during this session with Brad Monk. Good morning. It's really wonderful to have you all here and we're really looking forward to a very interactive session, but definitely, certainly, obviously, we want to keep with the theme of every moderator that aims to finish on time and we're gonna try to achieve that. So, Brad, please help me out on this segment. Thank you. So, the first presentation is titled, Is Cervical Cancer a Single Disease? Pathologic and Molecular Characterization of a Complex Tumor, and this is gonna be presented by Dr. Kay Park. All right, so apologies, I had a, either I misread the script or I had a different script. So the first presentation is going to be, I don't think so, Why Do We Still Discuss a Disease That Can Be Prevented? State-of-the-art HPV Vaccines and Pre-Cancerous Lesions Treatment. I hate it when he goes off script. So happy to be with you, multidisciplinary here today. It's gonna be a lot of fun. Welcome. Good morning. Hello, good morning, everybody. Hi, Pedro, Professor Monk. It's a pleasure to be here. I would like to, thanks for the invitation. It's really nice to see, to meet everybody again. And I'm supposed to say and to share with you my thoughts and concerns about cervical cancer. Why do we still discuss a disease that can be prevented? It's a really nice answer. We don't have the answer for this, but we are going to discuss the state-of-the-art of HPV vaccines and pre-cancerous lesion treatment. There are my disclosures for this presentation. As you know, cervical cancer is one of the most preventable and treatable type of cancer. We know that. And we also know that screening and vaccination are the key to prevent this disease. We are going to talk about equity, diversity, inclusion, and everything else. And for cervical cancer, it's very important. We know that in many high-income countries, cervical cancer is not so common anymore. Almost 90% of the cases, more than 90% of deaths, occur in middle and low-income countries. And we know that screening and vaccination, again, against HPV, can save lives. So we are talking about saving lives of a disease that we know the natural history of this disease, and we know how to prevent and to save these lives. We know that vaccines exist, and they protect against the carcinogenic HPV types. And we also know that the screening programs can detect early signs of disease. And we also know the natural history of the cancer. We have pre-invasive lesions. That treatment, it's almost 100% effective against the cancer. But at the same time, one life is lost every two minutes to cervical cancer all over the world. So we have much more to do for these women that are dying from cervical cancer. In Brazil, each day, what we see, younger women with cervical cancer, advanced disease. We are not discussing about to prevent fertility, minimally invasive surgery. We are talking about preventing deaths due to cervical cancer in Brazil. And the situation is that. Today, we have around 600,000 new cases per year. And in 20, in the next 20 years, we feel still as we are now, we're supposed to have almost 50% more death due to cervical cancer. So we have to do something. The World Health Organization launched the call to action, the global strategy to accelerate and eliminate cervical cancer all over the world. We have two main pillars of this. Everything, it has a reason. It's due to the natural history of the disease, but it's based on HPV vaccination, cervical cancer screening, and also management of detectable disease. What do we have regarding HPV vaccination? Our goal, to vaccinate 90% of girls fully vaccinated by the age of 15 years. We know that vaccination of HPV is effective. We have great long-term benefit of HPV vaccination. And we also know the herb immunity associated to HPV vaccination. So it's really nice if we can spread vaccination all over the world. And vaccination in young women, in adolescents, is the most effective long-term intervention for reducing the risk for developing cervical cancer. So when we say about the state of art, vaccination have to be and must be in our minds. But we have problems. HPV vaccine, we have disparity, equity is a problem, because when we see where HPV vaccines, they are into their national immunization schedules, what do we see? In more than 85% of the high-income countries where HPV cervical cancer is not just a big problem, we have a scene. But in low-income countries, only one in four countries, we have HPV vaccine, access to HPV vaccine in a public system. So it's a great problem we have to talk about more broadly when we think about cervical cancer. Angelica had a nice paper recently showing that in Latin America, we have the risk of repeating the same problems associated with HPV test programs. It's an efficient, life-saving tool, but unfortunately, it's underutilized for cancer prevention in low-income countries. So we have to do something. And one of the things, we have to have affordable HPV vaccines, we have to have higher coverage of vaccination, and we have to improve communication and innovate. Communication may be the main goal that we have to do regarding HPV vaccination. To vaccinate younger is better. We know that. But what we have new about this, it's the World Health Organization said that one-dose HPV vaccine offers solid protection against cervical cancer. So it's really nice. We can use one- or two-dose schedule for HPV. It's immunocompromised individuals. It's still receiving the three doses, but it's something that can spread HPV vaccination all over the world. Even in countries that we have a low coverage of vaccination, we can achieve higher coverage with the single dose when you compare to multiple doses. And we also can, we know that today, that the current approach with at least two doses is less efficient and less equitable. So you have to immediately implement single-dose vaccination all over the world. Princess Nocteba said this. With this strategy, with this single-dose recommendation, we can achieve this 90% of girls vaccinated by age 15 in 2030. So it's a nice strategy to do single-dose vaccination. But we have many problems regarding HPV vaccination. The lack of knowledge of HPV and also HPV vaccine. We have concerns regarding safety and efficiency of the vaccination. Cost, it's a great problem all over the world. And discrimination. And communication is really important. We published recently a paper regarding quality of HPV vaccine in Brazil. What do we see? That we have low quality of HPV, information of HPV vaccine in Brazil. So we have this misinformation. It can lead to wrong and even dangerous conclusions and decisions. We have to do something. We have to communicate better regarding HPV all over the world. And we know that parents who are exposed to misinformation on social medias, they are less likely to vaccinate their children. So we have to change minds. We know that. And a key message for this is that HPV vaccine is against cancer. It's really important. So we have to change parents' minds to have a higher coverage of HPV vaccine. Another issue that's really important is where we are going to vaccinate against HPV. We have that experience in Brazil. When we began in the public system, the vaccine against HPV, we had a high coverage, 92%. It was a school-based vaccination. Now we have around 70%. We know that this kind of approach, this school-based vaccination, is really important. We have data for Brazil. Using this strategy, we can increase almost 80% in the first dose of vaccination of HPV in Brazil. So it's really important that we change how we are delivering HPV vaccine all over the world. We know that. We learned that countries with high and sustained vaccine coverage, such as Australia, Canada, Sweden, and Malaysia, opted for this school-based strategy. So HPV is that. We have to expand vaccine, a close follow-up to implementation process. One dose is really important, and a school-based program. So it's important. But communication, we have to have clear messages. HPV vaccine is against cancer, and HPV vaccine is safe. It's really important. Another goal is management of detectable disease. So what do we have? The goal of the World Health Organization is 90% of women identified with cervical disease are treated, 90% of women with pre-cancer treated, and 90% of women with invasive cancer management. To do that, we know that the principle, the main goal of secondary prevention is to reduce cancer incidence and mortality. But at the same time, we have to take in mind this message. Cervical cancer screening will require a much increase in capacity for treatment of detectable lesions. As a screening woman, women without access to treatment is unethical. So it's not just screening. It's not just vaccinating. We have to treat these women, because we have these ethical issues associated just to screening. And we know that to do this, it's not easy. Equity, diversity, access, it's a problem all over the world. For example, pathological services, cancer surgery, chemo, and radiotherapy, we have these in high-income countries, where cervical cancer, it's no more a big problem. In low-income countries, we have these services in less than 30% of the country. So once more, it's important to think broadly about saving lives due to cervical cancer all over the world. And when we have, how can we treat these lesions? We have to have this broad vision of everything, of the whole process. We have to understand barriers. We have to ensure affordable supply for testing and also for treatment. We have to integrate screening in treatment. And we also have to strengthen laboratory capacity. But to promote a screen and treat approach, it should be very important. The World Health Organization recently expanded to ablation, including thermal ablation, as a therapeutic modality for women who have pre-cancer lesions eligible to ablation. So we have to consider the context to take decisions. We have to do that. We know that excision, it's better. But sometimes, ablative procedures could be simple, safe, acceptable, feasible to many countries. We have to do something else. We see in Brazil that it's a big country. We have different regions, different problems. And maybe we have to have different solutions for different problems in Brazil. So cervical cancer programs should be situated within this holistic approach to the health systems that it's people-centered and responsive to the needs of women across the life course. We have to think broadly on this. And the global strategy to eliminate cervical cancer as a public health problem will require political support and international and local leaders. This Congress is so important. Coordinated cooperation among multi-sectoral partners, effective resource mobilization, health system strengthening, vigorous health promotion at all levels, and broad support for equitable access in the context of the global. So equity, diversity, inclusion, access to therapy, to vaccine is really important all over the world. So as the key messages, we know that through cost-effective, evidence-based intervention, including HPV vaccination of girls, screening treatment of precancerous lesions, improving access to diagnosis and treatment invasive cancers, we can eliminate cervical cancer as a public health problem and make it a disease of the past. This is our dream. Dr. Tedros said that one woman dies of cervical cancer each two minutes. Each one, it's a tragedy. And we can't prevent it. That's the problem. Each life can be prevented. We have to think about this. So today, that's not our reality regarding cervical cancer. Many new cases per year, many deaths per year. We hope that in the future, we're going to have this, the first generation without cervical cancer. We'll have to do our job, think broadly, and assure that people would have access to HPV vaccines and treatment all over the world. Thank you very much. Thank you so much, Agnaldo. A great presentation. And I think that thank you for finishing a bit early. So I think we have time for one question. I wanted to ask you, one of the slides you presented at, one of the obstacles is the issue of misinformation. And certainly, we know about misinformation regarding vaccines, actually any type of vaccine, not just HPV vaccine. It's become a political issue. It's become a political issue. It's become a religious issue. It's become an issue with patients. Frankly, I think your country is going into an election that is very polarized tomorrow. So how do we tackle the issue of misinformation? Because I think that that's incredibly important and a potential barrier to actually achieving the WHO plan. Pedro, thank you for the question. I think it's a great problem. It's not a problem. It's a great