Peers Discuss Molecular Testing and Time of Recurrence in Endometrial Cancer

Michael J. Birrer, MD, PhD (Moderator)

Vice Chancellor, University of Arkansas Medical School

Director, Winthrop P. Rockefeller Cancer Institute

Little Rock, AR

EVENT REGION New England and Mid-Atlantic

PARTICIPANT LIST Joshua Strauss, MD | Sandeep Malik, MD | Richard Penson, MD | Susana Campos, MD | Anita Gul, MD | Madhavi Gorusu, MD | Peter Georges, MD | Jose Silva, MD

Birrer: Should every patient with endometrial cancer undergo molecular testing? What biomarkers are you testing for? For a neoadjuvant patient, are you doing it on the endometrial biopsy? What specifically are you ordering? And then how does that factor into your decision-making?

Strauss: I like to know the MMR status. In patients with locally advanced or metastatic disease I’ll also check next-generation sequencing [NGS]. We usually send to Foundation Medicine, so hopefully we’ve gotten enough tumor tissue, and we will send that for NGS.

Birrer: MSI status is important because that might guide you sooner than later, although maybe later, about what you might use to treat patients.

Malik: I would agree with Dr Strauss, and then I would want to look at HER2/neu status also.

Penson: [At Massachusetts General Hospital in Boston], we do p53, MMR by immunohistochemistry [IHC], and HER2 on everybody now. There’s a debate about POLE. Some of the [patients with p53 mutations] will do better with a POLE mutation as a secondary event. That’s coming but isn’t available [yet].

Birrer: [The POLE gene] is big, and it’s hard to sequence.

Campos: How long does that take to come back?

Penson: The problem is not so much how long it takes to come back; it takes 10 days once you get tissue. [Depending on the hospital,] it is difficult to get tissue.… They can take 2 or 3 weeks to get tissue, and then it takes 4 weeks [total] to get an answer, but most of the time it’s fast.

Gul: I have started doing it more in the first-line setting at the time of diagnosis. I don’t know if it’s the right thing to do.

Gorusu: I would concur with what others have said. In-house we do the HER2 and the panel of the 4 MMR proteins as well.

Campos: We’ve had a debate…getting HER2/neu on every specimen as opposed to having to ask for it, which is problematic. I was wondering if everybody has that luxury of having HER2/neu every time there’s a serous histology.

Birrer: It’s a good question because the answer here [at Winthrop P. Rockefeller Cancer Institute in Little Rock, Arkansas] is no.

Campos: Yes, that is [the answer at Dana-Farber Cancer Institute in Boston] too.

Birrer: Yes, we have to push for it. And DESTINY-PanTumor02 [NCT04482309], which I think was a spectacular study, has made it more problematic. We need it. Frankly, I think repeat staining later in the natural history of disease is also necessary.

Campos: Yes, I agree.

DISCUSSION QUESTION

• Do you routinely recommend genetic counseling and/or genetic tumor evaluation at diagnosis?

Campos: I’ve tended to just take a history, and if there’s a significant family history, then I send patients off. I’d be curious to see what other people do.

Gorusu: I have a very low threshold to get the genetics team involved. I would leave it to the genetics team if the insurance approves it, and then they can get the testing done. If they don’t have any family and progeny, that’s a different thing.

Birrer: Have you had insurance refuse it?

Gorusu: Rarely. I don’t think I have come across anything recently that I think should change my practice. But, for the most part, they have been covering it.

Birrer: Yes, I would agree on that, which is in stark contrast to 8 years ago, where we were challenged a lot on this.

DISCUSSION QUESTION

• How relevant are the subtypes of molecular endometrial cancer to your practice?

Birrer: The National Comprehensive Cancer Network [NCCN] supports 4 clinically significant molecular subgroups: the POLE mutation, MSI-high/MMR deficient, nonspecific molecular phenotype, and the p53 abnormal.¹ The p53 abnormal [subtype] tracks with papillary serous tumors, although there will be some high-grade endometrioid carcinomas in there.

Are you all thinking about these when you begin to treat a patient with endometrial cancer or is it just dMMR because it [indicates treatment with] IO [immunotherapy] and serous histology, or do you think about these 4 significant molecular subgroups?

Strauss: I don’t think the p53 has any clinical utility right now. I don’t think it helps you choose.

Georges: The p53 might have some implications in the future with maintenance therapy if selinexor [Xpovio] gets approved, but I’m not sure. Are you able to use [the p53 subgroup] in your practice at this point?

Birrer: I think it’s a great observation…. My view is p53, and even POLE mutation, are a bit on the edge, POLE being a subgroup where you might not have to do anything and p53 being a poor prognostic feature which some studies said those are the patients who benefit from adjuvant therapy and chemotherapy. But to me it’s not level 1 evidence yet. If you’re doing the selinexor trial [ENGOT-EN5/GOG-3055/SIENDO (NCT03555422)] where you need a wild type [p53], then you need to know what the p53 status is, but that’s a clinical trial.

Penson: Before the threshold for adjuvant chemotherapy became node positivity, there was a lot of interest in the deeply invasive high-grade tumors being ones that might benefit from adjuvant chemotherapy. In that group, we do use p53 as the discriminator, with about 10% of high-grade endometrioid tumors harboring a p53 mutation, and they probably get benefit.

Birrer: That is, benefit from adjuvant chemotherapy?

Penson: Yes, exactly, and not node positive. But they are…highly invasive grade 3 endometrioid tumors. It feels like they’re dangerous, and they probably would benefit. There’s no evidence base to hang that on. Dr Campos is on the NCCN committee, and I think that’s why the wording [in the guidelines] is so nebulous and yet encourages…thinking about these 4 subtypes.

