Okay, perfect. So thank you guys for the invitation to speak today. This is something that came up in our tumor board, so I thought it was a timely topic, but universal germline genetic testing in endometrial cancer. I don't have any disclosures. So this we all know, depending on ethnicity of the patient population, it's estimated that 2 to 5% of endometrial cancers are due to an inherited susceptibility. The most common type, of course, is Lynch syndrome, which is mutations in our DNA repair genes, with Cowden syndrome being a distant second contributing to a much smaller fraction of patients with inherited susceptibility to endometrial cancer. So for the sake of this quick talk, we'll focus on Lynch syndrome testing. So how do we identify patients at risk for Lynch syndrome? Just going off of the ESGO guidelines, which was the first one listed on the IGCS, testing for MMR deficiency by IHC or microsatellite instability by PCR-based methods does not allow for direct identification of patients with Lynch syndrome, since MMR deficiency or microsatellite instability is frequently due to sporadic events such as bioallelic somatic mutations or hypermethylation. So in the absence of hypermethylation, the recommendation from ESGO is referral to genetic counseling to evaluate for the presence of a germline mutation. In addition, when familial history is highly suspicious of Lynch syndrome, genetic testing is recommended independent of a patient's MMR status. So what does that look like for most of our clinics? As you can see here, for most of our patients, at least here in the United States, are getting IHC evaluation or microsatellite instability testing for all newly diagnosed endometrial cancers and colorectal cancers. Patients who are MMR proficient likely do not have Lynch syndrome, and they would only get genetic testing if they have a strong family or personal history of the patients with MMR deficiency. If there is an MLH1 loss identified, then they will undergo hypermethylation testing. If that is positive, then they are unlikely to have Lynch syndrome, but can get tested based on family history or personal history. If patients do not have hypermethylation, they get genetic testing. And if patients have MSH2, MSH6, or PMS2 loss, then they also get germline genetic testing. Interestingly, in the most recent update for NCCN, the guidance around germline testing for endometrial cancer has changed a little bit. It allows for more permissive referrals to genetics and supports a shift in more universal germline testing for patients with endometrial cancer, more in line with an ovarian cancer dogma of screen everyone and opt out. So in the most recent guidelines, any patient who is less than 50, they recommend germline genetic testing. And they specifically recommend these multi-gene panels that are going to include our high penetrant genes that we think of with our Lynch patients and our homologous recombination defect genes, like our BRCA1 and our BRCA2. For patients who are older than 50, if they're MMR deficient, you can just do germline testing, or you can base your decision on germline testing based on other tumor-based testing, which would be hypermethylation. But if they are MMR proficient, you could still do germline testing. They still support that or decide on germline testing based on family history or tumor factors. So they write a lot to try and rationalize this because there's no one big individual study that says that this should be the big shift. It's kind of pulling together a lot of retrospective cohort data. And I try to distill this down as much as possible for the sake of this talk. But under the pros column, they cite the higher sensitivity that you're going to have for Lynch syndrome if you were to do universal germline testing for patients with endometrial cancer. The other big bonus would be the identification of other pathogenic mutations. So identification of more patients who have those BRCA1s, those BRCA2s, those high penitent genes that are going to have implications for patients' own personal cancer risk for other cancers, and as well as patients' family risk of cancers in the future. The other thing that they cite is just the simplicity of referrals. Instead of trying to go through these different algorithms that are interpreted differently by different physicians at different institutions saying, well, why don't we just test everyone? That way we're not going to miss anyone if we try and test everyone. In the cons column, if we're being honest, knowing a patient's germline status isn't going to change decision making for a vast majority of our patients with endometrial cancer, at least in the upfront setting. In addition, the more germline genetic tests you send out, the more variants of unknown significance you're going to detect in having to counsel that volume of patients on what to do with that information. What about survivors? We have millions of people just in this country who are survivors of endometrial cancer. Do we then say that they should then go back and have genetic testing? And of course, kind of the big elephant in the room, the cost, cost here in the United States where we spend a lot of money per cancer case, but also internationally in lower resource settings, are we going to say that this is the standard of care now and it'll be the standard of care here in the United States and we're only creating kind of a bigger wedge between standard of care here and standard of care elsewhere. So sensitivity of testing for Lynch syndrome. So based on compiled data that we have, testing patients based on these family history based testing