Intro: Welcome to the CGA-ICG podcast series, brought to you by CGA's Education Committee and made possible through the generous support of our sponsor, Lynsight. Each episode aims to bring you an in-depth discussion related to emerging data, clinical challenges, and unique perspectives in the world of hereditary GI cancers.

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Emma Kiel (Host): Hello, and welcome to the CGA-IGC Podcast series of 2025. My name is Emma Kiel, and I will be your host for today. I have the pleasure of introducing doctors Ying Liu and Nicole Edison, who will be talking to us about gynecologic cancer risk and Lynch syndrome and the data driving NCCN guideline changes.

Dr. Liu is a medical oncologist at Memorial Sloan Kettering Cancer Center, and Dr. Edison is a gynecologist at the University of Chicago. Both specialize in the care and management of patients with hereditary cancer predisposition syndromes such as HBOC and Lynch syndrome. I want to hand it over to Dr. Liu and Dr. Edison. Could you both briefly introduce yourself and tell us about your role at your institution?

Dr. Ying Liu: So, my name is Ying Liu. I'm a GYN Medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. I also lead our Inherited GYN Cancer Program, and my focus is really on treating women with gynecologic cancers, as well as counseling all patients on inherited risks with a focus on gynecologic cancers.

Dr. Nicole Edison: And I'm Nicole Edison. I'm a gynecologist at University of Chicago. And I'm a benign gynecologist, so I don't treat people with an actual diagnosis of cancer. But I focus on benign gynecologic pathology and preventing cancer in hereditary cancer patients. I do risk-reducing surgeries and hormone replacement as well.

Host: Great. Thank you both. So first, I want to level set and make sure that all of our listeners are on the same page. We saw a pretty significant change to the NCCN guidelines last September with regards to the gynecologic cancer risk management and surgical recommendations for folks with Lynch syndrome. Could we briefly just review those changes?

Dr. Ying Liu: Sure. I'm happy to do that, Emma. I think we have to look back a little bit at the guideline evolution over the last five years. You know, I think five or ten years ago, we were really counseling our women on gynecologic risk in a very general way. We would sort of say there is increased risk of both endometrial and ovarian cancer. You should consider risk-reducing surgery at some point, but not too early, and probably not before the age of 35 or 40, and really kind of depending on your childbearing. There was really very little guidance. And so, I'm actually extremely happy that the NCCN and other guidelines are focusing more on gynecologic cancers and there's this growing awareness of them and how to counsel around them. So, I think that's wonderful. They were even incorporated into the title this year, which I think is really great.

I think starting around 2020, maybe five years ago, there was kind of a greater appreciation internationally about gene-specific risks for Lynch syndrome and that not all genes are the same, and I know this started initially with colon cancer, but we're starting to understand that more and more for the gynecologic cancers, both uterine and ovarian. So around 2020, that's when a lot of guidelines stopped being general for just Lynch syndrome and started to be more gene-specific.

And I think the major change with the gynecologic cancers was sort of the understanding that PMS2 potentially had less risk of both uterine and ovarian cancer. And it was even controversial at the time if there was increased risk of ovarian cancer and should risk-reducing surgery be done. There was a little understanding about MSH6 as well with maybe slightly decreased risk of ovarian cancer.

But last year, in the fall of 2024, we saw some major changes in the guidelines. And I think they're all good changes, and they're all generating a lot of conversation. But I'm so happy that we're doing this podcast so we can understand the nuances and kind of help counsel our patients through them.

So, I think one of the most important things that was introduced in the guidelines, in addition to sort of gene-specific recommendations, was also this idea of a staged surgery, which I know Dr. Edison's going to talk more about. This is something that we've been doing in practice and talking to our women about, but it was great to see that the guidelines were incorporating this. And I think it's important to understand the nuances of that. And what I mean about staged surgery is potentially doing a hysterectomy to remove the uterus, and then a salpingectomy to remove the tubes, but leaving the ovaries in place and then potentially removing those at a later date closer to menopause.

And I think the idea of a staged surgery is important, because it gives our patients more options, but it also can be tailored to really fit the gene-specific risks. And there was sort of some back and forth about exactly which ages to consider this for which genes. But I think sort of at the end of all the changes in the fall, the consensus from the guidelines was that MLH1, MSH6, and MSH2 have really high uterine cancer risks, and hysterectomy should be considered a little earlier maybe than PMS2. But then, the ovarian cancer risk varies with, I think, MLH1; MSH2, still being the highest risk in the earliest; MSH6, potentially a little later; and MSH6 is where I think really the staged surgery approach is probably the most appropriate. And then, PMS2 being, you know, lower risk of both uterine and ovarian, but still potentially could consider risk-reducing surgery kind of closer to menopause. So, I think that's been the biggest evolution.

