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Mismatch Repair–Deficient/Microsatellite Instability–High Recurrent Endometrial Cancer

This is Part 4 of Updates in Gynecologic Oncology, a four-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

In this video, Ursula Matulonis, MD; Joyce F. Liu, MD, MPH; and Bobbie J. Rimel, MD, focus on a case of mismatch repair–deficient/microsatellite instability–high recurrent endometrial cancer. They discuss the range of treatment options for patients with mismatch repair–deficient cancer, including the potential utility of single-agent immune checkpoint inhibitors such as pembrolizumab.


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Transcript

DR. URSULA MATULONIS: Welcome back to The ASCO Post Roundtable discussion on gynecologic oncology. I’m Dr. Ursula Matulonis from the Dana-Farber Cancer Institute in Boston, Massachusetts. And I’d like to welcome back my two fantastic, really exceedingly well respected GYN oncology clinicians, Dr. Joyce Liu and Dr. BJ Rimel. Joyce, would you like to introduce yourself first? DR. JOYCE LIU Sure. I'm Joyce Liu, I'm the Associate Chief at the Division of GYN-oncology here at the Dana-Farber Cancer Institute in Boston, Massachusetts. DR. BJ RIMEL: Hi, I'm BJ Rimel. I am a gynecologic oncologist at Cedars-Sinai Medical Center in Los Angeles, California and the Associate Director of Clinical Trials in GYN oncology here. DR. MATULONIS: Great. Thank you so much both for joining me here today. And in our last case, case number 4, we'll be focusing on a case of recurrent microsatellite instable recurrent endometrial cancer. So I'm gonna start with the case first, and then Joyce, ask you about your comments here. So this is a 70-year old black woman diagnosed 6 years ago with a stage IA grade 2 endometrioid endometrial cancer, and 3 years after diagnosis she presents with a left-sided pelvic mass. And you can see that on the scan here. A biopsy was consistent with endometrioid cancer, and the tumor was estrogen receptor–positive. Mismatch repair testing was not normal. MLH1 and PMS2 protein expression was abnormal, and follow-up testing revealed MLH1 promoter hypermethylation, which was positive. So let's start there. She obviously goes on to receive carboplatin/paclitaxel, as you can see from this case, but the tumor was estrogen receptor–positive. What do you think about treatment options for this patient? She's microsatellite instable, she's estrogen receptor–positive, so the number of treatment option exist. What would you pick? What would you have picked? DR. LIU: So I think, you know, as you mentioned, there's a number of options for this patient. She's estrogen receptor–positive, so hormonal therapy is absolutely something that can be considered for somebody. I can't remember if you said she was symptomatic or not. DR. MATULONIS: She did present with, she presented with pain, yes. So hip discomfort. DR. LIU: So I will say that I think that hormonal therapies can be very effective for women with ER-positive, relatively low-grade endometrioid endometrial cancers. We know that the hormonal therapies in and of themselves can, the progestins or the SERMs, can have activity alternating, they can also have activity, the combination of everolimus and letrozole had quite good response rates in the 30% range. Somebody who is, however, symptomatic, I worry that the time frame of that activity may be slower, and so, you know, that's somebody where then you bring in the considerations. Would you give them chemotherapy? Carboplatin and paclitaxel we know can be active. And in somebody who has a mismatch repair–deficient cancer, clearly that also opens the door up for immunotherapy, so our immune checkpoint inhibitors. DR. MATULONIS: Right. And it's conceivable that some of the audience is probably asking, "So why not give the patient pembrolizumab or lenvatinib?" Well, that currently, under FDA approval is for patients with mismatch repair–proficient tumors, not instable cancer, so that's an important distinction. So the patient goes on to get six cycles of paclitaxel chemotherapy, and at the completion of chemotherapy, there's residual tumor. And her gynecologic oncologist ends up taking her to surgical resection followed by radiation therapy. And BJ, what do you think about the possibility of surgery here? I know we talked a little bit about surgery in recurrent ovarian cancer, but what about for recurrent endometrial cancer? DR. RIMEL: There's very little data to guide us. There's certainly not been a prospective study looking at secondary cytoreduction for endometrial cancer. That being said, in a patient that has significant pain from a single isolated recurrence, maybe we might even call her oligometastatic disease, I don't think that resection to palliate the patient's pain, especially to do it quickly if the patient's otherwise very fit and has not had multiple prior surgeries, I don't think it's unreasonable to consider, especially if you're planning to follow with radiation or you're at a center that can offer interoperative postresection radiation at the time of resection. Those are exciting areas, but we really don't have data to guide us. DR. MATULONIS: Gotcha. Good, thanks. So about 6 months after the radiation therapy and the surgery were completed, there was an increased size of her pelvic mass. You can see this on the scan. So not only is the mass bigger, but it's starting to invade bone. And she comes in with a cane and she's on narcotics, because the pain is so significant. So at that point, she was placed on treatment that was targeting the estrogen receptor. She goes on everolimus and letrozole, something that Joyce had mentioned before, but unfortunately quickly developed pneumonitis. And