problem. It's not easy to communicate to women. It's a challenge. We are used to communicate for health care providers and everything else. And we know how social medias can do, can have a great role in everything. But at the same time, we have problems. And HPV is like that. I think we can have a key message that HPV vaccination is against cancer, something important, not related to sexual behavior and everything else. So we have to do it. It can be really clear, this kind of message. And to work in social medias. In Brazil, it's spread a lot. We did this paper recently. And what we saw, mainly the information are not associated to medical societies. And we have a low quality information regarding HPV and HPV vaccine. And misinformation. It's too dangerous for everybody. Wow. Thank you very much. It's a powerful message. And we are off to a great start. Amazing slides, on time. And thank you and congratulations. Thank you very much. Thank you. So indeed, we are off to a great start. I think if we've learned anything from the pandemic, that if you don't get vaccinated, you might die. I was very inspired by Talzak's keynote presentation. Thank you, Audrey, for having that, and Brian Slomovitz. But it's a powerful message. And it's directly related to what we're doing to try to stop this tragedy known as cervical cancer. So our next speaker will be Kate Park from Memorial Sloan Kettering. Is cervical cancer a single disease? We know the answer to that. But she's going to tell us why it's not. Thank you and welcome. Thank you. Thank you so much for inviting me. And welcome to all of you to my hometown. I hope you're enjoying New York City. You sort of stole my thunder a little bit. Yes, the answer is no, it's not a single disease. I have no disclosures. So I hope to kind of show why cervical cancer is not a single disease in the next 10, 15 minutes. I'll go over sort of the new WHO classification for cervical cancer that's kind of changed how we categorize cervical cancer pathologically. I'll talk a little bit about what we know in terms of molecular drivers of cervical cancer. And then I'll end talking about some specific types of adenocarcinomas that are rarer, but HPV-independent and sort of what we know in that realm. So the 2020 WHO classification reclassified cervical cancers. It was sort of a paradigm shift. It used to be, if you looked at the old WHOs, it was just based on what we saw under the microscope pathologically. Was it keratinizing? Was it basaloid? Was it mucinous? But in the revision in 2020, we categorized them based on their etiologic link to HPV. Because now we know that both squamous and glandular lesions in the cervix have HPV-associated lesions, as well as HPV-independent tumors. So I'll be talking about that. Obviously, there are other types of tumors in the cervix, like neuroendocrine and otherwise, which I won't be touching on today. If you look at most of the outcomes data for cervical cancer, they've traditionally not been broken down by HPV status or histotype, because it was traditionally thought that nearly all cervical cancers are caused by HPV. So I think we need to start thinking about these and creating and having different kinds of data. So if you look at this really nice review by Fernandez that all just looking at all the literature and what we know has been published about HPV status in squamous cells and adenose and adenosquamous carcinomas, you can see that lots of different methodologies have been used in the past, including PCR-ish, different primers for PCR. And in squamous and adenose, and even in some neuroendocrine tumors, you can see that there are certain populations that are HPV negative, and they range from 5% up to 100%. Of course, that was our study that looked specifically at HPV-negative tumors. And if you look at the outcomes, for all comers, squamous and adenocarcinomas, like in other organ sites, like the vulva, like in the head and neck squamous cells, the HPV-negative tumors do seem to do worse. This is a nice study published by Xiaomi Ordi in Barcelona that looked at squamous cells, adenos, adenosquamous neuroendocrine carcinomas. And again, showed that both overall and disease-free survival were much worse for the HPV-negative subtype. So in terms of how many of these types of tumors are HPV-independent, for squamous cell, yes, the vast majority HPV-associated. But there is a small, about 5% component that are HPV-negative, very few cases reported up to date. And according to the WHO, we really should be doing P16 or HPV to determine that. But practically speaking, I don't think anybody really does that unless there's some morphologic suggestions that it may be HPV-independent. For adenocarcinomas, it's slightly different, about 15% are HPV-independent. Again, small but significant, and these, many studies have now shown that these all have worse outcomes than HPV-associated tumors. Now, in contrast to what was just shown in the U.S., if you look at CIR data, projected new cases of cervical cancer in the U.S. is about 14,000. That's because, of course, we have good screening programs. But if you take 15% adeno, 5% squamous, that's 20% of all the cases. You have about 2,800 cases that could be HPV-independent annually. In terms of what is the molecular characterization of cervical cancers, there's not a ton out there, but of course, we have TCGA data published in 2017. And just to remind you, this was a total of 178 samples, 144 of which were squamous cells, 31 of which were adenocarcinomas, and three were adenosquamous. And they were mostly early-stage diseases. And each of the bars that you see up here are samples. And so, this blue, that's squamous cell carcinoma. The dark gray is adeno, and this light gray is adenosquamous. And the HPV-clade, of course, most of them are either clade 9 or clade 7, HPV-16 or 18. But you can see that some of them are grayed out, which means some of them are indeed HPV-negative. The other interesting thing to note is this category here, uterine endometrial cancer-like mutagenesis signature. So, there were a few cases that had a mutational signature similar to uterine endometrial cancer. And you can see that the most common mutations, both for squamous and adenocarcinomas, were PIK3CA. You could also see that KRAS was more common in the adenocarcinomas, some ARID1A mutations as well, and then, of course, lots of gains in chromosome 3q. So, when you're thinking about progression of cancer cells in general, they sort of have to have several or all of these so-called cancer hallmarks. So, with HPV, how does that fit into what we know now about the molecular profile? Obviously, the oncoproteins E6 and E7, they knock out P53 and RB, and that sort of hits several of these cancer hallmarks. So, they evade growth suppressors, evade apoptosis, have immortality. But then, you sort of acquire additional mutational signatures that can help progress towards cancer. For example, in the proliferative signaling, you have the PI3K-AKT-MTOR pathway activation, and we saw, of course, PIK3CA as part of that pathway, and we saw a lot of mutations in that gene, as well as chromosomal gains. So, if you look a little bit closely at the HPV-negative squamous cell carcinomas, because, again, there's just not a lot of data out there, there were only four cases in the TCGA, and these are the four, these gray boxes. And if you look a little bit closely at them, what's interesting is that two of them here, you can see, had this uterine endometrial cancer-like mutational profile, and one of them, if you look closely, actually had P10 and ARID1A and KRAS, and if you know about endometrial cancers, this is sort of like classic mutational profile for endometrial endometriate cancer. So, it made me think, like, okay, either some HPV-independent squamous cells have similar mutation profiles to endometrial cancer, or this was maybe an endometrial endometriate with lots of squamous differentiation that happened to invade into the cervix and got put into this dataset. So, what do we know about HPV-independent squamous cells? Really, mostly from the vulvovaginal literature. This is a study done by my colleagues at Memorial where they looked at HPV-positive and HPV-negative vulvovaginal squamous cell carcinomas, and as expected, you can see PIK3CA much more common in the HPV-positive cohort. We know about TP53 being mutated in the HPV-independent cohort, but also these tend to have much more TERT promoter mutations. Let's turn to adenocarcinomas. As I mentioned, you have HPV-associated and HPV-independent. The HPV-associated ones, most of them are just usual type, you know, classic, conventional, endocervical adenocarcinoma. Sometimes they have some mucin, and they could be mucinous NOS, intestinal type, signet ring cell, et cetera. The HPV-independent types are the gastric type, clear cell type, mesonephric, and endometrioid. Yes, uncommon, and certainly in low-income countries, probably non-existent, just because they're sort of overwhelmed by the HPV-associated, but we see quite a few of these here, so I'm gonna talk about these individually. I'll go through their histology, what we know about their molecular profiles, how they behave clinically, and what the therapeutic options are. So gastric type is about 10% of all cervical adenocarcinomas. Morphologically, they basically look like upper GI pancreatic biliary tumors. You may know them better as minimal deviation or adenoma malignum. Now we know that those tumors are just very well-differentiated morphologic variants of gastric type, so they're sort of under that same umbrella. Voluminous, clear cytoplasm, very distinct cell borders, and can be very well-differentiated to very poorly differentiated. In terms of their molecular profile, this is a study we published a couple years ago, and not surprisingly, very similar to other HPV-associated versus not in the GMIN tract. You can see that the usual HPV-associated tumors have lots of PIK3CA, whereas the gastric types have lots of TP53 and KRAS mutations. Also like to point out here, STK11, you see several of our cases had STK11 mutations, and you know that gene, when it's mutated in the germline, leads to Poitier-Gerr syndrome, but you can also see somatic STK11 mutations in gastric type carcinomas. In terms of outcomes, again, no surprise, sort of in line with what we know about HPV-independent tumors across different organ sites. These tumors do worse than conventional HPV-associated tumors, and even when we limited the study to just stage one cases, they had worse disease-specific and overall survival. In terms of what we know therapeutically, these are highly resistant to conventional chemo RT. We don't have any good targeted therapies right now. There's starting to, emerging literature is showing that these tumors do express PD-L1, whether that translates into response to immunotherapy, we don't know. About 15% of these tumors can also show HER2 amplification, but again, not sure if that translates into therapeutic benefit. Clear cell carcinomas, even rarer, about two to 3% of all adenocarcinomas. You all know, hobnail, tubulocystic, solid, lots of clear cytoplasm filled with glycogen. Traditionally, we know that if you have in utero exposure to DES, that's a risk factor, but in terms of what drives them molecularly, we really, there's not a lot out there. And so, this was a study we published this year from my brilliant colleagues at Memorial, Berta Weigelt and our Geinog fellow, Sarah Kim, who just graduated and is now on faculty. We looked at a bunch of clear cell carcinomas of the cervix and what they found was that there were recurrent mutations in this gene, WWTR1, and the HIPPO pathway, which are related, and it's a very beautiful, complex study. I hardly understand it, but the one thing I'll point out that was really interesting from that study was that they did in vitro and mouse model studies looking at sort of the tumor genicity of this particular mutation. And what you can see here is that the control cells and the WTR1 wild type cells sort of have this steady growth, but when it's mutated, you have this exponential growth of the tumor cells. And you might see here, start of VP, what is VP? This is vertiporphin, and vertiporphin is an FDA-approved drug. It's a photosensitizing agent that is used in the treatment of vascular diseases of the eye, like macular degeneration. It somehow inhibits the HIPPO pathway, so they figured, well, let's try it since we now know this, and look at this beyond, you know, this is the tumor cells with the mutation, and when they got vertiporphin, it completely sort of decreased the tumor growth potential. And there are a couple of, I think, clinical trials ongoing for using vertiporphin in the treatment of cutaneous