Considerations for Ordering Biomarker Testing in Endometrial Cancer

Bradley Corr, MD

Associate Professor, Department of Ob/Gyn-Gynecologic Oncology

LeBert-Suess Family Endowed Professorship in Ovarian Cancer Research

Director of Clinical Research for Gynecologic Oncology

University of Colorado School of Medicine

Aurora, CO

DISCUSSION QUESTIONS

• Should every post-menopausal patient with signs and symptoms suggestive of endometrial cancer undergo molecular testing? ​
  • For which biomarkers do you test and why?​
  • When should you order testing?​
• What kind of testing do you use in practice? ​

BRADLEY CORR, MD: Which biomarkers do you test for and why? When should you order testing? What kind of testing do you use in practice, and how are you applying test results?

VISHAL RANA, MD: In my practice for the very few patients I see [with endometrial cancer], I make sure they get MSI-H [microsatellite instability-high] and dMMR [mismatch repair deficiency] testing at diagnosis. At progression and recurrence, we do a next-generation sequencing [NGS] panel of common mutations.

CORR: Is that consistent with everybody else? Is it mostly centered around dMMR or MSI-H?

ARIEL SORIANO, MD: For localized disease, I would do just that. Once it’s recurrent and metastatic, then I start to send for the NGS testing.

CORR: Is there anything else that anybody wants to test for?

RAO MUSHTAQ, MD: Yes, I do NGS initially when I see the patient including the POLE mutation, MSI status, and I also look for MLH1 mutations in these patients. The NGS includes [testing for] NTRK, and that also includes tumor mutational burden too.

CORR: I’m happy that no one said [they would test for expression of] PD-L1. It is sometimes misunderstood [when we are] categorizing PD-L1 and MMR or MSI as the same thing, and they’re not. Specific to endometrial cancer, PD-L1 testing has no correlative significance with response to immunotherapy.¹ A lot of times we’ll get [PD-L1 testing] because when we order our FoundationOne or Caris testing [or] whichever platform you’re using for NGS, you get to check off the box if you want PD-L1 testing, but it’s important to recognize that for endometrial cancer, there is no correlation with response to that. It is solely [based] on MMR or MSI. That’s important to recognize.

The other thing I want to point out is TP53. Depending on the pathology from where the patient came from, TP53 [testing] is routinely being done by a lot of institutions, but not by all. I think TP53 is an important biomarker at this point. There are going to be a lot more data coming out over the next couple of years, but we already have good data to show that TP53 mutations, whether by NGS or immunohistochemistry, is more responsive to chemotherapy.² These are patients who, if you’re unsure about therapy decisions, [could receive] radiation therapy or chemotherapy; chemotherapy should be a mainstay of treatment with TP53 mutations. This is why it’s important to get testing at diagnosis.

The other reason [for testing at diagnosis] is because we’re centered around dMMR, and we still pick up patients who have Lynch syndrome.… It’s not uncommon that I’ll get a patient who has undiagnosed Lynch syndrome with diagnosis of endometrial cancer, and [oncologists should understand] the downfall cascade of what that entails for not only them but family members [at risk]. I also think it’s important to recognize that not all dMMR is Lynch syndrome. The most common is hypermethylation of MLH1 like [Dr Mushtaq] was mentioning. [There could be a] discussion about response to immunotherapy with hypermethylation. We know that they respond better than the MMR proficient patients, but they’re not quite as good as the patients with dMMR as if it was a patient with PMS2 or MSH6 mutation [associated with Lynch syndrome].³

We know that patients with POLE mutations or hypermutations typically have a better prognosis.² I would say we’re not quite at the point of completely deescalating therapy, but I would predict that in the not-too-distant future, patients with POLE mutations will instill no further therapy. But the important part that I want instill is early testing, and testing by whatever means is most efficient for you and the patients, whether that’s talking to your pathologists to do immunohistochemistry staining, or doing the NGS testing that most of you are doing.

_References:

_{1. Cao W, Ma X, Fischer JV, Sun C, Kong B, Zhang Q. Immunotherapy in endometrial cancer: rationale, practice and perspectives. Biomark Res. 2021;9(1):49. doi:10.1186/s40364-021-00301-z}

_{2. Corr B, Cosgrove C, Spinosa D, Guntupalli S. Endometrial cancer: molecular classification and future treatments. BMJ Med. 2022;1(1):e000152. doi:10.1136/bmjmed-2022-000152}

_{3. Toboni MD, Wu S, Farrell A, et al. Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 “Lynch-like” mismatch repair gene mutation. Gynecol Oncol. 2023;177:132-141. doi:10.1016/j.ygyno.2023.08.015}