There was also more incorporation of language around hormone replacement therapy. So, I think overall all really good changes that are giving our patients more options, but it's really important to understand the nuances of the data that surround this so that you can properly counsel patients.

Host: So, I do want to talk a little bit about this staged surgery. Can you tell me about the data that went into this decision and why this might be beneficial for patients doing this staged surgery?

Dr. Ying Liu: So, the staged surgery approach really comes from the BRCA data. And it's something that's being done for patients with germline BRCA1 and 2 mutations, because there's pretty good scientific evidence to suggest that the precursor lesion for your traditional high-grade serous ovarian cancer is actually the fallopian tube. And the thought is if you can remove the fallopian tubes early, you can get some benefit with ovarian cancer prevention, but also defer that surgical menopause. And we're seeing very promising epidemiological data from Canada, the U.S. and internationally, although the large clinical trials are still ongoing and have not reported out.

So, this is being sort of adopted in Lynch syndrome, but we do have less data. So, we think that the origin of the ovarian cancers in Lynch syndrome are different. We think they're more related to endometriosis, potentially coming from ectopic endometrial tissue. So, the biological rationale for doing salpingectomy is a little less robust. And we also have less clinical data. A lot of the patients with Lynch syndrome weren't included in these studies.

So, what I tell my patients is that the staged surgery is a very attractive approach, but salpingectomy for Lynch syndrome is really opportunistic. We don't have good data to show that it actually prevents ovarian cancer. But if you're done with childbearing, it's not harmful to do it. And we're actually recommending this for many women without a hereditary predisposition to cancer just as an opportunistic procedure. But the actual risk reduction benefit for ovarian cancer is unknown. And that's why this is a really important caveat to emphasize when we counsel them.

Dr. Nicole Edison: I thought it was an interesting idea. When you do a hysterectomy for whatever reason, you'll never leave the tubes behind. So, I think it's hard to know, you know, are we removing the tubes because we're doing the hysterectomy? Are we removing the tubes to kind of just also affect the ovarian cancer risk?

My sense was we're doing the uterine portion to protect for the endometrial cancer. But particularly for MSH6, the mortality benefit for removing the ovaries can be seen a little bit later. And so if you can defer that surgical menopause, you can talk to them about it because removing the ovaries is actually not a major surgery in and of itself. It's usually about a 45-minute surgery. Patients are sort of back on their feet by the next day. It's more the side effects that we worry about.

The interesting thing is you sort of think, "Well, if you're taking out the ovaries, that there's no harm realistically in giving back hormone replacement therapy, at least until the age of natural menopause, well, why put someone through two surgeries?" And there's some data that is suggesting that even with hormone replacement therapy, there may still be a decreased quality of life from surgical menopause. I think that that's a very hard question because those studies don't look into account how are people prescribing hormone replacement therapy? What doses are they prescribing them? Because in my actual experience, I find if you are-- I don't know if I want to use the word aggressive-- but if you're following someone very closely for hormone replacement therapy and not just doing a one-size-fits-all, that patients generally are very happy after salpingectomy, and you can get them fairly symptom-free. But I think that that's really the consideration about leaving the ovaries in longer is a concern about quality of life and maybe not losing anything with the ovarian cancer mortality risk.

Host: I do want to ask a followup question about this because I think, in CGA, a lot of us are gastroenterologists, genetic counselors. Can you tell us a little bit about what those surgical menopause risks are and how you are prescribing that hormone replacement therapy?

Dr. Nicole Edison: The surgical menopause risks that are, I think, covered in the guidelines are risk of osteoporosis or decreased bone density. Estrogen is also really important for vascular health, so increased risk around cardiovascular morbidity. And I think there's also potentially some questions too about mood, neurologic impact, dementia risks that we don't really know but is still out there. And then, also sexual functioning, because estrogen can help mostly with the vaginal moisture and pliability. But then also there's some testosterone production in the ovaries as well that can lead to libido, and then vasomotor symptoms. So, I think it's a mixture of medical risks and then patient quality of life issues that we're thinking about. If we're giving hormone replacement therapy, particularly through a patch or a gel, so you're giving it transdermally, and it's just estrogen. You don't see necessarily an increased blood clot risk. That's one of the things that we worry, worry about. And we also have not seen with estrogen replacement therapy alone unless you're on it for a very long time, like 20 years after menopause, really a significant increase breast cancer risk. The progesterone is really what leads to the increased breast cancer risk with hormone replacement therapy, and it's not something that you have to give if someone has had a hysterectomy.