metastases from breast cancer and pancreatic cancer, so is this a possible treatment option for our clear cell patients? In terms of outcomes, again, there wasn't a lot out there specifically on cervical clear cells, but this is a study we published. I published with my colleague, Simona Stelnicu in Romania this year, and showing that, yes, stage is obviously the most important but that clear cell is worse than conventional HPV-associated tumors as well. Mesonephric carcinoma, even rarer, about 1% of all adenocarcinomas, they are derived from the Wolfian or mesonephric rests. In the male, you know, they develop into seminal vesicles, ejaculatory ducts, in the female, they're sort of embryologic remnants, but you can get cancers that arise from those, right? So they can look very morphologically varied, endometrioid, papillary, tubulocystic. In terms of their molecular profiles, a seminal study from Mirkovic et al. at Brigham showing that most of them actually had KRAS or NRAS mutations as well as gains in 1Q and loss in 1P. In terms of outcomes, this was a study done by my colleague, Lin Huang, in Vancouver, showing that the mesonephric carcinomas, in terms of overall survival, were sort of in between other HPV-independent tumors and HPV-associated tumors, but when it came to progression-free survival, they were similar to HPV-independent tumors. And if you've dealt with mesonephric adenocarcinomas, you know that they love to go to the lung. That's their favorite place of recurrence as well as local recurrence. And they're pretty hard to treat, so in terms of what are potential therapeutic targets, well, now that we know that they have RAS mutations, we have lots of drugs already that target that RAS-RAF pathway. Is this a potential avenue to treat these patients? Endometriic carcinomas, the rarest of them all. Hardly ever see them. If you look at the old literature, what things were called endometrioid are actually probably just usual type, and they look just like their corpus counterparts. I have nothing to say, because we really don't know anything about these tumors. And hopefully we can start to look at these and find out more about these. So just looking ahead, we need new therapies for these HPV-independent tumors. Whether the anti-PD therapies, targeted therapies, maybe those are options. The HPV-independent tumors tend to have lower expression of the inflammatory-associated genes. Whether that means they have worse response rate to checkpoint inhibition, we don't know. So in conclusion, cervical cancer is not a single disease. HPV status is important for prognosis and potential therapies. The HPV-independent tumors are indeed aggressive, and we do need to start thinking about new therapies for these very aggressive tumors. And molecular profiling may help identify future potential targets. Thank you very much. Thank you very much. So again, thank you for being on time. That earns you a question. And we'll have all of our speakers come up for a question and answer, and then we'll have some more speakers and we'll finish with some more Q&A. Those sorts of talks take a lot of work. Yeah. And I appreciate it. And it shows, and we're grateful. And you could see from the audience that they were really listening and engaged. And again, I'm sincerely grateful. One of the things that you did not talk about is neuroendocrine tumors. I get the sense that some neuroendocrine tumors are HPV-positive and some are not. Most are HPV-positive. There have now been a few cases that have been HPV-negative. So to the point, why do these HPV-positive tumors, neuroendocrine tumors, behave so poorly? Because I think you showed very nicely that the HPV-positive tumors should do well. What is it about the biology of neuroendocrine HPV-positive tumors that caused them to do so poorly? So as you know, neuroendocrine tumors occur anywhere in the body. We know most familiar with lung, small cell carcinomas, but you can get small cell carcinomas anywhere, the bladder, cervix, obviously. And what neuroendocrine, like small cell carcinomas, what they tend to have in common from a molecular standpoint is RB loss, MYC amplification, other tumor markers that are sort of in common across that histotype, regardless of sort of where they arise. And it may be because of those molecular features that translate into neuroendocrine morphology that just sort of tells you that it's gonna be a bad tumor. The morphology's informing what's happening at the molecular level. So I used to say that, and then someone comes up to me and says, come on, Brad, neuroendocrine of the pancreas doesn't have HPV in it. Well, neuroendocrine of the pancreas, there's a whole grade, right? There's a whole range, carcinoid all the way to small cell. But other neuroendocrine tumors do not have HPV. Right, but they have same molecular signatures in terms of RB mutations, MYC amplifications, and other things that are not, because it's not just, I mean, you can have HPV. It doesn't mean you're gonna get small cell, right? So there's lots of things that go into causing a tumor like that. It's not sort of a one fit for everything, right? But I think just neuroendocrine tumors across all organ types must have some sort of commonality on the molecular level, independent of HPV, honestly. Brilliant, congratulations. Thank you, thank you. Thank you. Fantastic job, Kate. Did that remind you of your boards? No. So we're really happy again that everyone's staying on time. And it is a pleasure to present our next speaker, who is Dr. Alexandra Taylor from the Royal Marsden. And she's going to speak on radiotherapy in cervical cancer treatment, resource-adapted standard of care. Thanks, these are my disclosures. And yes, I'm gonna be talking about radiotherapy for treatment of cervical cancer. As we all know, access to radiotherapy treatment is essential for successful management of cervical cancer. And over the recent years, we've seen a rapid evolution in the techniques that we can offer. But as we've already heard this morning, what WHO Global Strategy is aiming for is for 90% of women with cervical cancer to have access to treatment. But we have such huge disparity in availability globally. If we look, and again, we've already heard this morning, we can see that cervical cancer mortality, 85% of it occurs in low and low middle income countries. And if we put that beside the availability of radiotherapy machines, again, we can see almost an inverse relationship to incidence of cervical cancer. So the challenges that we have for many patients is access to equipment, training and support of staff and other health and social priorities. But I'm focusing today really on the technical aspects of the radiotherapy. And the challenge here for any radiotherapy department is how do we use our available resource to maximize outcomes for the particular patient, but also considering for the whole population how we use the resource. So when we look at radiotherapy developments over the 20th century, it sort of established our basic principles of combining external beam radiotherapy and brachytherapy, the importance of oxygen, maintaining the hemoglobin, not having any gaps in treatment. And we had this sort of seminal change in 1999 at the end of the century with the addition of cisplatin chemotherapy to radiotherapy. And it's just highlighting in those studies that was conventional radiotherapy and point-based brachytherapy that was still achieving very good results. And so basics work and we need to have equipment to do this. But over the past few years, we've also then expanded what we can be doing in terms of new techniques like IMRT, image-guided treatment and brachytherapy. So thinking about how we apply our resource, we have several societies that have produced guidelines on resource-adapted care. We have what's optimal treatment and what can be options when there's limited resource. But really, it's usually very much center-dependent on what is available. So going through the options. In terms of external beam radiotherapy, again, we have this sort of range of planning and delivery techniques of external beam treatment. And as we move through them, it's increasing time and resource, increased time for the clinician, for the physicists, and also time on the machine as you increase your complexity. So if we start with a clinical markup or using bony landmarks, using two fields, moving to four fields, you improve your dose and we are treating a large area. But we're not really individualizing the approach. If you have access to CT, the next most straightforward step is what we call virtual simulation, where you can apply the fields but ensure that you are covering the plan. But if you want to start individualizing, then we have to think about target volume definition and that involves time for contouring the structures and to improve quality, we have atlases. And it's very important, again, consensus documents and training and peer review to produce what we see on the right, much more agreement with inter-observer variation being minimized. Now, the technique that that can lead to is intensity-modulated radiotherapy. Again, further shaping to the volume that you've drawn can spare more normal tissue, but actually that has its own challenges and you have to have caution when you're starting to think about new techniques. As you're fitting more closely, you have to take into account that the uterus is highly mobile and affected by the bladder and the rectum. You have to put in big margins. The tumor shrinks throughout treatment and the pattern of shift can change. And actually, by the time you put those margins in, you're sparing very little more tissue compared to your more conventional fields. And so really the big, again, if we're using IMRT, what's the advantage is you can dose paint. And again, you can then deliver nodal boosts that are fixed within the treatment that we're delivering. And again, it depends on your access to imaging and staging how you are gonna be thinking about nodal boosts. I'm sort of putting in, again, hypofractionation because we're thinking about how we're gonna be delivering care. If you can reduce time on the machine, that's an advantage for the patient and also for the department. And it may justify using more resource in planning if you're freeing up machine time. And we're certainly seeing in other tumor types over the past few years in breast cancer moving to five fractions rather than 25. And similarly in prostate cancer, even when treating the nodes, you can hypofractionate, so a bigger dose per day for the treatment. In cervical cancer, we're treating much bigger volumes. There's more caution unless you are sparing more tissue. And we really need larger scale studies to review this. Where's our big challenges in terms of access to brachytherapy? And again, intrauterine brachytherapy is an essential component of the treatment. And again, I'm putting up the maps of even more depressing access to machines in that we can see even fewer countries have even one machine available and that the vast majority of brachytherapy machines are high-income countries. And so we really have to think about how we're using it and getting greater access. But the big shift, again, in the last 10 to 20 years has really been transforming how we've moved from 2D brachytherapy to three-dimensional MRI-guided brachytherapy. And the Geck-Estro group have been seminal in divining the target volumes in terms of how we need to be delivering dose to the high-risk CTV to the cervix and really escalating up the dose from what we can give with an external beam of 65 gray up to 85, 90 gray, and truly improving outcomes. And we've seen this now in the results from the EMBRACE study, a very large multi-center observational study of MR-guided brachytherapy, and we see here the survival curves that even with very advanced disease, you can achieve local control above 90% for these tumors. But again, you have to have access to the resource, and we have the IAEA recommendations in terms of how to think about transitioning. You're not going to go straight in with using high-resource techniques, but it's very much an evolution. And we can think about what the approaches are. Level one is library-based. You have a standard applicator. You've got a pre-plan. You insert this into the patient, and you just deliver the dose. And then the next step is taking x-rays and using point-based, because you're going to assess where the bladder and the rectum are by using markers, and reconstruct that. And some individualization is feasible, but really level three is where you can truly individualize and move to volume-based approaches. Now, what I tried to pull together is, what's the impact of this in terms of