Evaluating the Molecular Landscape in Endometrial Cancer to Optimize Treatment

The rapid integration of precision medicine into the treatment of endometrial cancer has transformed clinical workflows, shifting the focus from broad histopathologic categories to specific molecular drivers. However, as the reliance on next-generation sequencing (NGS) grows, clinicians face a significant dilemma: balancing the convenience of reflexive use of comprehensive panels with the need for rigorous, guideline-driven patient selection. While NGS provides a wealth of genomic data, questions remain regarding whether automated processes capture every critical biomarker—such as mismatch repair (MMR), p53, estrogen receptor (ER), progesterone receptor (PR), and HER2—necessary for optimizing modern therapeutic regimens.

In a Community Case Forum event, John K. Chan, MD, director of Gynecologic Oncology and a specialist in the surgical and medical treatment of ovarian and other complex pelvic cancers at the UCSF Helen Diller Family Comprehensive Cancer Center, moderated a discussion with oncologists in Denver, Colorado about molecular testing and treatment decisions in patients with endometrial cancer.

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CASE SUMMARY

A 71-year-old postmenopausal woman presented with abnormal uterine bleeding, increasing urinary frequency, nausea, and abdominal cramping for approximately 6 months.

Medical history:

1. BMI of 32
2. Type 1 diabetes since childhood, well controlled with daily insulin

Focused physical examination:

• Vital signs: blood pressure normotensive at 118/76 mmHg; heart rate 70 BPM, regular rate and rhythm
• ECG: normal sinus rhythm
• Notable for enlarged uterus and right lower quadrant abdominal tenderness on palpation
• ECOG performance status of 1
  

First line systemic therapy:

• Carboplatin/paclitaxel was initiated every 21 days for 6 cycles
• Treatment was well tolerated other than grade 1 peripheral neuropathy and vomiting

Two months after treatment initiation:

• Complete resolution of symptoms
• No evidence of disease on PET scan

Six months after completing chemotherapy:

• Rising CA-125 level is documented
• A/P CT demonstrates new suspicious peritoneal lymph nodes
• PET scan: intense Fludeoxyglucose F18 avid lesions in lungs, peritoneum, as well as
• Para-aortic lymph nodes
  • Interventional radiology biopsy revealed recurrent endometrial carcinoma

DISCUSSION QUESTIONS

• What diagnostic testing do you apply to a patient who presents with endometrial cancer?
• For which biomarkers do you test, and why?
• How are you applying molecular test results to therapeutic decision-making?
• How do you assess prognostic risk?

Benjamin Scheier, MD: I think the challenge now is the NGS panels are automatic. You can just request Caris NGS, and then you just put faith that they’re going to run, ideally, everything you need for patient selection and perhaps prognostication. That’s fine when it’s a DNA- or an RNA-based assessment. What’s more challenging, and for me, an uncomfortable unknown is, are there specific tests that should be requested and they won’t run them unless I ask? Can I trust an ER, PR, HER2 result on an NGS, because that’s more like a molecular assessment, not really immunohistochemistry (IHC), so I struggle with that a little bit. I’m certainly looking for MMR in this case, for example. But I think it’s tough to know, should I be doing more than just asking my nurse to send Caris NGS? Will Caris take over?

John K. Chan, MD: You’re almost making the assumption that Caris, FoundationOne, Tempus, all these people know what the guidelines are, know what the treatment algorithm should be, and that’s why they’re testing this. You’re almost relying on them, especially when uterine cancer is not the predominant disease that you deal with, right? It’s probably less than 5% of what you deal with. Now you’re just hoping some of these testing companies will be able to keep updated on FDA approvals, NCCN guidelines and subsequent therapies, and if they don’t get a good result from NGS, they’ll run the IHC for you or something like that, right?

Jeffrey James, DO: There are a handful that definitely do MMR, and they all do p53 and so they’ll do a handful of them, but if they have either a rare or aggressive histology, or if they have advanced metastatic disease, even on initial diagnosis, I send them all for NGS, plus the IHC panel that we have preset for endometrial [cancer] and advanced endometrial [cancer]. So we try to streamline it as much as possible per disease site, which I know is far more difficult for you all that are treating multiple disease sites. We only treat 5 cancers and 2 of which we almost never see. So, we have a little bit of a hand up in that way.

We have a pretty preset way that we approach it based upon their disease site. Whatever new FDA approved or upcoming approvals need for specific biomarkers, we’re testing. And then, I test on recurrence as well. For this patient, they had a biopsy of the periodic lymph node, I would retest on the periodic lymph node. Tempus will allow you to retest within a year without having to charge the insurance or the patient. I do think with patients who are treated, the molecular makeup of the tumor that recurs may be different than what was initially identified. So, I always retest them because maybe they didn’t hit on a HER2, and they’re not a HER2 candidate on primary tissue analysis, but they are on the recurrence.

I think one of the big problems that we have in our field is that…we still don’t know the global tumor evaluation. We’re not doing cell free DNA analysis yet, so we’re still hoping that we hit on one specific area.

Chan: He brings up a good point…Like discrepancies in ER [or] PR, let’s say your genomic data is different than in your IHC data. Which one is more reliable, which one is more predictive?

Scheier: The HER2 one is tough, because the FDA approval for [fam-trastuzumab deruxtecan-nxki (Enhertu)]¹ is pretty strict about IHC being that termination....I imagine it’s tough, because the NGS at Caris, for example, will just say, HER2 amplified, if it was tested via their molecular DNA. I think that is challenging. Does insurance block you? Does it actually work? Those are questions I have.

Hanne Schuleter, PA-C: That’s why we’ve actually started using Tempus as well for patients with endometrial and ovarian [cancer], for the same reason, just because we can resend tissue if we’ve gone through 1 line of therapy and we want to try sending more samples, it’s usually within a year.

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DISCLOSURES: Chan previously reported consulting fees from AstraZeneca, Daiichi Sankyo, Eisai, Ethicon, GlaxoSmithKline, Genmab, Immunogen, Karyopharm, Merck, Mersana, Moon Surgical, Myriad, Pfizer, Roche and Seagen; honoraria from AstraZeneca, Eisai, Ethicon, Genmab, GlaxoSmithKline, Immunogen, Merck, Myriad and Seagen; support for travel to attend meetings from AstraZeneca, Eisai, Ethicon, Genmab, GlaxoSmithKline, Immunogen, Merck, Myriad, Seagen and Pfizer; and participation on advisory board for AstraZeneca, GlaxoSmithKline and Myriad.

REFERENCE

1. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. Published April 5, 2024. Accessed January 28, 2026. https://tinyurl.com/ykvaskfu