Host: Now, how are you counseling these patients on these new guidelines? I'm thinking about the patients that have been in our clinics for several years and we're told one thing. And now with these changes, maybe told something different.

Dr. Ying Liu: Yeah, Emma, that's a great question. And we talked a lot about that as a group, how to kind of reconcile these changes with the approach that we've been using. So, in general, what I tell women with MLH1 and MSH2, and I want to be very clear that I still consider these two together. I know the guideline changes in the fall had initially recommended that patients with MLH1-associated Lynch syndrome could potentially delay BSO until age 50. But I want to be very clear that I think the data, especially the data from the prospective Lynch syndrome database, which is the best we have, really does still show an increased risk for ovarian cancer. For MLH1, yes, it's slightly lower than MSH2, but it is higher than MSH6, and it does start to increase above sort of the population rate before age 50. So, I was really happy when the guidelines actually shifted that back to be very similar.

So for MLH1 and MSH2, I do tell our patients that the risk of endometrial cancer is very high, lifetime risk anywhere upwards of 40-50%. And that risk starts to increase in the 40s. And so, if they're done having children, I think it's reasonable to consider risk-reducing hysterectomy around age 40 starting at that point. And I do think it's reasonable to consider a BSO for ovarian cancer prevention at that time, and then to take hormone replacement therapy. Then, that's how I counsel. And we go over the risks. And I sometimes show them the curves and the data. And if they're not ready to do the BSO and want to defer, then I do recommend at least removing the tubes and then doing a BSO a little bit later. But my initial recommendation is still to consider it at the time of hysterectomy, at least for MLH1 and MSH2, because the ovarian cancer risk is still quite high in addition to that uterine cancer risk.

For MSH6, it's a little bit more nuanced because what I want people not to forget is that the risk of uterine cancer is still very high. And it's our most common gene associated with uterine cancer. And that risk does increase, you know, in the 40s and can be just as high as MLH1, MSH2, if not higher. And so, I do think it's really important to recommend risk-reducing hysterectomy still to consider that around 40 and not forget about that. But here is where the risk of ovarian cancer is lower. There's a big range. It's variable in different databases. I will say that PLSD database has slightly lower numbers, but we published a cohort from MSK showing, we're still seeing early-onset ovarian cancer in MSH6 and even some PMS2 mutation carriers. So, I think we're still pretty conservative saying that there is an increased ovarian. But because it seems to be a little bit delayed in onset, it's reasonable to do a staged surgery here and maybe wait to do the BSO until you're closer to 50. Although if someone wants to do the BSO earlier and take home and replacement therapy, that's fine. And this is where family history really does play a role, because MSH6 can be a little nuanced. And then, PMS2, you know, the risk of uterine cancer is still higher than the average woman. It could be anywhere up to, you know, 20% lifetime risk. But that risk does start to increase a little bit later. So, I think it's okay to wait to do the risk-reducing hysterectomy closer to 50. Although some women, they're done having children, they want to have it earlier than 50. And so, I think that should still be okay. I hope the guidelines don't limit women from having the hysterectomy earlier if they choose. But I do think it's okay to wait until 50 to do the BSO for PMS2. And that also depends on family history. You know, we're now counseling if someone doesn't want to do a BSO, there's no family history of ovarian cancer. Maybe the risk with PMS2 is not that high, but some of the studies and some of the American data still show that there is a risk. So we are still recommending it, but probably closer to menopause. Dr. Edison, is that similar to your practice?

Dr. Nicole Edison: Yeah. That's, I think, very similar to mine, especially for MLH1, MSH2, I really stress that, yes, the uterine cancer risk is high, and people focus on that. But the hysterectomy is more done to avoid your experience, but not necessarily for a mortality benefit. And the ovarian cancer is really the cancer that makes us nervous where, even if the risk is lower, we may not be able to cure it. So, I do tend to focus on that with them to really discuss the BSO and to have a long discussion about hormone replacement therapy. Sometimes for certain patients, we will start it in the OR. I will put the estrogen patch on them right at the time of hysterectomy. Whether or not you have to do that is questionable. But I think for some patients, it is reassuring. That's not something that we want them to have to believe that they just sort of need to deal with afterwards, but that really considering their ovarian cancer risk is an important part of their overall health.