resource? We can see that if you're doing library-based, it's a very rapid turnaround, low-cost, needs less manpower. But my sort of estimation of pathways, again, varies from department to department. But you can see, as you move up to volumetric, this can be an entire day, and it's unrealistic if you're in a department treating 700 patients a year with brachytherapy that you're going to be able to do this on each patient. And so you need to be selecting, maybe, which patients would particularly benefit from 3D versus level one care. So when we think about who will benefit most from image-guided brachytherapy, we have an example here of a patient on MRI. I've marked the GTV, so that the residual disease at the time of brachytherapy is small. The high recidivity, the cervix. And then in purple, this is what we would achieve if you apply just a standard plan. And you can see you get very good coverage, and actually higher doses if you're giving the dose to our standard point of point A, compared to the volume. And we've looked at that in that with smaller tumors, actually using standard plans give very good outcomes. But obviously, the problem is when you have larger tumors, have not had a response, this is when you may need to want to put more resource in terms of interstitial. And this is, again, shown here in that, actually, for smaller tumors, less than four centimeters at the time of brachytherapy in terms of the cervix, there's really limited gain in moving to interstitial or adaptive approaches, whereas you see a big advantage with the larger tumors. And we have now the ICR 89 guidelines that have taken this on board. Thinking about approaches to support brachytherapy and the quality of the brachytherapy, actually one of the issues we have is unsuspecting perforation can be up to 10 percent. And that's often you've had large tumors, it's friable, and if you don't have guidance. And the issue from that is that you're not going to be treating the volume, but also, as you can see here, the tube is actually going into the sigmoid. And this may account for some of our late toxicities of fistulation with unsuspecting perforation. And the very simple and cheap method to reduce that is to have intraoperative ultrasound. It actually speeds up the procedure. You can detect and guide where you're going. And it actually supports training, because you can support where it's being delivered. And taking that further, you can use ultrasound to actually guide the brachytherapy. And this is a group from Peter McAllen's group, done a lot of work with trans-abdominal ultrasound in terms of guiding the brachytherapy, not only the insertion, but exporting the images into the planning system and overlaying the applicator and generating an individualized plan. And this can be combined subsequently with cross-sectional imaging. But it's certainly an approach to consider. We talk about MRI-guided brachytherapy, but again, very few centers actually have MRI. CT is much more widely available. And we know that on CT scan, the volumes that you see on CT are larger than what you would deliver on MRI. So you need to take that into account when we're thinking about doses. Because the target, if we're trying to get 85, 90 gray into a smaller volume, the same plan would deliver only 75 gray to a CT volume. And we now have IBS-Geck-Estro guidelines that have now developed CT-based contouring guidelines, builds on the MRI guidelines, but takes into account the varying resources that may be available. And if we look at the difference here, just in terms of the concepts, it's got a big emphasis on clinical examination with the measurements and the concept of near maximum distance from the os to the lateral parametrial treatment, which again may help identify which patients would need interstitial and can be applied in different imaging resources. So what if we don't have brachytherapy? And again, very different to high-resource centers to low. But I'm just going to talk about what the options are. And the alternatives, not as good, but you can use external beam radiotherapy. You can only really get adequate doses in if you're having some form of imaging with your technique. And so you can use IMRT, but also stereotactic radiotherapy, where there is increasing evidence of using this. I think we can see across the board, giving stereotactic or contouring is much more convenient for the clinician. The patient's preference would be for this. Tariff is usually higher, but we can see the impact of that when we look at the National Cancer Database that was showed, actually, in the US, the use of brachytherapy decreased between 2004 and 2011, with IMRT going up to 13%, and that, accordingly, survival decreased. So it's really strong the message that brachytherapy is required, if feasible. But we do have those patients where, due to topography or to other circumstances that it's not feasible, and actually with stereotactic treatment, you can achieve sometimes better lateral doses to the tumor, and we're seeing very good control being reported in some cases. Just my final point is to really think about what's coming down the line, because this really can transform what we're going to be doing. So the emergent technologies in terms of IT, and already being used more frequently, web-based solutions, so you can do the contouring remotely. You can have peer review and training remotely, and that can be something that's going on. Again, some centers work that the planning doesn't have to be done on site. You can centralize it and have it done remotely, and similarly, virtual meetings are already in place. What's going to really speed up that time-consuming thing that we do of manually contouring, which is now probably the biggest source of error in radiotherapy, is more and more systems are coming on board for automated contouring. I would say to date, they're still in progress. We still don't have validated systems for assessing and implementing this, but it truly has potential for us to train and deliver automatic contouring. Similarly, what's coming down with the manufacturers is automated, sorry, this is the Chinese contouring, is planning. Also, again, you can generate and train on, this is done on a variant system in terms of selecting plans, different techniques in terms of this. And again, it's still being developed. It's not reproducible, but we are learning how to be training this, and again, it will make a huge impact in lower resource centers if you can have automated processes. It's not going to replace the clinician, still needs quality assurance, but training may be different if we have this alongside. And finally, sort of, again, coming in, and it's going to guide the future, is real-time online adaptive planning. So we have the MRLinux, where people can be, again, this is currently manually, but with automated recognition of the volumes, adapting the treatment plan in real-time while the patient's on the bed, and we have that with the new ethos machines with Varian. So in conclusion, there are very significant challenges to ensure equitable access to radiotherapy, but it is developing rapidly, and it has great potential to transform how we deliver care for women. Thank you. Excellent job, Alexandra, and we're still perfectly on time, so we have about 10 minutes for discussions and some additional questions that we have for the speakers, so we would like to invite them up to the stage, and certainly we welcome your questions as well. Alexandra, again, congratulations. Takes a lot of work to do those slides, and I recognize it, and I appreciate it, and you taught us a lot. Let me just ask you a controversial question. So we've learned from you and others that compression of the treatment time is important. So what happens is you have to sort of decide the trade-off of when to do the brachytherapy with the external beam. If you do the brachytherapy too early, then you have abnormal geometry and very difficult in your image-guided brachytherapy. If you do it, let's say, after all the external beam is delivered, or maybe even a week or two after, then you prolong the treatment time. How do you make the decision to begin the brachytherapy during, right after, or even a week or two after external beam? He starts with the easy questions. I know, and I think it highlights, again, it's a resource issue sometimes. I mean, in terms of clinical setting, you're right. In terms of total treatment time, I mean, the data we have is for each day that you extend treatment, there's a 1% reduction in overall survival, and so we aim to complete as quickly as possible, and may be that just sandwiching or just the week after. We would typically try and do it, because if you do it too early, it's overlapping with your chemotherapy, but also there can be the issues with blood counts and taking the treatment. Typically aim to do it within the week of finishing external beam, but each department is very different, because some centers will do multiple insertions, and others will do a single time and give all the brachytherapy in one go, and minimize time that way. So I think every department has to deal with this challenge. From an optimal standpoint, how many brachytherapy insertions using HDR would you recommend? I mean, we would follow, again, what the Geck-Estros standard is, two insertions under two fractions per insertion. It gives you time to adapt, but it varies. I would say during COVID, that changed again and became one, and we were resource-deducted, and again, it depends what you have available. Thank you. Let's have some questions from the audience, or Pedro, either one. Yeah, actually, while we wait for some questions from the audience, Kay, again, thank you for your presentation, excellent presentation. I wanted to have you potentially address, there are some who suggest that all cervical cancers are HPV positive, that there's not really an HPV negative cervical cancer, it's just in the methodology, you just didn't detect it. What would you say to that argument? Yeah, I mean, that's a common argument in a lot of these papers, but I think if you look at the breadth of the literature that is out there now, you really can't deny it. All the different methodologies that we've used, we've done studies where we've used multiple methodologies, and I didn't talk about this, but with the MSK impact, the next generation sequencing, one of my colleagues, he's devised a way to detect non-human sequences, so we can detect viruses, fungi, bacteria, because that's all open source, all those sequences. So, now, we can detect HPV just through next generation sequencing, and we know that there are definitely HPV negative cervical cancers, so I think it's an unquestionable fact at this point. And Kay, I have a follow-up question, and you had alluded to this in one of your slides, and in fact, I've had actually several patients come to clinic already with a testing with cervical cancer for HER2. Is this more frequently done? Should we routinely be ordering HER2 for management of treatment? So, the HER2 story is really in the gastric types, the minimal deviation, the HPV negative ones, and those are the ones that tend to have the HER2, either mutation or amplification. I have no idea if trastuzumab is going to help those patients. Nobody knows. So, it's a TKI opportunity, so there's a lipatinib, as an example, in the TCGA. There's a neratinib paper that there's active almost exclusively in adenocarcinomas, you said. So, identify yourself, and then we're happy to hear your question. Thank you. Go ahead. I can't see because the lights are burning my retina. No problem. Sarah Finlayson. If up to 20% of cervical cancers are indeed HPV independent, what do you think the clinical implications to our screening programs ought to be, given that many places are moving to, you know, HPV primary screening? Yeah, I've thought about this, because as someone who studies HPV negative cervical cancers, I'm like, well, we're going to miss all these patients, but honestly, those patients don't get even caught on those PAPs, on the screenings anyway, because they're rare. It's hard to recognize them pathologically, you know, cytologically, and they often present at high stage. You know, the gastric patients, even if you catch them early, they're so aggressive. I'm not sure how much screening will actually help in that setting, but I am, like, a little wary of just going to HPV-only screening, but it's an unanswerable question. I honestly don't know, you know, what is the best way. It's such a small population of patients, but of course, when you're that patient, it's so important, but I just don't know that screening can actually move the needle on these HPV negative. Ignaldo, that's a great question