systems, and the most often used is the revised Bethesda guidelines, has a sensitivity of about 82%, but about 50% of patients who meet criteria and have endometrial cancer do not have Lynch syndrome. For IHC based IHC based staining, the sensitivity is about 83% for microsatellite instability. There's a little bit of a wider range depending on the study you look at 77 to 91%. And in theory, the authors say, you know, universal screening should have 100% sensitivity, but that's, it's a big in theory that that's assuming that we're actually able to get all patients tested, we should be able to detect all all cases of endometrial cancer caused by Lynch syndrome. So where are we now in the United States, Korean et al published the rates of germline genetic testing for over a million patients diagnosed with all cancers in two states here in the United States, and just under 7% of patients had germline testing. And of the patients with endometrial cancer, if you look here, the rates of germline testing has been increasing with time, but as it stands right now, only about 6% of patients in this study with endometrial cancer received germline testing. Now, what if we did a more universal germline testing model. So this study wasn't a pure universal germline testing model, because the study methods didn't dive into what exactly was the provider rationale, but it was a wider, wider net of germline testing that didn't adhere as strictly to those guidelines set out by as go, they collected about 6000 patients with endometrial cancer, and who underwent germline testing. And of those patients, about 13% of them had a pathogenic mutation. And one of these multi gene panels, 60% of them were a gene for Lynch syndrome, 1.5% for Cowden syndrome, a p 10 mutation, and just under 40% of patients had other pathogenic mutations that they that were detected with their germline testing. And Memorial Sloan Kettering, and this was published kind of just after I left, but we're Honda's and all looked at what was the data that we collected from our homegrown in house panel at Memorial Sloan Kettering and at Memorial Sloan Kettering, all patients with endometrial cancer are offered universal germline and somatic testing. So there's just a wealth of data to be able to look at kind of that in theory situation, what what would we yield from patients? And what was interesting about this paper is they wanted to look at, yes, what kind of germline pathogenic variants were identified, but also did these pathogenic variants drive the endometrial cancers for those patients. And they did this by looking at biallelic versus monoallelic loss of these genes that were identified. So if you look here, you know, in this top corner, you can see the high penetrance genes, there's some moderate penetrance genes, and some more smaller, you know, uncertain penetrance genes across the bottom, and 32% of all germline pathogenic variants exhibited biallelic and activation within tumors. So only 32% of patients with a germline mutation was that germline mutation driving their endometrial cancer. But if you look at this high penetrance group, that number is a lot higher. So 63% of patients with a high penetrance germline pathogenic variant exhibited this biallelic inactivation, which, you know, interestingly, a lot of our BRCA1s, a lot of our BRCA2s, these homologous recombination defect genes, when patients had these germline genes, they were actually the drivers of their endometrial cancer. Now, cost, cost is the big elephant in the room, how are we going to pay for all of this? So Levine et al, and this is the group from Ohio State, created a decision analysis where they looked at kind of two different theoretical approaches to care for endometrial cancer patients. What if we did universal MMR-IHC, and then triaged our germline testing from there, which is what we do at most institutions, or universal germline testing, and then actually reserving the MMR-IHC for the recurrent setting, which, you know, with the push for molecular identification of endometrial cancer, I think this is a lot more controversial than it was back in 2022, but that's kind of how they broke down their theoretical model. And if you reserve that MMR-IHC for after germline testing and only use it in the recurrent setting, then universal germline testing was actually cost-saving to the patient. You were able to identify 1% additional cases in the United States in theory of Lynch syndrome, so that was another 660 cases a year, and another 1% of endometrial cancer patients who had a BRCA1 or a BRCA2 mutation, another 660 cases for that year. But admittedly, in looking through their models, and I like cost modeling, so I dug a little deep, you know, this is really dependent on losing that upfront IHC, and I think that that would be very uncomfortable for a lot of people to kind of lose that information in that upfront setting. So, is universal germline genetic testing the new standard of care for patients with endometrial cancer here in the United States or elsewhere? I don't think we know. I think that it is nice when NCCN loosens their grip on some of their recommendation because it allows us to be more flexible and to push back here in the United States on insurance for when we want things covered to our patients, but what that means, you know, for our patients, I think, you know, has yet to be determined, but I think it's an interesting space to think about how we're going to change what we offer patients in the future. And I'll take any questions. Okay.

germline genetic testing

endometrial cancer

Lynch syndrome

multi-gene panels

pathogenic mutations