so about that time, that's when the initial FDA approvals were coming out for the use of pembrolizumab as kind of a pan-tumor indication. Joyce, do you wanna talk about that? The importance of that pan-tumor indication and what exactly it is for? DR. LIU: Yeah, so pembrolizumab was approved by the FDA for any solid tumor that was mismatch repair–deficient, and subsequently has actually added indication for any solid tumor that has a tumor mutational burden of greater than 10. And so this has really opened the door to allow us to treat patients with mismatch repair–deficient tumors, whether they are endometrial, which is where we most commonly see them in GYN cancers, but also in ovarian cancer some of them are mismatch repair–deficient, has allowed us to add pembrolizumab to our armamentarium. DR. MATULONIS: Yeah. And updated data from JCO, um, last year shows that single-agent pembrolizumab for recurrent microsatellite instable cancers is around 57%, so you know, pretty good, response rates. Other checkpoint inhibitors are also quite active. But right now, per FDA, we've got one available to us. And she ends up going on that drug. So she starts pembrolizumab, and as you can see on this scan there is some reduction in the tumor size, but that translates into really significant, I would almost say transformative, significant benefit. She comes off narcotics and is able to walk without the use of any kind of device. So now fast forward, she's on this therapy for around 2 years, and she's starting to think about, should I continue on? Should I not continue on? BJ, how would you counsel her at this point? DR. RIMEL: So the original study stopped patients at 2 years that had a complete response, and I have several of those patients actually in my practice from that original study. For those patients that had, you know, a complete response to their disease and stopped at two years, most of my patients have not had a recurrence at this time, but we don't know if they ultimately will and whether they can be retreated. For patients that don't have a complete response, it's really hard to stop a drug we think may be working that may be holding the disease sort of stable. And in those situations, I just, you know, consistent counseling of the patient about the risks and benefits. There are still immunologic toxicities that can occur after years of treatment, so we still have to be very vigilant about these things, and some of them can be fairly unpleasant, like the development of type I diabetes, which I've seen a couple of times. Patients do not thank you for giving them that. So I think that there's definitely, a critical need for the gathering of more data about the long-term use of these agents, especially in the long-term use in patients that have had a dramatic response, and what we can do to sort of either stop or halt or decrease the dose. Like, there's just a lot of exciting places to go with that. DR. MATULONIS: Yeah. And I think for the first time probably ever, we're starting to see in GYN oncology situations where patients are having really tremendous responses to treatment, and then we have to start counseling them about kind of coming off that treatment, because you're right. You wanna make sure that the benefits continue but the risks don't overshadow our benefits. Joyce, for this patient, what would you, what would you recommend to her? Stopping, or would you continue? DR. LIU: Well, so she's still got a little bit of tissue that you could see there. I would probably consider doing a PET/CT, which is not something I always do on my patients, but I would consider doing a PET/CT to understand if there's evidence of activity still within that tumor. If that was FDG negative, so no longer avid, I would probably counsel her to stop. We don't know that there's benefit for patients who are in complete response, but if she still had evidence that there was some activity there, then I think I, you know, I would agree with BJ It's just hard to tell somebody to stop when you think there might still be active disease. DR. MATULONIS: Yeah. So for this patient, it was a little bit more straightforward because she really wanted to stop. DR. LIU: Even better. DR. MATULONIS: Yeah, she was tired of coming in for every-3-week treatment. The last treatment I actually had given to her every 6 weeks because she was just tired of coming back and forth. And so it's been about 9 months and she is still in remission with that same kind of scarred area. I didn't do a PET, and I've just done CT scans. Clinically she's doing just fine. I think this is a situation where we just don't know. BJ, let's say this lady, or one of your patients who you ended up stopping treatment on, or checkpoint inhibitor for recurrent microsatellite instable endometrial cancer. You stop and then let's say they recur, and it's been at least a year plus. Would you ever consider restarting the checkpoint inhibitor? DR. RIMEL: Yeah. I actually have a patient exactly like that, and I did exactly that. I restarted the pembrolizumab. I boldly went and got a tumor biopsy to see if the mismatch repair deficiency was still present in the remaining, in the recurrent tumor, and it was and I told her, "Let's try the pembro again. If it works, well, good for us, and if it doesn't, I'll probably try to add some lenvatinib and maybe see if we can get some more mileage out of this." DR. MATULONIS: So what happened? DR. RIMEL: She is doing great and she’s been a year on pembro. DR. MATULONIS: Whoa. You need to write that up. DR. RIMEL: Okay. (Laughs) DR. MATULONIS: (Laughs) Because that's the kind of data that's gonna help us. I think there are gonna be very few trials that are asking these questions, because they're just not- not a lot of... That's