Genomic testing matters in endometrial cancer both for prognostication and therapeutic selection, but there’s work to do in making sure it reaches all women.
“It is a very exciting time for endometrial cancer drug development, and it really comes down to the understanding of the different cancers, taking into account the genomics of the cancer,” said Ursula A. Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber Cancer Institute in Boston.
Endometrioid and non-endometrioid replaced the type 1 and 2 designations and are now further defined by four molecular subtypes based on genomic abnormalities after findings of The Cancer Genome Atlas (TCGA) were released in 2013:
- DNA polymerase epsilon (POLE, ultramutated)
- Microsatellite instability (MSI, hypermutated)
- p53 abnormal (copy-number high)
- p53 wild-type/no specific molecular subtype (copy-number low)
Molecular subtyping technology and bioinformatics used in that study were out of reach for most clinical operations, noted Casey Cosgrove, MD, a gynecologic oncologist with the Ohio State University Comprehensive Cancer Center in Columbus.
Subsequent work to find clinically accessible testing strategies paid off. “TCGA molecular-based classification can be applied to clinical practice, by using a simplified surrogate that includes three immunohistochemical markers (p53, MSH6, and PMS2) and one molecular test (analysis for pathogenic POLE mutations),” noted the FIGO 2023 staging updates.
Prognostication and Therapeutic Selection
“Utilizing these clinically accessible tests, we are able to better understand tumors that are going to have a better or poorer prognosis, not just based off of how they look under the microscope, but what their genetics are telling us,” Cosgrove told MedPage Today.
Algorithms for risk stratification based on genomics include the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and similar models from the European PORTEC group and the GOG group in the U.S., all developed from 2014 through 2017.
While genomics are increasingly important in prognostication, they also are shaping up for a key role in therapeutic options.
Trastuzumab deruxtecan (Enhertu) is FDA approved for all solid tumors with HER2 overexpression, as marked by immunohistochemical (IHC) 3+ staining, and recommended in the National Comprehensive Cancer Network guidelines for HER2 IHC 2+ or 3+ endometrial cancer.
Even with low levels of expression, finding HER2 positivity predicts response to HER2 antibody-drug conjugates.
And there’s more ahead. For example, polymutated tumors, “since they have exceptionally great outcomes” are being looked at in molecular-based management trials to see if deescalating therapy to avoid the toxicities and expense of therapies can still maintain outcomes. “Those will be really exciting in the future for precision medicine and counseling for our patients,” Cosgrove noted. Mismatch repair-deficient tumors, which make up approximately 25-35% of all endometrial cancer cases may have poorer outcomes but also had “extraordinarily long and durable responses” with immunotherapy, he added.
Cancers with amplified cyclin E copy number on next generation sequencing or RAS or ARID1A mutation can also point to drug targets as well, Matulonis said.
“It’s really becoming standard care for our endometrial cancer patients to be classified not just with how they look under the microscope, not just with their stage or if the cancer spread to different places, but also based off of what their molecular profiles are,” Cosgrove said.
This has been recognized in the FIGO 2023 staging updates, which recommend that “when feasible, the addition of molecular subtype evaluation to the staging criteria should be performed as it allows a better prediction of prognosis in a staging/prognosis scheme. The performance of complete molecular classification … is encouraged in all cases of endometrial carcinoma for prognostic risk-group stratification and as potential influencing factors for adjuvant or systemic treatment decisions.”
A biopsy specimen “may allow for a better performance of immunohistochemical and molecular techniques than on the final hysterectomy specimen,” the update suggested.
Standardization in Practice
But that standard hasn’t reached all patients.
Mismatch repair testing rates have improved, Matulonis said. However, “even with BRCA testing in ovarian cancer, it’s still not perfect. We as oncologists have to … remind everybody that these are important things to do. And then, you know, if a patient comes in for a second opinion and I notice that the mismatch repair testing hasn’t been done, I usually contact the pathologist and ask them to do it, reminding them that is a standard of care thing to do.”
A decision analysis study for newly diagnosed endometrial cancer compared the current algorithm of universal mismatch repair IHC against giving all patients upfront multi-gene panel testing and reserving mismatch repair IHC for recurrent cases. It showed that an upfront multi-gene panel testing strategy would catch an additional 1% of cases as having Lynch syndrome and pick up BRCA1 or BRCA2 pathogenic variants in another 1%, while saving $259 per patient relative to the current testing algorithm.
“Incorporation of germline genetic testing in the upfront setting represents an opportunity to improve access to genetic counseling and testing, and ultimately an avenue to achieve equity and improve the lives of our patients with [endometrial cancer] and their families,” the authors of that study in Gynecologic Oncology concluded.
Equity in Practice
Minority women with endometrial cancer may also be a population at risk of missing out on genomic testing.
“Endometrial cancer is already a cancer that has some of the greatest, if not the most, disparities and outcomes amongst different races and ethnicities,” Cosgrove added. “We also know that access to care has been an issue for endometrial cancer in the past. And so if we’re adding extra testing on, we have to make sure that is fair and equitable across patients.”
“Nonstandardization of how oncologists order these tests” is a problem too, Matulonis said. Some get sequencing results and tumor mutational burden, some see whether the tumor is homologous recombination deficient, and not all include immunohistochemistry results.
Circulating tumor DNA readouts are sometimes ordered too, but their utility in gynecologic cancers “has not been well sorted out yet,” she added.
Disclosures
Cosgrove disclosed relationships with GSK, Merck, ImmunoGen, Intuitive, and AstraZeneca.
Matulonis disclosed financial relationships with Allarity, NextCure, Alkermes, Symphogen, GSK, Agenus, Profound, Novartis, Boehringer Ingelheim, ImmunoGen, Eli Lilly, Tango Therapeutics, Eisai, and the Ovarian Cancer Research Alliance.
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