for you. You know, you're an advocate, wonderful talk on HPV. Does that mean that cytology needs to continue to detect these non-HPV tumors? We have so many problems with HPV-positive cervical cancer. Imagine now with negative HPV cervical cancer, so let's see. We are discussing, it's not so easy to, I say, regarding Brazil. It's difficult. We had a study, maybe two years ago, that were, the problem is not just the coverage of Pap smear or even the DNA test in Brazil, but the quality of Pap smear in Brazil. We have great problems. We are moving forward to change our screening program in Brazil. We are going to adopt DNA tests there. And as you know, it's a big country, and sometimes the possibility to auto-test, it's really interesting for Brazil. So let's see what's going to happen. We did not, our job with HPV-positive cervical cancer, let's see in the future. Thank you for what you're doing. Andreas, I think you have a question. Thank you. So, first of all, thank you very much for a great presentation, Andreas Obermeier from Brisbane, Australia. I am going to, kind of in the same direction as the previous question, so in my personal practice, in the last two months, I've seen three HPV-independent cervical cancers, and I think the first time I thought, oh my God, how rare is this, because I grew up in a thing that all cervical cancers are HPV-positive, right? Then the second one, I thought something's wrong here, and the third one, I was rattled. And so I'm just wondering if this is really, if we need to think about changing our language, and therefore also our thinking, because I'm just wondering if this is really such a rare event, and if it is not such a rare event, then I guess there would be implications for, first of all, further research. Australia is a country with extremely high vaccination rates, so I'm just wondering whether the HPV vaccination has some impact on the HPV types. And the second thing is, certainly I would want some more research on whether the paradigm of five-yearly HPV-based screening is still accurate if we're saying that HPV-independent tumors are not rare. Yeah, I mean, how do you define rare, right? These are still uncommon, but maybe not as rare as we once thought, and it also depends geographically. I don't know if we have any colleagues from East Asia here, Japan or Korea, but the HPV-independent gastric type is much more common there. My colleagues say 25, 30% of their cervical cancer is adenocarcinoma, so you're right that maybe they're not as rare as we once thought. Thank you. Yeah, and I have a pathology colleague in Australia, and she's done a lot of work on these, too. I'm surprised that you've seen three cases in the past couple of months, actually. Thank you very much. We have one last question. Chris Tawari. Hi. Chris from UCI. I loved all three presentations. Maz, I love your passion, but Dr. Park, the HPV-negative cancers, are there efforts to exclude endometrial cancers in those cases? Because in the few cases I've seen that were HPV-negative, they actually turned out to be either a locally advanced endometrial cancer or an endometrial cancer that got picked up on an ECC. Yeah. Yeah, absolutely. That's something we also deal with, especially on small biopsies, if they're big tumors. Sometimes it's impossible to know where it's coming from based on its morphology. And now, I don't know if you know, but the gastric-type histology, now there's an entity in the endometrium, and you can get gastric-type endometrial cancers, as well. It's sort of an emerging entity. So sometimes we can't tell. It's really just geographic. If you see that the tumor's limited to the cervix and there's nothing in the corpus, then that's one way to say. You are looking at the corpus also? Oh, yeah. Absolutely. Yeah. Absolutely. Yeah. Well, thank you so, so much. These have been excellent presentations. And we thank you again for being on time. And we're actually transitioning on to the second portion with 28 seconds left. So we're really very, very proud of all of you, and then thank you for your time. Congratulations. Thank you. So this is a lot of fun. Very... Excuse me. Sorry about that. Yeah. So this is a lot of fun. And again, a lot of work has gone into those presentations. And I learned a tremendous amount. We're going to transition to treatment. We have three final presentations, one on surgery, immune therapy, and then the future. Our next will be on surgery. And what's perhaps most exciting is fertility sparing. And thank you, Dr. Kohler from Hamburg. Germany. Yeah. Thank you so much. Emberlin. Ladies and gentlemen, dear chairman, thank you again for giving me the opportunity to speak in front of this distinguished meeting. It's a great honor for me. But in contrast to the previous fantastic speakers, I'm rather raising some questions and give some answers and an overview because I got hot topics and hot topics is a field of controversies. I'm a little bit in an enemy territory here, because you see all the shots coming, and I could show you a hundred more against any minimal invasive surgery. And I try to uphold a little bit of minimal invasive surgery here in this auditory and show you if there's still a place for it, and where can I find this place. The first field, I think, is fertility-sparing treatment. And again, coming back, we had a wonderful session with Marie Plante two days ago. If you talk to these patients, none of these patients would like to have any compromise with regard to her oncologic safety. This is the top one for this patient, and the second one is to get, in the future, pregnant. And we have always to keep this in mind. And it was a huge merit of this French colleague, Daniel Dargent, who gave us the opportunity 25 years ago with his radical vaginal trachelectomy to offer these young patients any possibility to get pregnant under strict limitations with small tumors less than two centimeters, two more free lymph nodes, it's marked in red, and I come back to this, and with usual type carcinomas. Now, there is a clear tendency in the literature in the world to tailor radicality, as we all know, that we do have in nearly two-thirds of spasms after trachelectomy, no residual tumor. So we shift a little bit from radical trachelectomy to simple trachelectomy to cone. But the question is, what is the best and the safest procedure for this individual woman? And it's sometimes difficult to decide, because all the publications and studies do have different inclusion criteria. And I'm not sure at the moment what is the best. We did a lot of radical vaginal trachelectomies, you can see 471 cases, there was a high pregnancy rate and a follow-up rate of 150 months, the recurrence rate is 3.4%, and the death rate 2.1%. And also we tried to do some simple trachelectomies in earlier cases, but again, it was only after discussion with the patient, she refused to have a radical trachelectomy, or we thought it could be enough. Again, in 36 patients, high pregnancy rate, no preterm delivery, no recurrence in this lower-risk population. But again, it was rather an individual decision and a planned decision. And if you look at this just-published meta-analysis from the French guys who tried to analyze all the fertility spurring procedures in the world, you see the recurrence rate is now for all procedures, tailored procedures, radical trachelectomy, abdominal radical trachelectomy in the same range. But it is still the same, the abdominal radical trachelectomy has the lowest pregnancy rate and the preterm delivery is more than 10% lower for the cone or simple trachelectomies. We have to keep in mind if we counsel the patient. The second problem is, what can we offer to patients in tumors larger than two centimeters, two to four centimeters? And we also had a pro and cons debate two days ago about the upfront radical trachelectomy or the concept of neoadjuvant chemotherapy followed by any kind of fertility spurring surgery, cone, simple, or radical trachelectomy. And as you can see in this beautiful review given in 2009 by Frank Cole, that the recurrence rate in the upfront radical trachelectomy is slightly lower than the neoadjuvant chemotherapy group, but the chance to get pregnant and to have a live birth at home is definitely higher in the neoadjuvant group. And we did also some cases of these patients, again, we found in 55% residual tumor for these patients who responded, good chance to get pregnant, but the recurrence rate is definitely three times higher than for the radical vaginal trachelectomy in tumors less than two centimeters. There are a lot of unanswered questions still that I cannot answer and probably nobody in the world is able to give you the best answer for this. The upfront radical, this abdominal radical hysterectomy has an adjuvant treatment in nearly 50%, again, the lowest pregnancy rate, but a lower recurrence rate, whereas the neoadjuvant group has also a lot of unanswered questions. What is the best chemo regimen? What is the best number of cycles of chemo to be applied? What is the best measurement method, probably the MRI, and which kind of search we should do following a neoadjuvant chemo? Cone only, depending from the response, a simple trachelectomy, a radical, what is safer for the patient? I don't know it. Anyway, probably there will no randomized trial exist in the future, and again, we have to take in mind not only the oncologic aspect, also the fetal outcome of the babies. And that's why I love this talk from Dr. Park. We really urgently search for new criteria to avoid an over- or under-treatment, and the most important precondition for fertility sparing are tumor-free lymph nodes, and that can be easily done by a laparoscopic approach. Coming to the minimal invasive surgery, probably this was the intention for radical hysterectomy, I hope, Petro, as a chair of the session. Okay, we all were on the way that all kinds of radical hysterectomy are equal, and then Petro's study came up in 2018 and blew up this statement. Again, it is, in my opinion, and it is written in the paper, not minimal invasive in general. It is a total laparoscopic or total robotic, and we all were thinking all over the world what could be the reasons for this inferiority of the minimal invasive way, and what can we avoid in the future? And there are, in my opinion, two easy things is the use of the manipulator in the clothes of the vaginal cuff, and that's why we analyzed our data, because we have never done this technique with a manipulator given in the upper line. We always use the technique with a consequent closure of the vaginal cuff, and in our cohort, it's a monocentric retrospective analysis of the prospective database with a long-time follow-up. We would have fulfilled this statistical hypothesis, but again, two different types in the randomized trial is a better level of evidence, no doubt. In the SUCCOR study from the European multicenter group, they confirmed both results. The entire cohort was inferior, the minimal invasive group, compared to the optimal radical hysterectomy, but if you did a subgroup analysis for those where no manipulator was used and for those where the vaginal cuff was closed, you found similar results. The disease-free survival rate was 93% without vaginal closure and 20% less, sorry, 93% with vaginal closure and 20% less without, as you can see in the curve. The second one analyzes, in my opinion, is a very interesting one because it analyzes if a cone was done prior to a radical hysterectomy or not was also a very beneficial procedure. The hazard ratio is 0.35, but you have, in my opinion, to raise the question, which was the intent or type of conussation? Was this rather diagnostic to a clear measure of the extent of the disease? Was this decisive if it was not totally clear if it is a resectable disease or rather go to chemoadhesion, or even therapeutic if it was a small lesion, and I'm coming back to this at the end. Meanwhile, we are discussing worldwide and battling what is the best approach for the radical hysterectomy, but next year, if we get the results from the SHAPE trial, what can occur? The easy and low-risk cases go to simple hysterectomy and the other cases with two or more intermediate risk factors or other, even more, go to primary chemoadhesion and we don't need any radical anymore. Then the discussion was totally useless. Let's see. The last point that was given to me is surgical staging. We all know that the lymph node status is the most important factor for the prognosis of the patient, and the Sentinel concept is a promising concept. It's more and more accepted in the world, despite the fact that we haven't had before any data that combines the morbidity and the oncologic result, and that's why we urgently