I think for MSH6, it's interesting, I haven't had a ton of patients, or the patients I have have been diagnosed a little bit later. So, you know, if they're coming to me and they're 45, do I think it's necessary for them necessarily to do a staged surgery? Potentially, no. But I think, especially if they are having a hysterectomy very close to 40 and we think it might be 10 years and certain patients are much more reticent around hormone replacement therapy and surgical menopause than others, and their family history looks okay, then I do talk to them about that option.

Host: Now, I'm wondering how these kind of recommendations might change for somebody that's coming with cancer history, particularly colorectal cancer history who've had surgery already. Are there considerations about scar tissue and kind of repeat operations in that area?

Dr. Nicole Edison: when I was looking at the guidelines and it mentioned, you know, you can consider doing the hysterectomy portion with potentially a colectomy and then, you know, are those patients that I really want to go back for their ovaries? No. I think it would be a little bit of a hard discussion for me to have with them. I think there's scarring that happens. It's also for risk-reducing oophorectomy. There's a lot of concern about getting a certain amount of kind of surrounding tissue. It's not just kind of taking off the ovaries, but you want to get a good margin on them. And I worry about the planes being a little bit obliterated after potentially colectomy and reconstructive surgery for that.

So, I think in those cases I really try to discuss what healthy hormone replacement therapy will look like, and also discuss the risks of repeat surgery of potentially bowel injury, probably being the thing that we would worry about the most, but also maybe our ability to do the surgery, as kind of completely as we would like.

Dr. Ying Liu: Dr. Edison, that's a great point, and I think that's important for our listeners to remember that, if a female with Lynch syndrome is diagnosed with colon cancer, it's a good opportunity to talk about concurrent surgery and to do the risk-reducing hysterectomy and BSO at the time of colon cancer surgery to avoid these issues in the future.

Host: For patients that are a little bit apprehensive about surgery and hormone replacement therapy, are there other cancer screening tools that you are discussing with your patients and what do you think about these?

Dr. Nicole Edison: There have been a lot of thought around how can we predict ovarian cancer. I think the more and more data we're getting, the more we're moving away from ultrasound and CA-125. And I'm very clear with my patients that there is not evidence that this really changes ovarian cancer mortality and likely not ovarian cancer staging. If they're going to do it, you know, I never tell them that they can't do it, although maybe we will move towards that at some point. But it should be done at least every six months. I would never start IT sort of before the age of recommendation for removal. And I give sort of all of those caveats that this is probably more for your own anxiety than it is for us to detect something. I read ultrasound, so I do find it interesting, you know, the CA125. I've seen it jump around so much in these patients that I do think it really just causes anxiety and it's really hard for it to be predictive when they're premenopausal, like most of these patients are.

The biggest thing I think mostly that I talk about with these patients is prevention, which we can talk about that in the guidelines about birth control pills, how much of a role there is for that. But there's fairly good evidence in the average population that for endometrial cancer and ovarian cancer and all ovarian cancers, not just serous, which is what we think about with the salpingectomy, that hormonal birth control is effective reducing risk by probably about at least 50% for the ovaries and lasting for several decades. So, that is kind of more what I want to make sure my patients have sort of thought about, our ovarian and endometrial cancer protection more than screening.

Dr. Ying Liu: I will echo that. And just say we don't have great screening, even endometrial biopsies, which are not so much fun for our patients, are not that accurate. We've done some internal studies looking at patients who have been diagnosed with cancer, with Lynch syndrome, who have had endometrial biopsies, even just the year before. And the concordance there is not great. So, I think we need better screening methods.

And there's some really promising new studies looking at how to sample closer to the uterus and ovaries and sampling new kind of novel biomarkers that are very interesting. But until we have better data for that, I think that the best data we have for prevention of gynecologic cancers and Lynch syndrome is still unfortunately surgery. And so, I do think that should be a part of the counseling.

Host: Thinking about surgery, what are the different options for these surgeries? I know we talk about minimally invasive and what does this look like for patients so that we can counsel 'em on this?

