Dr. Tewari:
Welcome to Navigating the Immunotherapy Landscape in Advanced and Recurrent Endometrial Cancer, an ASCO Post Roundtable. I'm Dr. Krishnansu Tewari. I'm a Professor and gynecologic oncologist at the University of California in Irvine. And joining me today are two of my colleagues. Dr. Cloven, you want to introduce yourself and tell us where you're Zooming from?
Dr. Cloven:
Hi, everyone. My name's Noelle Cloven. I'm a gynecologic oncologist who is Zooming from Fort Worth, Texas. I work with Texas Oncology. I'm also the Executive Chair for the Research Committee for Sarah Cannon Research Institute.
Dr. Tewari:
Dr. Bujnak.
Dr. Bujnak:
Hi, everyone. My name's Alyssa Bujnak. I'm an Assistant Gynecologic Oncology Professor at the University of Chicago. I'm Zooming from Chicago.
Dr. Tewari:
Wonderful. So why don't we jump into this case number 3. We have a 72-year-old Caucasian woman who has given birth twice. She's had bleeding, postmenopausal vaginal bleeding for 2 months. She has well-controlled hypertension, a BMI of 22. Her family history is non-contributory with respect to cancer, or at least the cancers we're interested in, and you can see them on our slide.
On review of systems, she has, in addition to vaginal bleeding, some mild diffuse abdominal discomfort and constipation. She has some questionable palpable omental disease on her abdominal exam. No inguinofemoral or supraclavicular adenopathy that can be felt.
On pelvic exam, her cervix is not expanded. The uterus is in the upper limits of normal size, about 10 cm, with no adnexal masses, but she does have some cul-de-sac nodularity. You can see her ultrasound has a pretty large endometrial mass. This is invading at least 50%, actually more than 50% of the wall of the uterus based on this ultrasound, which is a very good, clear image.
Endometrial biopsy is noteworthy for a uterine papillary serous carcinoma. It kind of looks like ovarian cancer under the microscope, at least one of the most common ovarian cancers.
She undergoes CT imaging, and you can see an uterine enlargement with pelvic extension, as well as a splenic metastasis on the right side. The opportunity to consider surgery is discussed with the patient, and she undergoes diagnostic laparoscopy. And while there's no ascites, which is what we typically see with, for example, ovarian cancer of that histology, there are also no ovarian metastases, but she does have upper abdominal metastases, including the splenic lesion that was seen on the imaging, and she has disease in the pelvis.
Dr. Cloven, how do you manage this patient? These are the findings. This is a laparoscopic image of what we're seeing.
Dr. Cloven:
Yeah. So as all of us know, as gynecologic oncologists, high-grade serous endometrial cancer is a more aggressive subtype of endometrial cancer, and is associated with an increased risk of advanced disease. You kind of suspected, a patient has symptoms of abdominal pain, the nodularity on exam, maybe a palpable omental mass.
I think that there were some signs indicating that she was going to have advanced diseases confirmed at laparoscopy. I think the big question, I think you go either way. Is this somebody that you're going to debulk upfront, almost treat like an ovarian cancer, you do a full hysterectomy, bilateral salpingo-oophorectomy, omentectomy, debulk as much of the disease you can, or would you at that point stop and go with neoadjuvant chemotherapy? And I think either is an acceptable choice.
Dr. Tewari:
Thank you, Dr. Cloven. I totally agree with you. Do we have data on neoadjuvant chemotherapy in endometrial cancer? We all do it. And I'd just like to get your thoughts on this, Dr. Bujnak.
Dr. Bujnak:
There's not been a prospective trial, at least to my knowledge. The data that we have is mostly from retrospective data as well as meta-analysis. But yeah, we all do it, and it's in the NCCN Guidelines that you can offer primary debulking surgery for these patients.
Dr. Tewari:
And what's the goal for primary debulking surgery? Is it the same as the goal for ovarian cancer when we do that?
Dr. Bujnak:
Yeah, the goal is that patients do better, at least from the meta-analysis, if you get the meta-residual disease of zero.
Dr. Tewari:
Okay. So this patient specifically undergoes exploratory laparotomy, so they pulled the laparoscope out and made an incision. She had her uterus and ovaries removed en bloc with the rectosigmoid colon. She had the splenic flexor taken down, and she was reconnected down below so she didn't have to have a colostomy bag.
Omentectomy was performed en bloc with a splenectomy and distal pancreatectomy. Also had full thickness diaphragm resection. If you remember, there was some studying of the diaphragm peritoneum, we saw in that laparoscopic picture, and primary closure of the diaphragm.
Her postoperative course was unremarkable. Surgical pathology confirmed a FIGO stage IVB uterine papillary serious carcinoma, mismatch repair–proficient, p53-positive. Postsurgical PET CT shows no measurable disease.
