't really be using them. How about in the future? I think we're all working on functional tests to see if that might be useful. Shallow whole genome signatures, or maybe we can just get the information from a simple H&E slide. I'd like to end by saying that we shouldn't only focus on high-grade ovarian cancer, and here I go back a bit to what David Tan spoke about earlier, that we have a lot of very different biomarkers and rare ovarian tumor types, and all of these may be actionable. Do we know that they're actionable? Well, we need to do the prospective trials to prove that, okay? Retrospective data won't be enough, and the good news is we're starting to do them. In ARID1A, it was already mentioned, there's a trial led by Susie Banerjee, and ARID1A mutated clear-cell ovarian cancer. Might they respond to ATR inhibitors? There's good preclinical data, so here we need to validate it in a prospective trial. And then last but not least, there is another trial just about to start looking at, does it actually help our patients? If we match patients with rare ovarian cancers, we look at their alteration, match them to the targeted therapy, does that benefit these patients? And so this is a prospective study that will be doing this, where if they have AKT alterations, they go into an AKT inhibitor, RAS, RAF, they get a MEK inhibitor, ERB alterations, they get trastuzumab ADC, and if they're not matched, they'll get a disassociation. But this is proof that even in rare cancers, we're trying to prospectively validate that you can match a drug to an alteration in ovarian cancer patients. Thank you very much for your attention. Thank you very much, Alex. And so if I could ask everyone to come for questions, that would be fantastic. I think this has been a really brilliant session showing that there is a huge amount of work going on, and at the same time, we have a long way to go, because there's a lot of good translational work that's been done, but there's a lot of work that we need to do with a lot of tissue that needs to be, some of which has been collected, but more that needs to be collected from here. So while perhaps we're waiting for questions to come through. I have a question. Great, go for it, Alex. For Charlie. So I like to comment about the impact of BRCA on whether or not you do lymph nodes surgery. I like to push it even further. Do you ever have the impression that especially your BRCA mutated tend to have more lymph node only disease, okay? So do you feel comfortable in patients who have really small amount of peritoneal disease, they have a BRCA mutation, mainly lymph nodes, or in the future, are you comfortable even in those not removing their lymph nodes? Because often you have a teeny bit of peritoneal disease, a little bit of stick in the fallopian tube, you don't look in your lymph nodes, but aren't you worried that three years later that's where they might relapse? Yeah, well, it's a good point. I have to say, you've obviously made this sort of clinical observation that we've seen as well, that people with BRCA mutations often have nodal dominant disease. And quite often, you know how you occasionally get people with superclinical fossil lymphadenopathy, et cetera, and, you know, it's just lymph nodes all the way up, quite often we've seen that. So, you know, I guess we're kind of guided by the LION study for the advanced stage disease. And so if there are visible nodes, then we'd want them taken out if possible. But I know where you're coming from in that, it all comes back to this whole thing about wanting rid of as many clones as possible before you expose them to the platinum. And I've got no evidence to really back that up, that's kind of a bit hand wavy, but, you know, I can't help thinking that in patients with BRCA mutations who may have an exceptional outcome, it'd be better to get rid of as many cells before you give them the chemo as possible. Maybe in the future, the LION trial will have the data of relapse sites for their BRCA mutated patients enrolled in LION and that might help us. Well, that would be awesome because then if they could stratify, you know, if they could do a subgroup analysis based on the biology, that would be brilliant. I mean, I certainly agree that it would be likely that, you know, reducing the incidence of loss of, you know, methylation and incidence of reversion, all those sorts of clones would be likely to be reduced if there was a smaller amount of tissue present at the end of, you know, that first period of maintenance therapy. So I'm a proponent of reducing tissue tumor burden at any point that you can really. Maybe would someone like to comment on secondary debulking in that regard? We haven't got a surgeon here, but it's the same idea. Hi, sorry, I'm here. I don't know if you can see me. Hi. So I don't think we will ever have to be honest, the data of the Lyon relapse sites very concretely because we don't have the, this is an older study. We did a long follow-up. We just do not have the BRCA studies for all our patients, unfortunately. And also never forget these patients that when we initially operate on them, not all of them had a CT pre-op, you know, many of them just had an ultrasound, et cetera. So it will be tricky to assess how everything will be, but the TRUST study, the TRUST study is a study where it will be a very robust study where we can see the patterns of relapse, et cetera. In any case, we have seen from the Lyon study that to remove or not remove microscopically involved nodes doesn't matter really at the end. We know that if somebody relapses mainly in the nodes, as Alexandra said, they're prognostically better. So there are even