wait on the result of the SENTIC study that is finished and the SENTICOL trial that is ongoing, the French prospective randomized trial, because both of them collect the oncologic data and the morbidity, and we actively participated in the SENTIC trial, but a few of the results that have been already published are a little bit discouraging, because you see, if you send the frozen section within the trial to the Sentinel, the frozen section, it fails in nearly half of the patient to detect the positivity of the lymph node, but from this frozen section, we make our decision how we continue with this patient. Moreover, there were some problems with the local and the central pathology, but the second one was also not so encouraging, that we cannot avoid the rate of lower lymphedema. Also in the Sentinel group, there was a 26% of risk to develop a lower lymphedema, which shouldn't occur in the Sentinel procedure. The second question is the question of lymph node staging in locally advanced cancers. We have, in Germany, designed the UTROS-11 study in order to show if a surgical staging done by laparoscopy and primary chemoidation according to the histologic result is better than a radiologic staging followed by chemoidation. Both groups were comparable with the toxicity. There was no delay in both groups for the beginning of chemoidation, and there was no morbidity and only mild problems, complications in the surgical arm. This was not the reason. Our main problem was the poor statistics that we have used. That's why it was finally a negative trial, because our primary endpoints were disease free survival and overall survival. For this, it's statistically negative. The cancer-specific survival was not the endpoint. This was a significant one. The only one is the group 2B, the subgroup analysis, showed a significant benefit. But again, this study was, in general, negative. The problem, the main problem today is that the majority of developed countries shifts to the PADCT, and this was not included in this trial. But we know that the false negative rate of PADCT for nodal involvement in the parotid region, especially in patients with positive pelvic nodes, is between 8 to 15 or 20%. But the PADCT is not everywhere available. The costs, if they are covered by the insurance, is not clear in all countries. And there's a potential benefit for the parotid lymph node dissection, because it's not so difficult to do an inframesentary parotid lymph node dissection. Then you have a clear decision, and hopefully the PAROLAS trial from the French colleagues will be open to answer these questions. Coming back to the cone, to the smaller tumors, the cone, and the problem of the high rate of false negative findings in the frozen section of sentinels. I was on the way to discuss with other colleagues why we don't do always a two-step procedure in these patients. In step one, we do a cone, and we get an exact histologic examination with all the factors we need, even better one for molecular profile in the future. We can send the lymph nodes for immune histochemistry and ultrastaging. And having together these results with the result of the imaging, we find either no lymph node involvement, then we can follow with the surgery as a fertility sparing, and then probably we can better decide which is the best way, tailored or not tailored, or which access for the radical hysterectomy is a safe procedure for this patient. And in case of positive lymph nodes, we can perform an ovarian transposition if it's a young patient, and send the patient to chemo radiation. I hope we are still friends, as we are, and this is a medical problem. In conclusion, this slide, sorry, is gone. In conclusion, I think there is a place for minimal invasive surgery, but we have now to individualize the surgical therapy for the patients. And I think we have more unanswered questions at the moment than answered questions. Thank you for the opportunity to speak. It's wonderful. Thank you. Well, Chrysler, thank you so much. Obviously, I will have a question for you at the end of the session in the discussion, but we do want to keep on time, and we'll bring you back up for a discussion. So thank you for your presentation. We're really very happy to have on now the next presenter, Ketela Russo, from Gemelli in Rome. She's going to talk to us about the role of immunotherapy in cervical cancer. Good morning. Thank you so much for your kind invitation in this amazing meeting and amazing city. And yes, my role is to speak about the role of immunotherapy. These are my disclosures. As already said, cervical cancer still remains an international health concern, with more than 500,000 new cases every year and more than 300,000 deaths every year. And it is also an example, a good example of social inequality, because 84% of cancer occur in low-resource countries, where also 88% of deaths are registered. The low-resource countries are the countries where there is no screening, no HPV vaccination, neither immunotherapy. Stages of disease still remain the most important prognostic factor. Early-stage patients are well-cured with radical surgery and eventually tailored adjuvant therapy. Patients with locally advanced disease are treated with concurrent chemo-radiation, but there is a room of improvement, because they experience five-year disease-free survival around 60%. And the management of women with advanced metastatic stage IV-B disease, but also recurring disease, still represent an unmet clinical need. A few years ago, the GOG 240 changed the standards of care in the treatment of metastatic disease by demonstrating that the addition of Bevacizumab to platinum paclitaxel chemotherapy increased overall survival by around four months. But unfortunately, the post-progression survival still remains very bad, suggesting that after failure of platinum paclitaxel, this patient has no potent weapon in their armamentarium. In fact, whichever drug you use after platinum paclitaxel, the response rate is around 10% or even less, and the median overall survival is around seven months. In this scenario, immunotherapy may represent a strategy. Immunotherapy, as already said, 85% of cervical cancer are linked to HPV infection, and PTL-1 is expressed in up to 88% of squamous tumor, and in up to 65% of adenocarcinoma. Moreover, tumor mutational burden, which is a well-recognized biomarker of immune efficacy, is quite high in cervical carcinoma. For all these reasons, there was a good rationale in evaluating immunotherapy in cervical cancer, and in fact, all the phase two single-arm trials reported very interesting response, up to 50% to 26% when immunotherapy was used as a single agent in advanced patients treated with at least two prior lines of therapy. Very interesting, PTL-1 gave inconsistent results among the trial in terms of predictive factor of efficacy of immunotherapy, and in K0-158 with pembrolizumab, CPS score less than 1 was predictive of no response to immunotherapy, but it was not the case of CHECKMATE-358 with divolumab. But based on this research, in 2018, FDA approved pembrolizumab for the treatment of cervical cancer patients who failed platelung-based chemotherapy and who expressed a CPS score more than one. FDA was waiting for a confirmatory trial but even more, EMA is waiting for a randomized trial before approving a new drug for cervical cancer patient and the trial arrived. This is the Empowered Cervical One trial exploring anti-PD-1 semiplimbab versus physician choice chemotherapy in a population of recurrent and metastatic cervical cancer regardless PD-L1 expression. The primary endpoint of the trial was overall survival and the trial met its primary endpoint with a significant increase in overall survival with an acceleration of 0.69 reported for semiplimbab in the squamous cell patient but also in the overall population and exploratory analysis in adenocarcinoma were really surprising with five months increase in overall survival in this population. Very interesting, PD-L1 does not seem to be a good predictor of efficacy and response were seen regardless PD-L1 expression in the trial. What after Empowered? K0826 was the first randomized phase 3 trial exploring the combination of immunotherapy with carboplatin or cisplatin paclitaxel plus or minus bevacizumab in a population of persistent recurrent or metastatic cervical cancer chemo naive no prior systemic therapy for advanced disease. The trial is a double primary endpoint overall survival and progression-free survival and for the first time we see an increase in overall survival when we combine immunotherapy with chemotherapy in the CPS score more than one population but also in intention to treat population. Whole camera patient experience a significant increase in progression-free and overall survival when PEMBRO was combined to chemo plus or minus bevacizumab but unfortunately based on the forest plot analysis which are exploratory I want to underline but based on this analysis who did not see any benefit of PEMBRO in CPS score less than one patient which represented only 11% of patient in this trial the authorities both FDA but also EMA approved PEMBRO lizumab in combination with chemo plus or minus bev only for CPS score patient positive. The consistency of data is also reported by a significant 20% increase in the overall response rate with the significant increase in the duration of response of patient receiving PEMBRO and quite comfortable the toxicity profile of the drug because only 5% of patient discontinued treatment for immune related PEMBRO related adverse event. What kind of events we have to expect from this combination mainly tyroditis hyper or hypothyroiditis followed by colitis or skin reaction which were as you can see mainly grade one two and most important did not impact on quality of life of our patient also a significant improvement in time to deterioration of symptoms was reported in patient receiving PEMBRO Another trial will come very soon. BCC trial is exploring atezolizumab antipedial one drug in combination with bevacizumab in combination with platinum-based chemotherapy in the same setting of disease. So this is a reality we can use or we will use in Europe in few weeks we hope so this combo and more and more patient will receive immunotherapy but if immunotherapy works why not try to move immunotherapy earlier in the treatment algorithm where we can cure our patient. This was the end point of KALLA trial that Dr. Monk presented two years two days ago it seems two years but immunotherapy was combined to chemo radiation in the locally advanced setting but unfortunately the trial did not meet its primary endpoint and the PFS was not increased with a I have to say no significant trend to a better distant control of disease at two years. It was a great pity I have to say for clinician and for patient but we will receive the results in few months I hope of another trial using a different drug in a probably higher risk population and we will see if there is a place for this strategy in our armamentarium. The reality is that more and more patient will be treated with immunotherapy what after immunotherapy this patient will became an emerging population in our treatment strategies. I will sure you will find the answer to this question in the next talk with the Dr. Tewari but there are some interesting information for immunotherapy pre-treated patient that may arise from immunotherapy setting. So what is clear is that immunotherapy pathway is a complex pathway with several negative feedback and preclinical data suggests that the dual blockage synergistically may enhance anti-tumor activity. So if we block in parallel CTL4A and anti-PDL1 which move two different phase of the immunotherapy response the priming phase and the effector phase probably we can achieve better results. This is what is suggested by the checkmate 358 trial which combine an anti-CTL4 and anti-PDL1 nivolumab plus ipilimumab which seems to report better response and better, I would say, control of disease when nivolumab was combined with ipilimumab particularly in the nivo1 ip3 schedule. And this is also suggested by another trial combining bastillimab plus zalinefrinib which report good control of disease with 32% response rate with the combo of the two drugs. The rapid trial has been already concluded. It was exploring this strategy in a prospective randomized way. The trial has been concluded and we will see if really the combo is better than the single agent. It is a pity that this trial did not enroll immunopretreated patient because in my vision a space for the combo may be in the patient who have already received immunotherapy or at least it could be interesting to see if there are signals of efficacy. If the combo works, why