Dr. Cloven, talk to me about biomarker testing. Talk to all of us about adjuvant therapy for this patient.
Dr. Cloven:
Yeah, so thank you for asking me that question. So of course, that was exactly what was going through my mind, is what are her biomarkers? And that's what all of us should be thinking with this patient. Of course, we're going to get the typical biomarkers that we get on all patients routinely now. The mismatch repair status would be important. Well, it's also very important to check for HER2 expression. This is something that can be useful, particularly in patients with high-grade serious ovarian cancer. They're almost all p53-mutated. That's one of the ways that they diagnose it.
So those would be the biomarkers I'd be thinking of. And I would also probably at this point, because she's stage IV, do a full molecular panel on her, send the tissue off for testing.
Dr. Tewari:
Thank you. Dr. Bujnak, we've now got FIGO molecular staging for endometrial cancer. The NCCN has not updated their treatment recommendations according to the molecular staging classification scheme. But when we're thinking about endometrial cancer, I think the easiest way to distinguish between, separate out endometrial cancer is between mismatch repair–deficient and mismatch repair–proficient.
With the mismatch repair–proficient patients like this patient and our case number 2 being the higher risk patients, because they don't respond as well to immunotherapy. But can we further tease out patients based on prognosis using biomarker testing, as Dr. Cloven alluded to, in the mismatch repair–proficient group? How do we carve out the mismatch repair–proficient patients into different groups?
Dr. Bujnak:
Yeah, so we can test for POLE and we know that those patients will have a pretty favorable response if they have a POLE mutation. Every patient should also have a p53 test performed; those patients, while they have a worse prognosis than mismatch repair–deficient patients or POLE patients, they tend to potentially respond to chemotherapy. And then there's patients that don't have any markers. They're mismatch repair–proficient, they are p53 wild-type, and they're POLE-negative, and those patients tend to respond probably the worst or have the least favorable response.
Dr. Tewari:
I like that. So you have your POLE-mutated patients, which may have a favorable outcome just because they're kind of low risk in the mismatch repair–proficient group. What do you feel about deescalation in patients of the POLE mutation, Dr. Cloven? And explain to us what deescalation would be. If you have an advanced-stage patient with a POLE mutation, endometrial cancer, mismatch repair–proficient, POLE, is there an opportunity for deescalation, and what does that mean?
Dr. Cloven:
Yeah, you're asking me a question I don't really have a good answer to, I'm going to admit. I know that all of the suggested algorithms indicate that POLE should be the first test that we do, but I've only ordered that a handful of times in my clinical practice, which is not something that I generally do.
I agree with you that you're going to stratify patients more based on their mismatch repair proteins rather than POLE. And I think I'd feel a little bit uncomfortable not giving chemo to a patient with stage IV high-grade serous disease. I mean, even with a POLE, I think I would probably still give the carboplatinum and paclitaxel. Could you maybe deescalate during the maintenance phase? I don't know about that. I'd be really more focused on the HER2 expression for this patient, I think.
Dr. Tewari:
Well, let's hypothesize, and let's pretend our first patient had stage IIIC1 disease based on a positive sentinel node. Suppose she was mismatch repair–proficient. Would this be someone that maybe if she had a POLE mutation, could we deescalate and not give her the chemo, and just treat her with immunotherapy?
Dr. Cloven:
I know, Alyssa, why don't you tackle it? Like I said, I don't have that much experience with POLE, and I think I feel more comfortable in that setting for sure, but I'd still be a little worried.
Dr. Tewari:
Better than a stage IV, right?
Dr. Cloven:
Yeah.
Dr. Bujnak:
Yeah. I mean, again, I think it's tempting, and I think that hopefully at some point we'll have data supporting that. It makes sense to me that that would be an option.
Dr. Tewari:
Okay. So let's take it back. Let's talk about what Alyssa said earlier. If we take our mismatch repair–proficient patients, we can take all comers endometrial, we can separate into mismatch repair–deficient, mismatch repair–proficient.
Then if we take the mismatch repair–proficient patients, according to Dr. Bujnak, do the biomarker testing Dr. Cloven was talking about, we have three groups that emerge. We have our POLE, which may have a very favorable prognosis. We have our p53-mutated patients, and while they're in trouble, because they're mismatch repair–proficient, at least the p53-mutated patients will be expected to respond to chemotherapy.
And then finally, we have a third group of mismatch repair–proficient patients that are not POLE-mutated and not p53-mutated. But bringing up something Dr. Cloven mentioned earlier with a recently completed study that's not reported yet, it's possible that the p53 wild-type patients could potentially have an option with selinexor. I'm excited to hear if that shows some clinical benefit, because then we would have potentially a biomarker of wild-type p53, that is predictive of a good outcome with the targeted agent.