really impressive. And so she had tumor shrinkage with the reinstitution of the pembrolizumab. DR. RIMEL: Yep. It came back in the same location, so I wonder if it had really ever been gone. But it certainly didn't grow or didn't bother her for a year, and then it just started to enlarge and cause some pain and, you know, we rebiopsied. DR. MATULONIS: And this was, this was pembro alone? DR. RIMEL: Pembro alone. DR. MATULONIS: Pembro alone, yeah. DR. RIMEL: And the MLH-promoter methylation, it was retained in both the primary specimen and the recurrent. Dr. Ursula Matuloni: Yep. DR. LIU: Did she go back into complete response, BJ? DR. RIMEL: By CT, yeah. I didn't get a PET. DR. LIU: Yeah. DR. MATULONIS: Good for her. Well, great. So we're winding down this case and I wanna ask both of you two questions. One is, and Joyce I wanna start with you first, any thoughts about this particular case that you wanted to add? And then secondly, I just wanted to get your thoughts about what you're finding exciting in the field of endometrial cancer. Because I really do think we're starting on a, it's a new world, which is really exciting for us and for our patients. DR. LIU: I think we've talked through many of the things I would sort of wanna emphasize about it. I think it is sort of, again, an emphasis that we have to do mismatch repair testing or MSI testing in our women with endometrial cancer that the immune checkpoint inhibitors can be very effective in these women. And then the other reason, of course, we do this testing is to make sure that there's not a hereditary syndrome, Lynch syndrome, that could have contributed to the endometrial cancer, because the implications for family members, of course, are humongous. DR. MATULONIS: Yep. DR. LIU: In terms of endometrial cancer, I mean, I think it's a really exciting time. You know, for years, we've toiled in like, this doesn't work, that doesn't work, and suddenly we have things that work. And I think one of the things that's really exciting is that we're really finally leveraging the data that we got from TCGA, from our molecular sort of testing to think about endometrial cancer not as one sort of type of cancer or even as sort of a histologically-based set of cancers, but to think about it based upon molecular sort of subsets, that we have our POLE tumors that we haven't talked about today. We have our MSI-high mismatch repair proficient tumors, that we have our endometrioid that are mismatch repair–proficient, and then we have our serous-like, which also encompasses some of the grade 3 endrometrioids. And that, you know, that, the breakdown of the tumors this way I think is gonna really help us develop more effective therapies and really sort of, not one size fits all but really sort of to break these tumors down into their molecular types and target our therapies appropriately that way. DR. MATULONIS: Yeah, that's great. Thanks so much. And BJ I'm just gonna change my question a little bit to you, and kind of bring it back to your initial thoughts during case number 3 when you talked about how you think about treatment of patients with recurrent endometrial cancer and you talked about histology, and you talked about the mismatch repair testing importance. In patients with recurrent endometrial cancer or patients who are newly diagnosed, how do you incorporate genetic testing? So how do you incorporate somatic testing? And do you ever incorporate germline testing? We know that for patients with ovary cancer, it's standard of care. They're gonna get germline tested, and hopefully, most, if not all, will undergo somatic testing as well based upon what Joyce said as well, but how do you do that in patients with endometrial cancer? DR. RIMEL: For our patients that have endometrial cancer, they mostly start out with a hysterectomy specimen at the time of diagnosis, and we can use that to perform standard of care, even a histochemistry for mismatch repair proteins. And so that's a good starting place. We also have implemented a standard of care histologic assessment for HER2 for all of our serious cancers. So that covers two things. For patients that have mismatch repair deficiency defined by IHC loss of one or multiple proteins, we're obviously looking for MLH1 methylation which captures about 26% or so of all of that MSI-high group. But then for the rest, there's gonna be a germline somewhere. And so those patients that have demonstrated IHC loss of a mismatch repair protein all get directly referred to our genetic counselors and get germline genetic testing. We have seen a few serous cancers of the uterus come back as positive for a couple of other strange things, couple of BRCAs, couple of this and that, and so we considered for patients that have any family history whatsoever of cancers in their first-degree relatives to have those patients go and see our genetic counselors as well. And I don't know if that's an LA thing, but we're definitely seeing a little bit more germline positivity in that group than I had previously sort of anticipated. DR. MATULONIS: Yeah. Yeah. I think, you know, here where, at Dana-Farber, we have a program where we can, we can offer germline testing to all patients who have endometrial cancer as part of a research trial. So I think we're moving in that direction, slowly, but definitely moving in that direction. Drs. Liu and Rimel, I wanna thank you so much for being here today and engaging in this really wonderful discussion that I think is gonna be really pertinent for our audience. I’d like to thank the audience for being here today, and also thank ASCO Post for sponsoring this today. So please see us and take a look at us again on ascopost.com. Take care, everybody.
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