patients who relapse, who come with a lymph node relapse, you operate on them and then they're cured. They never come back again, which would never happen in a peritoneal disease, in a peritoneal relapse, would it? So there are still many things, many things to learn though. Yeah. Claire, I noticed in the questions there, somebody was asking about my comment about lymphadenectomy. I perhaps didn't put it very well. So maybe if I could have another go at that. So, I mean, I get nervous about stage one or stage two high-grade serious ovarian cancer. I do too. Because I think it could well, there's quite a high chance it's actually stage three. And so that didn't used to bother me before power parameters are about, because whether we call them stage two or call them stage three, we're going to give them chemo anyway. But if a lady has had an operation and had her chemo and comes to me to discuss what we do next, and she's called stage two, and I know by that time she's got a BRCA mutation, I'm really thinking, I want to know if you've got something in your lymph nodes or not, because that's going to determine whether I can give you a laparib or not. And this may differ- Can you explain why? It's because of the reimbursement rules. Yeah. So, well, the license and the reimbursement are both for stage three and stage four disease, so not for stage two. And so I'm now sitting there. So if she doesn't have a BRCA mutation, I'm thinking, well, this isn't ideal, but would I really want to put her through another operation? I'm thinking maybe, maybe not, you know? And you could feed HRD into the same discussion. So that was what I was trying to explain there, and apologies for not putting that over very well. But that's something that we also see, I'm sorry, we also see it now as a surgency. Now oncologists come to us, there is a patient that in the past, you know, she had peritoneal biopsy and mantectomy, it's a stage one, and then we are being sent the patients back to say, can you completely impair the nectomy? Because we don't know, are they eligible for the PARP trials? Are they eligible for the PARP? So I'm not sure whether the next step is to remove the lymph nodes to see which stage they have, or to just give a license to the PARPs also in earlier stages. I'm not really sure. I'm not really sure to do studies for that. We can say that the trials were done under the same conditions or under the conditions where your eyes were as good as your eyes were, and we should trust that. But of course we're pushing it all the time. I agree with Charlie. I mean, we definitely feel that way. Yeah, I just want to give a surgeon perspective too as a GYN oncologist. You know, it's interesting that we're having this discussion about lymph nodes and that we need to do these studies. And I'm so happy they did the Lyons trial, but let's remember we started doing lymph nodes in the absence of any studies to direct us to do so. So it's a very important area potentially for future clinical trials. But I don't know how much more we have in the session. I just want to congratulate all the presenters. It has been just an honor and privilege to be in this session with you. Amazing presentations and a great platform to jump off to future directions. Yeah, and I just really like to thank IGCS now, organizers who've helped us put all of this together, our speakers and participants who've asked questions and our wider audience who are out there listening. We've had fantastic attendance at this session. I think it's been very interactive. We've covered what we consider to be the most urgent issues in ovarian cancer. And we've really tried to also look at those that require our global consideration and particularly issues of equity. So we've heard about the magic of how to achieve a complete resection, no matter what we've had to do to get there. We've had to look at biomarkers and remember that indication is the science. We've had to look at what we know and what we don't know. I think we've had to look at issues about how we can make surgery safer. We've particularly had to realize how many of our patients are not from high income countries. The majority, that's 84%, unbelievable figures. We were really privileged, I think, to hear about how safe fertility sparing surgery is and to be reminded about a lot of that and to hear some of this very recent data in that regard. And then we were taken on a positive whirlwind tour, thanks to a number of our speakers of fantastic translational data related to PARP inhibitor resistance and to non-conventional therapy options. They were just spectacular talks. I think that Charlie has really brought it home in terms of thinking about biomarkers in a detailed fashion. And then to honestly hear ESMO guidelines about HRD testing, which is, for a lot of us, to get to the guideline setting is really a testament to everyone's hard work in the field. You need a hell of a lot of clinical trials to get there. So that's really very impressive. And then to have Alex take us into the future, well, I think I would like to pause and stop there and just let us all reflect on really what was a fabulous session. So I was honored to give the close and to take part in it and really want to acknowledge my co-chairs on putting together a spectacular session overall. So thank you, everyone. Thank you. Thank you, everyone. Thank you. Many thanks. Bye. Bye-bye.

high-risk patients

ovarian cancer

tumor grade

stage

histology

adverse factors

aggressive treatment

biomarkers

PARP inhibitor therapy

surgical management

complete resection

BRCA mutation status

prognostic biomarkers

predictive biomarkers

equity in access