not to use the combo in one single agent? This is the history of cadonilimab which is a next-generation first-in-class humanized bispecific antibody combining the targeting on the two PD-L1 and CT-L4. In this phase 2 single arm trial in an evenly pretreated population up to three prior line of therapy who has already received pembrolizumab and the chemoradiation, the trial reported the interesting signals of efficacy, 33% response rate with 52 patients experienced disease control and the median duration of response not reached. Now this strategy is part of the platinum paclitaxel plus or minus bevacizumab in chemo-naive patients to demonstrate a benefit. And lastly, there is another interesting target which is the anti-TGIT which is a co-inhibitory receptor is co-expressed with PD-1 on both CD4 and CD8 tumor infiltrating cells. So there is a strong rush. It seems that when we block anti-TGIT and anti-PD-1 we can act synergistically to increase CD8-O-C cell effector function. This is the KBVI-001 trial which explored the combination of an anti-TGIT plus pembrolizumab-X signals, and interesting signals of efficacy was reported with 20% of patient experiencing response in second and third line. And very interesting, it does not seem influenced by the expression of PD-1. So another trial will come answering, we hope, the same question. So it's a very, very interesting moment for immunotherapy in cervical cancer. It is a drug that really is changing the natural history of disease in first line, but also in the relapsed setting. This drug is reported to improve overall survival and progression-free survival with respect to the standard of care. Unfortunately, in this moment, we have no signals that it enhances treatment care in the locally advanced setting, and immunotherapy-resistant patients are an emerging issue, and also, in my opinion, the great challenge of the clinical research in the next year. Thank you for your attention. Thank you, Kera. Congratulations. Wonderful slides. Thank you. Very comprehensive. Thank you. Our last speaker will be Krishnansu Tiwari, What's Next? New Treatment Options in the Horizon Scanning of Cervical Cancer. Thank you. Thank you for having me. So I'm gonna talk about some of the non-immunotherapy options for patients with recurrent and metastatic cervical cancer. And I think I'll just jump right into antibody drug conjugates. Last year, we had, of course, the very first ADC approved in gynecologic cancers, and it was in cervical cancer. And as you know, these are kind of like a suicide bomber or a Trojan horse. You have an antibody that targets something specific on a tumor cell that's expressed preferentially, and then through endocytosis, the entire payload's engulfed, and then the chemotherapy component that's linked to the antibody does its work. In this case, with tesodamabidotin, which is the medicine that was approved for cervical cancer, it targets tissue factor, which is very much involved in the coagulation process during development. And this is a paper where you can see on the left slide, tissue factor expression is very almost ubiquitous in cervical cancer and absent in normal tissues, but it also, the degree of expression tracks with clinical stage, lymph node metastases, and distant metastases. On the left side of this slide are two patients, the first two images, two different patients with lymph node metastases and the staining with tissue factor compared to the two patients, C and D, that did not have lymph node metastases. And then over on the right, the same type of thing for patients with distant metastases. So tissue factor is highly expressed in cervical cancer, and the level of expression tracks with clinical stage, lymph node metastases, and distant metastases. So tesodamabidotin is, you can see it right here, this is a cartoon of it, and the antibody, again, targets tissue factor, and through the linker, the payload, which is a chemotherapeutic agent that interferes with microtubules, similar to paplitaxel, is then brought into the cell. And when this happens, it can work on the microtubules, but it also passively diffuses into other cancer cells in the region that may not have been hit by the antibody drug conjugate, so there's bystander effects. Cancer cells die this way. So there's three trials that were done in cervical cancer or are being performed. This is the trial that led to accelerated approval for tesodamab in cervical cancer. This is the Inova TV204. This was reported by Dr. Coleman. You can see the very top, it was a monotherapy single-arm trial for women with recurrent cervical cancer that had progressed, and over on the top right, you can see the objective response rate was 24%. You can see the disease control rate was even higher when we included stable disease. The progression-free survival, four months, and then overall survival of 12 months, and within six months of treatment, 60% of patients had reached that. Interestingly, because tissue factor was almost expressed on all of the patients' tumors, it didn't really track with response. Adverse effects, and I think it's important to conceptualize this, it is a targeted therapy because of the tissue factor-directed antibody, but again, remember, this is a microtubule-interfering chemotherapeutic agent, so we get some unique side effects and some other side effects that we're familiar with. For example, peripheral neuropathy. Because of the tissue factor issue, you do have some peripheral neuropathy, and that is something we need to counsel patients about, and it's similar to paclitaxel, where peripheral neuropathy is an issue. We have alopecia with paclitaxel, and you do have alopecia with this drug, although not as much. What's interesting, though, there's almost very little hematologic toxicity with this agent. There are some very unique side effects involving the eyes, and we'll talk about that a little bit more, and then there's also maybe a 1% incidence of pneumonitis, and we know from other studies using other antibody drug conjugates that with ADCs, pneumonitis can be a bigger problem. It's not that big of a problem in the Inova TV-204 study, or the next one that I'll be talking about. So let's look at some of the, if you look at all these side effects, you can see the vast majority of them are grade 1 and grade 2. A little bit, 2%, grade 3 and above, fatigue, some pruritus, 1%. Overall, pretty well tolerated. This, of course, led to accelerated approval. This got in just a few weeks before the full approval of Keynote 826, which, of course, brought chemotherapy plus pembrolizumab, with or without bevacizumab, into the first line, but also converted the previous accelerated approval of second-line pembrolizumab to full approval. So had this not got in, we would not have had an option for patients that were PD-L1 negative that could not receive pembrolizumab, and so this was just in the nick of time. Now, regarding the ocular toxicity, the FDA has designed a very important eye toxicity mitigation plan, and there's several components to it. There's the eye drops component, there's the patient component, and then there's the eye specialist component. So, first of all, the eye specialist. Patients need to be seen at baseline by an optometrist or an ophthalmologist and have a visual acuity exam and a slit lamp examination. So we need to partner up with our eye specialists. Patients need to be instructed not to wear contact lenses, to do their own eye self-exams periodically, and also not to use fragrant soap on their face. And then, as far as during treatment, they use cooling packs on their eye pads. They get vasoconstricting eye drops during the infusion. The infusion is 30 minutes, but it's given over an hour. Same with the cooling packs. And they also get corticosteroids on the day of infusion and for a couple days afterwards. Corticosteroid eye drops, specifically. And then, up until the next dose, they get saline eye drops. So, three types of eye drops. Visual acuity tests, slit lamp examination, no contact lenses, cooling packs on the eyes. Very complicated, but once you get into it, it's pretty easy. And, you know, in our experience, this has really helped to mitigate a lot of the ocular side effects that were reported. This is the follow-up study. I know of a TV-205 as opposed to 201. And you can see what's going on here. There's dose escalation cohorts combining TV with bethacizumab, with pembrolizumab, and carboplatin. And what was reported at ASCO this year by my main man, Ignace Bregode, were the cohorts looking at tesodimab, fedodin, with pembrolizumab, and with carboplatin. And they did it in the first line and the second line. So, let's take a look at some of the data that was shared at ASCO. And here you can see the schema. The first line treatments were TV plus pembro and TV plus carboplatin. And in the second line and third line, it was TV plus checkpoint. So, these are the baseline demographics. Pretty well balanced amongst the three different cohorts. And let's look at the anti-tumor activity. You can see complete responses occurring not only in the first line, but also in the second line and third line with TV plus pembrolizumab. And you can see all various other partial responses. Let's look at them individually. In the first line, Tisodamab-vidodin plus Pembrolizumab, we've got a confirmed objective response rate of 40% and a median duration of response that has not been reached. This is in the first line. Second line, third line, Tisodamab-vidodin plus checkpoint, confirmed objective response of almost 40% and a median duration of response of 14 months. That's remarkable. Let's look at first line, TV plus carboplatin. 55% objective response rate, median duration of response 8 1⁄2 months. So, and this is the summary of the side effects that were most commonly reported in greater than 25% of patients. My slides are available in the interest of time. I'm not going to go through each of them, but really no new safety signals were observed even when combining this antibody drug conjugate with some of the other agents we have. And these are the areas of special interest. Again, because of the tissue factor issue, bleeding is another important unique side effect of this agent. And so, nosebleeds that we're familiar with, with pepicizumab use, you may experience them. You may avoid elective surgery when using this drug. But here you can see those peripheral neuropathy, ocular toxicity and bleeding. Very little grade 3 to 4 in these patients. Well, this is being followed up with a phase 3 randomized trial. The skeleton of this trial is very, very similar or almost exact to that of the Empower study that Dr. LaRusso presented earlier in the second line. And this is, again, a single agent to sodamab-vidodin as compared to physician's choice chemotherapy. And this will be the study that will hopefully convert the accelerated approval to full approval. And so what you can see, especially with the trial earlier, combining it with carboplatin, combining the drug with pembrolizumab, it's setting it up to possibly study this in the first line setting, possibly even to switch out paclitaxel for this drug. So what we can see here is this is where we've gone so far. So 2009, Dr. Monk reported QG204. At that time, no one was working in the area of recurrent and metastatic cervical cancer, just the GOG. This was followed up in 2013 when 240 reported. And then Keynote 826 just last year. So we've gone from 12 months to 24.4 months. We've doubled median overall survival. And we'll have to see what this next trial shows. It should be TB301, sorry about that. Okay. Really quickly in the last few minutes, I'm going to talk about a couple other therapies that I think you should be aware of. Autologous T-cell therapy. This is a surgical biopsy by laparoscopy or a core biopsy through interventional radiology of the tumor. You isolate the tumor-infiltrating lymphocytes and you grow them up. You expand them. You do myeloablative therapy to the patient and infuse these tumor-infiltrating lymphocytes that are specific for that patient back to the patient. This technology was pioneered at the National Cancer Institute by Christian Hendricks. He reported in 2015 a series of nine patients, two of whom were... well, they were all very heavily pretreated, but two of these patients had such a remarkable response to their TILs that their cancers completely disappeared. And they had a sustained complete response for nearly two years and beyond the time he published this work. The problem with this is the patients had to go to the NCI to have this done. So there's been an effort to try to bring this technology into the community, and that's where the LION trial... that's the goal of the LION trial. And