Dr. Nicole Edison: Unless there is some underlying other pathology, you know, extremely large fibroids or really severe adhesive disease, this should be done minimally invasively. Usually, that means still going through the abdomen through several small incisions. We fill the belly up with air and then we have ports that help us work through smaller instruments. It can be either laparoscopic or robotic-assisted laparoscopy, and that just gives us a little bit of a better view, a little bit better risk for control. But for the patient, it's ultimately sort of the same recovery. So, the surgery itself, if there's no other extenuating circumstances like endometriosis, fibroids, it probably takes about an hour, an hour and a half. And when we're in there, we sort of do extensive surveillance of sort of the peritoneal surfaces to make sure that we're not seeing any increased risk of an occult ovarian cancer. And we take some pelvic washings as well. And then, we do the hysterectomy portion usually, which means taking tubes, the uterus, and typically the cervix. Some patients in other cases will ask to retain their cervix, but especially in patients who have an endometrial cancer risk, there can be some lining still within the cervix. So usually, we'll recommend the total hysterectomy. The ovaries are sort of the plus minus, and that's the part where we talk about potentially doing a little bit of a larger resection of the tissue surrounding the ovaries to make sure that we're getting at all the ovarian tissue. We check afterwards, almost universally, to make sure that there's no increased risk of bladder injury by doing what we call a cystoscopy, so just putting a camera inside the bladder, and then sewing stitches that dissolve at the very top of the vagina. And so, usually, you know, the vaginal length might change by a centimeter or two, but not something that a patient should clinically notice. Afterwards, there can be moderate pain for the first two to three days. They might need something stronger than Motrin and Tylenol. But after that, it's mostly just fatigue, soreness and heavy lifting restrictions for the hysterectomy. So, I usually will tell patients no heavy lifting for four to six weeks, depending on the patient and their hernia risk and any concerns I have about the cuff healing.

Patients will usually go back to work depending on what their work is. If it's remote, like a lot of it is now, they might be back at one to two weeks. If they're on their feet all day, it might be more like six weeks. But really, after the first few days, they are able to do average things around the house. If they're not taking opiates, they can drive. It's mostly that I don't want them on their feet all day if they have a strenuous job to really let the cuff heal.

Host: To wrap this up, are there any other points or things that you feel it's important for our audience to know about patients with these risks?

Dr. Nicole Edison: From the sort of the OB hat, even though I don't do OB anymore, I've noticed in my own field that genetic counselors are usually much better about this. But the importance of doing carrier screening or just screening for the partner of a patient before they're planning to have children and having that discussion. I have residents come through my clinic and almost all of them that is new news to them regarding BRCA and Lynch syndrome, which makes me anxious. So, for younger patients or children of your patients who may not be sort of thinking through these bigger decisions around surgery, just knowing that when they're planning their family, that their partners are getting screened, so that they're avoiding the risk of potentially constitutional mismatch repair deficiency.

Dr. Ying Liu: I would say I'm just so happy that the guidelines in this podcast and others are really talking about gynecologic risk in Lynch syndrome. Because you don't want to forget that for many women, a gynecologic cancer is the index cancer that leads to the diagnosis of Lynch syndrome and that could be the proband of a whole family. And so, it's really, really important to do more studies, international collaboration to learn about these cancers, especially ovarian cancer, because it's so rare, so that we really do understand the gene-specific risks, any differences across populations, how environmental exposures affect this, and how we can best counsel our patients.

Dr. Nicole Edison: I think it's really important that if you're seeing a patient who you have suspicion for Lynch syndrome based on their personal cancer history or their family history, you know, even if the IHC or the MSI testing is not consistent with Lynch to do the germline testing, because you will find pathogenic variants, especially sometimes I think with MSH6. So, I think sometimes it's easy for us to look at the tumor pathology and think, "Okay, great," you know, we can check that box and move on. But if something is not adding up, to really take the extra time to refer them for germline testing.

Dr. Ying Liu: A hundred percent. We know that IHC, MSI testing with various mechanisms is not perfect for gynecologic cancer. A lot of it was designed for colon and other GI cancers, and so completely agree. And I think there's a move towards more universal germline assessment and germline testing in endometrial cancer for exactly this reason.

That's

Host: wonderful. Great. Well, thank you both for your time. I really appreciated hearing about your roles and all of this expertise that you have. And I agree that things are changing for our patients, especially our female patients with regards to how we're going to be counseling them and managing their gynecologic risk. And I really like that there's more data and more attention being brought to this issue. And with that, we will end our fourth podcast at the CGA-IGC 2025 podcast series. Please be sure to check out our research collaboration series that completed in May and be on the lookout for some additional things coming this fall. Thank you.