3 Endometrial Cancer Clinical Vignettes: The Experts Weigh In

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Describe the evidence for contemporary and emerging biomarker testing strategies in individualizing therapy for patients with endometrial cancer

• Evaluate recent clinical trial data for the use of biomarker-driven therapies in advanced and recurrent endometrial cancer

Release Date: July 21, 2026

Expiration Date: July 21, 2027

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In 2026, an estimated 68,270 women in the United States will be diagnosed with endometrial cancer (EC), the most common gynecologic cancer.¹ Molecularly defined EC subgroups predict prognosis and also response to treatments such as immunotherapy and HER2-directed antibody-drug conjugates (ADC).^2,3 In a recent symposium, Drs Kathleen Moore, Ritu Salani, Casey Cosgrove, and Ebony Hoskins discussed how to use biomarkers to strategically select the most effective therapy for each unique case of EC. Here are 3 clinical vignettes illustrating these principles in practice.

Cosgrove / The 1 molecular test that everyone should be doing is mismatch repair deficiency/proficiency testing. But the addition of things like p53 has been increasingly done because it’s routinely available in our lab as an IHC [immunohistochemistry] test. We’ve had some challenges with POLE testing because we have to send that off. We initially started doing HER2 just for our carcinosarcomas and serous tumors, but we’ve been expanding it beyond that. [Regarding] ER/PR [estrogen receptor/progesterone receptor] status, we know that’s an important triage, particularly for the no-specific-molecular-profile group. Sometimes it’s easier to do a one-size-fits-all approach as opposed to triaging it, particularly with p53, which we have to wait for.

Moore / The real question is, are we waiting for POLE testing [to make a treatment] decision?

Cosgrove / In a perfect world, I would love to be able to send my preoperative biopsy for every patient off for molecular testing. But we’ve had some concerns that maybe insurance wouldn’t cover next-generation sequencing, even though National Comprehensive Cancer Network (NCCN) guidelines now are supportive of doing molecular testing on all EC patients (Figure 1).⁴

Moore / [Dr Hoskins,] can you share with the audience a little bit more about how we should be optimizing the workup and management of our Black patients with EC (Figure 2)?^5-9 

Hoskins / This is just practice based, but even if I see a patient now that pre-op has grade 1 EC, I’m staging them. I even stage all the EIN [endometrial intraepithelial neoplasia] because of how much cancer we’re seeing in these patients. We get p53, and you would be surprised on how many [cases are] p53 abnormal. I would love direction on what to do, especially with the early-stage serous cancer. We have a lot of retrospective data that says there is a survival improvement with chemotherapy in these patients.

Cosgrove / I feel the same way now as we’re doing molecular testing, and you have a head scratch on why a patient’s cancer came back, and then you find a p53 mutation. You’re like, oh my gosh, maybe we undertreated them.

Cosgrove / We had the RUBY (Figure 3) and NRG-GY018 (Figure 4) data,^10,11 which had more advanced and high-risk populations, that showed a benefit of immunotherapy for [patients with] mismatch repair deficient (dMMR) but also mismatch [repair] proficient (pMMR) [EC]. KEYNOTE-B21 (Figure 5) had a more bread-and-butter EC population: a high-risk population, but stage I, II, and III [were included].¹² And what was really intriguing was the pMMR group didn’t have that much benefit with the addition of immunotherapy to chemotherapy. The dMMR group demonstrated some benefit, although, in general, the magnitude of benefit for this better prognosis [in the KEYNOTE-B21 population] was probably a little less impressive than [what was reported for] the higher-risk NRG-GY018 and RUBY populations. I’ve incorporated these data into my practice for my stage I, II, and III patients, where I’m not using much immunotherapy for my pMMR group. But for my stage III EC patients with a mismatch repair deficiency, I am considering adding immunotherapy based on the KEYNOTE-B21 data.

Salani / I’m curious, do you [all] have any preference between the different checkpoint inhibitors that are FDA approved and NCCN compendium listed?

Moore / I’ve heard people say they use dostarlimab for carcinosarcoma because [those cases] were allowed in the RUBY trial. [But that’s] just how the studies were designed.

Cosgrove / I will offer a completely nonscientific consideration. In my mismatch repair proficient patients, I sometimes use pembrolizumab. Not just because NRG-GY018 was a little more powered for that, but because I just feel like it’s a little easier to add on [lenvatinib later] on as opposed to making a bunch of switches from an [immunotherapy] perspective (Figure 6).¹³

Cosgrove / What is your next step for this patient? She had previous platinum treatments and radiation; it doesn’t look like she had any immunotherapy before, so are you going with an antibody-drug conjugate HER2 direction or [an immunotherapy] approach for this?

Hoskins / I love the data from DESTINY-PanTumor02 (Figure 7).¹⁴ Obviously, it comes with some side effects, but I think we have a good opportunity and a great and durable response.

Cosgrove / I can also give immunotherapy with lenvatinib, and I may be a little bit more enthusiastic for that in the recurrent setting. But I also agree that the DESTINY-PanTumor02 endometrial [cancer cohort], particularly for the HER2 3+ [subgroup], is really exciting. Where I struggle is [the DESTINY-PanTumor02 trial had] a relatively small sample size compared to the lenvatinib and pembrolizumab phase 3 randomized control trial. I don’t think you make a wrong decision, whether it’s trastuzumab deruxtecan [T-DXd] or pembrolizumab and lenvatinib, understanding that carboplatin-paclitaxel-immunotherapy is another strategy.

Cosgrove / I was also intrigued by this patient [who had HER2 2+ EC] and then when retested, it was HER2 3+. In my practice, if I have a biomarker that I’m able to get a drug for, I’m not necessarily trying to retest it. And if I have a patient [whose EC] is negative for biomarkers, I am more likely to order repeat testing to see if I can catch a biomarker that might make a new therapy eligible for a patient.

Moore / We have this data [for trastuzumab pamirtecan] that was presented just a few weeks ago, where it’s one of our larger data sets. While DESTINY-PanTumor02 was transformative for a lot of tumors, it had only 40 patients [with EC]. [The trastuzumab pamirtecan study] has over 100 patients. The response rate was high for HER2 1+, HER2 2+, and HER2 3+ (Figure 8).^15,16 There was a big difference between HER2 3+ and HER2 1+ and 2+, but responses for HER2 1+ and HER2 2+ were about the same, and they’re both better than anything else I would want to use in that setting.

Moore / Right now, I wouldn’t want to disqualify someone if I could use T-DXd, because I think T-DXd is probably the same. I think it works in HER2 1+ [EC]; we just haven’t seen the data. But then you can see other options, and sacituzumab govitecan (Figure 9) is an example.¹⁷ There’s data from rinatabart sesutecan. We’ve seen puxitatug [samrotecan], which is a B7H4-targeting ADC in EC. In the future, I may want to re-biopsy because if I have a HER2 1+ tumor, I might want to use a different topoisomerase 1 ADC because I’m probably going to only get benefit from 1 of them.

Key References

3. Rios-Doria E, Momeni-Boroujeni A, Friedman CF, et al. Integration of clinical sequencing and immunohistochemistry for the molecular classification of endometrial carcinoma. Gynecol Oncol. 2023;174:262-272. doi:10.1016/j.ygyno.2023.05.059

12. Van Gorp T, Cibula D, Lv W, et al; ENGOT-en11/GOG-3053/KEYNOTE-B21 investigators. ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase 3 study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol. 2024;35(11):968-980. doi:10.1016/j.annonc.2024.08.2242

14. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase 2 trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/jco.23.02005

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