you can see the different cohorts here. Now, with the full approval... with the accelerated approval of pembrolizumab and the second line being converted to full approval, there's really no path forward with this study at this time. But I do want to share with you the Cohort 2, which includes patients that have had previous checkpoint. That is continuing to enroll. And so we'll see if there is a path forward for this. It'd be a shame to lose this, especially given that it did get breakthrough therapy designation by the FDA. But we're going to have to see what happens with Cohort 2. But it is ongoing. Last thing I wanted to talk about was HER. You know, about 5% of cervical cancers do express HER2, and you can see that there's different ways to measure it. Of course, there's with IHC, where if you have greater than or equal to 30% 3-plus staining, those are considered to be HER2 positive. You can also do FISH, where you use the centromere protein as the control, and FISH is often used in the HER2 over centromere score where greater than or equal to 2.0 is indicative of positive HER2 staining. Anna Oakman from Spain reported the Phase 2 summit study looking at patients with recurrent metastatic cervical cancer. They got oral neratinib, 240 mg daily, and the primary endpoint was objective response rate, which was 25% in this group of patients. This was an interesting thing that happened. So the idea was to expand on this and try to develop a test to easily test for HER2, and this was the HER-Seq clinical trial, but this study got... it disappeared because with the widespread availability of next-generation sequencing and identifying these mutations, there's really no need for this study. So that's it. I'm done. I was just going to end with a picture of Bob Dylan in New York City from 1962. Thank you. Wonderful. Great job. Congratulations. I'm going to invite our three speakers here. Thank you so much. Yes, if you could come and join us here. Thank you all for those wonderful presentations. I have some questions along with Professor Ramirez. Maybe I could start, Dr. Kohler, how do you handle the patient who comes in with a tumor which in your estimation is too large for fertility-sparing surgery, whatever that threshold is, and she says, no, it's going to be okay. I want to have a baby. How do you have that? Because I know that happens. It happens to me because people think they're invincible and it's just a little cervical cancer. How do you handle that conversation? It's a difficult conversation. Thank you for this question. Again, we are also following the strategy for neoadjuvant. I tell them it's an experimental approach with a higher recurrence rate as you have seen in the few cases we did. It is experimental, but if she insists on it, okay, then we do this with a lymph node dissection done by laparoscopy. If they are tumor-free, then we apply the chemotherapy and hope that it responds. Pedro, I want to hear from you. Can a patient insist? I don't want a C-section. I don't want a C-section. My baby's going to be just fine. The heart rate is going to come up. Can they insist on what you would think is the wrong treatment? I think that we have a responsibility to our patients to guide them with regards to what the best management would be for them based on evidence-based data, based on the guidelines. Certainly, we have patients, as I'm sure you have and we have all had, where they say, I still want a pelvic exenteration when I have multiple lung meds because that's what I want. I think it's our responsibility to say certainly that is not what I will provide. That is not within the standard of care and therefore then proceed and suggest to the patient to perhaps find a different provider. Tough question. Yes, hi. Thanks to all the speakers for the nice presentations. My name is Mignon van Gendt. I'm from Amsterdam. I have a question for Dr. Keuler concerning the abdominal radical trachelectomy or at least you presented that you had 50% adjuvant therapy needed for this group. I find it quite a lot of patients needing adjuvant therapy. And I was wondering were these tumors bigger than 4 centimeters or what was the risk factors? Because I think 50% is quite a high number. These are not our data. Thank you for this question. The data are from the review by Frank Cole and this is the table I have taken from his presentation. Again, this is an ongoing problem and Professor Wu who gave us his video in advance for the fertility sparing session two days ago, he also showed that he has a high rate of adjuvant therapy, more than 50%. I'm a little bit afraid if there's a need for doing this, then it's for me questionable to perform this procedure. I completely agree with you. Thank you. I have a question for Christa. Christa's a good friend, so I feel I can put him a little bit on the spot. I think that one of the principles that we are always taught, the principles that we learn, is that certainly practice should not be driven nor changed by cross-sessional analysis, cross-study analysis, by secondary analysis, by post hoc analysis. I think I heard you say on the subject of minimally invasive surgery and cervical cancer that the results of a prospective randomized trial that have driven all guideline changes in cervical cancer should be challenged by a retrospective study. On the subject of the uterine manipulator I think I heard you say that this is a secondary analysis of the SUCCOR trial so therefore not using the manipulator and doing a vaginal protective maneuver should drive practice. And then lastly I think I heard you say that based on the post hoc analysis of the uterus 11 whose primary objective was to demonstrate whether surgery or staging, clinical staging made a difference in patients with locally advanced cervical cancer that did not show a difference but a sub hoc analysis did show a difference in a subset of the population. So should we assume or ignore the fact that practice should not be driven or changed based on cross trial analyses, secondary analyses or post hoc analyses? I hope you're still friends after this. No, no. I think we stay good friends. Probably. I agree with you. The last trial is the best level of evidence, no doubt about it. But it must be allowed to also raise questions about the study. And if you perform a study, remember when you initiated this trial for the leg trial you also asked our center to participate and it was not allowed because we have this technique of closing the vagina. So this is a technique where and you gave me the answer during many talks that in all cases in this trial a manipulator was used, the vagina was opened and again this is for me a little bit like as you compare apples with oranges. It brings the oranges to the entire population of minimal invasive surgery and this is for me also not 100% fair. I agree with you with the uterus 11 trial there was it is a negative trial but again the question is not on the top again because we do have now the PET-CT and the PET-CT changed the practice dramatically. The radio-oncologists demand on a PET-CT and not on conventional CT so the time is over for this and we have definitely either to design a new trial or to give up and say okay do a PET-CT wherever and whenever you want. The question is the money. In Germany it's not paid for any patient in cervical cancer so it's still in our guideline to perform a surgical staging but again it may be an excuse in the world but again the next study must be PET-CT versus surgical staging if it is again on the table. Excellent. Excellent answer. Please. Hi. Thank you so much. Kay Park from Memorial Sloan-Kettering. So all these amazing trials, immunotherapy, upcoming for recurrent metastatic cervical cancer I see they usually separated by histotype squamous, adeno-adenosquamous of course I'm sure you can probably guess what my question is. Is there any thought or plan or ability to tease out their HPV status in terms of their response rates too? Because you know it's these HPV independent tumors that do so poorly to our traditional therapies. Is there any ability to sort of look into that into the data on any of these trials? Thank you for that excellent question. Ketter why don't you take that? I think it is really an excellent question. What we know now is that the PD-L1 expression may be a surrogate of HPV status. So according to this prerequisite, the results are really, really confounding. You see some trials report PD-L1 as a predictive factor of efficacy. Some other did not confirm. Probably single agent is more impacted by PD-L1 expression. The combo seems to lose the predictive effect. This is a really, really good question. My personal view is that probably we do not have the best test for PD-L1. Probably what we interpret as misleading results rely mainly on our incapability to really identify who are the PD-L1 positive patients because we do not have a single test consistency results cut off where to measure. It is more a problem of technique in the test, in my opinion. Thank you. There are sufficient biospecimens from Keynote 826 to answer much of those questions including next-gen sequencing which when you sequence a tumor you can tell if there is HPV in there. Krish, I loved your talk. Thank you very much. I love the enthusiasm. It is very exciting. As you know, it was presented at ASCO in 2019 44% response rate in 27 patients. We have not seen the results of Cohort 1. Cohort 1, it has been three years and obviously it has completed enrollment. You said, hey, there is no path to approval. Well, if it would be compared to 158, Pembrolizumab, 14.3% response rate but if Cohort 1 holds up in the 40% like response rate why wouldn't that get approved because in an inferential sort of way it is way better than checkpoint? I don't know. Logically, it makes sense that if Cohort 1 was that fantastic we would have it would be approved but then why it must not be that great, right? It has been a long time. We don't know what the objective response rate should be. The good news is that the technology has been filed on PD-L1 exposed melanoma and I think they have been very focused on that and now they need to start focusing on what we care about, cervical cancer. Not that we don't care about melanoma but we need to see the data. You are right though. Most of their efforts right now are in the melanoma space but I still think it is promising and maybe the way forward is in the PD-L1 exposed patients. Or the PD-L1 negative patients, right? But if it is better than checkpoint there are still substantial numbers of patients that remain checkpoint naive in the second line and if it is good maybe we should re-sequence. And then finally There was a curiosity because I did not join the trial. What was the feasibility of that strategy? Because I am not sure it will be a strategy for all the hospitals. It would have to be at tertiary centers and you are right and I personally on cohort 1 have two patients that are cured. So I am very passionate about it and I have one last question for you and so I hear and thank you for listening to me and Cal I am sorry. Pity, I like that. I hate the word but it is true that it sort of accurately reflects our emotion. You talk about keynote A18 being a higher risk group analysis of patients but it is really event driven. So when studies are event driven particularly in patients that are going to recur and die the risk really informs the sample size. So if you were to see let's say 246 events in A18 and I am not saying that that is the first interim analysis, would you expect keynote A18 to be positive because of the risk of the patients or because it is a PD1 and not a PD01? It is a very important question. You know in other solid tumor not in cervical cancer it seems that anti PD1 are more strong and more effective drug than anti PD1. That may be a possibility. Probably another possibility is a different selection of high risk patient. You know in A18 trial patient were selected according to the of at least two pelvic lymph nodes with at least 1.5 centimeter in the minor diameter and probably this will select an higher risk patient and probably in that patient something may be seen. Great. Thank you so much. This has been a fantastic session. Thank you to all six speakers. Thank you all for attending and staying through the sessions and congratulations to all for the work and the contributions you have made to gynecologic oncology. Thank you so much.

clinical implications

HPV-independent cervical cancers

screening programs

rare cancers

advanced stages

specific screening protocols

challenges

further research

improving Pap smear tests

DNA tests

non-HPV cervical cancers

immunotherapy

cervical cancer treatment

Pembrolizumab

antibody drug conjugates