What about clinical trials for this patient? She's got a papillary serous cancer, going back to this case three, and say she's a HER2 expressor, HER2 expressor. Any clinical trials that we could screen this patient for?
Dr. Cloven:
Yeah. So she would qualify also for the TroFuse-033. So remember, these are patients that have stage III, measurable stage IV, and they're mismatch repair–proficient.
But then there is another trial, DESTINY-Endometrial01, which is looking particularly at HER2 expression. It has the same criteria as TroFuse-033, but it adds in that they have to have either 3+ or 2+ HER2 expression. And it's a very interesting and compelling trial because it's a global phase III trial with three arms. One arm is looking at trastuzumab deruxtecan with pembrolizumab. There's an arm that's looking at trastuzumab deruxtecan with rilvegostomig. And then, the third arm is standard of care, which is carboplatin and paclitaxel and pembrolizumab. And so this is very interesting, bringing in two potential arms that don't have the chemotherapy backbone.
I think that that would be a good trial to consider for the patient. Of course, as you know, trastuzumab, deruxtecan, or T-DXd, is already FDA approved in a tumor agnostic setting for patients that have recurrent cancer after chemotherapy and have high expression of HER2, but this is looking at potentially bringing it into a frontline.
Dr. Tewari:
Right. And also the novel immunotherapy agent not only targets PD-1, but also targets TIGIT.
Dr. Cloven:
Yes.
Dr. Tewari:
It’s an interesting study.
Let's review the key clinical takeaways of case 3. Platinum and taxane-based chemotherapy, plus anti–PD-1 immunotherapy, is indicated for advanced uterine papular serious carcinoma.
There are also clinical trials that patients should be screened for, especially patients in this group, especially when the prognosis is relatively unfavorable. She's mismatch repair–proficient with advanced disease. She had to have a very extensive operation and the risk of recurrence is very high. And you mentioned the DESTINY-Endometrial01 and the TroFuse-033 study. Again, counsel on endocrinopathies and emerging autoimmune diseases that can be activated with immunotherapy, counsel patients regarding rash, colitis, pneumonitis, monitor thyroid function and cortisol surveillance.
And then if they do, this patient does indeed end up getting trastuzumab deruxtecan by virtue of being a HER2 expressor by immunohistochemistry. Patient needs to be counseled very carefully regarding interstitial lung disease. Baseline chest CT is reasonable.
Dr. Bujnak, for those patients that you're worried about the development of interstitial lung disease, do you also get baseline pulmonary function tests or just a CT of the chest?
Dr. Bujnak:
I wouldn't, unless they have an underlying risk factor for lung disease. I probably wouldn't get baseline PFDs. Do you do that?
Dr. Tewari:
I don't. Dr. Cloven?
Dr. Cloven:
No, same. If they have a history of lung disease, I would consider it, but I don't do that routinely. I think that counseling's the most important thing is that patient knows that if they develop any sort of symptoms at all, that they need to bring it to our awareness. And one thing that's also important is that if you're going to be treating a patient, they had a CT scan, this is something to think about if you want to make sure that you review the results.
So sometimes patient likes to get the CT scan right before their visit, and we'll go ahead and treat them before we know, but you would definitely want to risk doing that if the CT scan could potentially show some ground glass opacity.
Dr. Tewari:
I agree. And then just a quick word, Dr. Bujnak, do you use circulating tumor cell-free DNA in your patients that are in remission to look to see if the cancer's coming back within endometrial cancer, or do you use it during chemotherapy? Because we don't have a CA125 biomarker like we do for ovarian cancer. How do you use circulating tumor cell-free DNA?
Dr. Bujnak:
I'm not currently using it in practice. I think there's still a lot of questions to be answered and guidelines to be created before I would probably adopt using it, just because patients then have a lot of questions of how we're going to move forward or proceed with certain results that I wouldn't totally know how to answer, but I'm very interested in the potential. What do you all do?
Dr. Tewari:
Dr. Cloven?
Dr. Cloven:
Exactly what Dr. Bujnak does. I'm very interested in it. I think that it has a future. Right now, I don't really know what to do with it. I don't know when to order it. I don't know how often to order it. I think it's probably a poor prognostic factor.
And I kind of like the idea of using it to... You talked about before deescalating therapy, so maybe somebody that might not need immunotherapy for as long of a time for maintenance. That to me, that seems like a good place to look.
Dr. Tewari:
Fantastic. Well, this brings us to the end of our case. Please see other segments for further discussion about the latest research in endometrial cancer, or visit ascopost.com.