The next group to benefit from IO in NRG-GY018 [NCT03914612], the pembrolizumab study, is likely to be the [tumors carrying the p53 mutation]. It feels like the indication may expand to those. For those, I don’t add IO [yet]. I think we need the data because it’s not so much about [being able to] prevent recurrence and progression, it’s about impacting overall survival. I think the level of data is going to need to be greater for IO.

Campos: I completely agree, and there are also passenger mutations. What if you have a p53 mutation and dMMR? Which mutation predominates, and how should you navigate that therapy? There are no data because these are so rare.

Penson: Coming back to that insurance [question] is interesting. We take a risk by treating HER2 [IHC] 2+ tumors with trastuzumab deruxtecan [Enhertu] because the hospital used to be very generous, [but it] is no longer generous. There are bills that go through to the patient…. Likewise, with mirvetuximab soravtansine [Elahere] in ovarian cancer, we’re starting to treat patients with less than 75% [FRα] expression.… The advocacy for patients’ access to effective therapies has beaten back some of the resistance from insurers.

Campos: If the patient had a stage I endometrioid grade 3 p53-mutated uterine cancer, is the consensus to treat with chemotherapy or not?

Birrer: I would probably give them adjuvant therapy.

Campos: Right. What if the patient also had dMMR [status]?

Birrer: That would be an IO and chemotherapy in stage I, if you can get it covered. If I recall correctly, those are mostly patients with advanced disease.

Georges: I don’t have a big volume of endometrial cancer, but I would follow the NCCN guidelines…and not use anything off label, just adjuvant chemotherapy at this point.

DISCUSSION QUESTIONS

• Would your treatment approach have differed if the platinum-free interval had been longer than 6 months?
• If you chose chemotherapy rechallenge, would timing of disease recurrence have impacted your therapeutic choice, eg, 12 months, 14 months, etc?

Birrer: Particularly for those individuals you want to repeat treatment with systemic chemotherapy vs lenvatinib/pembrolizumab with pMMR [status], what determines that? Is it the platinum-free interval?

Strauss: I have rechallenged carboplatin/paclitaxel if [the interval] was more than a year, successfully. Sometimes carboplatin/paclitaxel is better tolerated than lenvatinib, and if you think that somebody is still platinum sensitive, I don’t mind not [avoiding carboplatin] completely.

Campos: I think that there was some subset analysis done on [NRG-GY018] that showed that with a platinum-free interval of greater than or equal to 12 months, you may benefit from carboplatin/paclitaxel plus pembrolizumab.² Then the question is would you benefit from carboplatin/paclitaxel plus [pembrolizumab] or would you rather go to pembrolizumab and lenvatinib. I do think there’s a point in time where carboplatin still holds some relevance; the question is when.

Birrer: From my perspective, I’ve never been as impressed with the platinum-free interval in endometrial cancer as I’ve been with [it in] ovarian [cancer]. I remain a little skeptical about that. In this case, I’m a big lenvatinib/pembrolizumab fan because I figure I can always go back to chemotherapy later, but I [understand].

Penson: [Lenvatinib/pembrolizumab before rechallenge] is my philosophy as well, I agree.

Campos: What is your cutoff? If a patient progresses at 6 months regardless of histology, you go to pembrolizumab/lenvatinib, but what if a patient relapses at 13 months?

Birrer: I personally don’t have a cutoff because I don’t believe the data [support rechallenge], but…if I had a patient who went on lenvatinib/pembrolizumab and went out 2.5 years [until progression], would I go back to chemotherapy? Yes, I would.

Campos: You have to go back to KEYNOTE-775 [NCT03517449], which didn’t have a platinum-based arm, so let’s factor that into the equation.

DISCUSSION QUESTIONS

• In the case of a patient with pMMR advanced or metastatic endometrial cancer who receives frontline IO plus chemotherapy, and then progresses on that regimen, what would be your subsequent treatment approach?
• To what degree does the actual time on maintenance IO prior to disease progression influence your subsequent treatment sequencing?

Birrer: In the case of a patient with pMMR advanced metastatic [disease] who receives frontline IO—because that’s where we are now—rather than chemotherapy [alone], and then progresses on that regimen, what will be your subsequent treatment approach?

Silva: Most likely I would add lenvatinib at this point…and maybe continue the IO.

Birrer: To what degree does the timeline on maintenance IO prior to disease progression influence your subsequent therapy? Let’s say the patient gets IO/chemotherapy, goes through all the IO, does well, and then has recurrence a year after. Is that the same as the first case or would you come back with lenvatinib/pembrolizumab and re-treat with pembrolizumab?

Georges: I would use combination lenvatinib with IO at that point. Although, they [had IO] previously, so it might not get as good of a response with the combination, but it’s worth a try.

Birrer: With NRG-GY018 and RUBY [NCT03981796], this is, frankly, what we’re dealing with now.

Campos: What if they were HER2/neu positive? Would you go to IO again or would you go to a [trastuzumab deruxtecan]-based regimen?

Birrer: It’s a great question. [DESTINY-PanTumor02] was very impressive. I might do [trastuzumab deruxtecan] knowing that I could go back to lenvatinib/pembrolizumab after that. Any thoughts on that?

Penson: I don’t think there are [many patients like that]…a HER2/neu-driven tumor is unlikely to be a tumor [that has no more] progression of disease 3 years into carboplatin/paclitaxel/pembrolizumab. They’re normally worse-behaving tumors. It is a great drug; I am completely on board with that. My practice has changed. The dMMR tumors [are indicated to] get 1 year of IO, and I continuously treat with pembrolizumab because it feels like these tumors relapse once you stop pembrolizumab. This question doesn’t quite fit our practice.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Uterine neoplasms, version 2.2024. Accessed August 14, 2024. https://tinyurl.com/4ktmxczw

2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312