Patients receiving an endometrial cancer diagnosis may encounter unfamiliar terminology in their pathology reports, such as “MMR-deficient” or “p53 abnormal.” To grasp the implications of these findings, Monica Avila, MD, MPH, a gynecologic oncologist at Moffitt Cancer Center, and Gulisa Turashvili, MD, PhD, subspecialty director of gynecologic pathology at Mass General Brigham, outlined the significance of biomarker testing.
Biomarker testing analyzes genetic material and proteins within a tumor to provide insights into its behavior and potential treatment responses. According to Dr. Avila, this testing is now a standard practice throughout the U.S. The initial evaluations focus on identifying absent proteins, which may indicate a connection to inherited conditions. Providers frequently opt for expanded genomic analysis to categorize endometrial cancers into four distinct molecular subtypes.
Dr. Turashvili explained that standard biomarker assessments include evaluating mismatch repair proteins, estrogen and progesterone receptors, p53, and POLE mutation status. These results can typically be derived from tissue samples collected during prior biopsy or surgical removal of the uterus.
Biomarker Testing Overview
The timeline for receiving biomarker test outcomes varies depending on the test type. Simpler techniques, such as immunohistochemistry, generally require 3-5 days, Dr. Turashvili noted. More full genomic analysis may take 2-4 weeks or longer, depending on the laboratory’s processes.
Dr. Turashvili advises patients to inquire with their healthcare team about the specific tests ordered and the expected timeline for results, as this can clarify the testing process and provide necessary guidance.
Genomic testing classifies endometrial cancers into four molecular subtypes: POLE, MMR-deficient, p53-abnormal, and NSMP. Each subtype presents unique characteristics and may respond differently to various treatments, Dr. Avila stated.
For instance, POLE tumors are characterized as the least aggressive molecularly. Research is exploring whether certain patients with POLE mutations can safely undergo reduced treatment regimens. MMR-deficient tumors, conversely, demonstrate strong responsiveness to immunotherapy interventions.
Dr. Avila described p53-abnormal tumors as the most aggressive subtype. The p53 protein typically suppresses tumor growth, and its malfunction can accelerate cancer progression.
NSMP tumors are considered unpredictable due to the absence of a single recurring mutation. The pattern of missing MMR proteins may offer insights into the underlying cause of the abnormal findings.
According to a 2026 review in the journal Cancers, approximately 7% of endometrial cancers are classified as POLE, 28% as MMR-deficient, and 40% as NSMP. The remaining cases are primarily p53-abnormal.
Understanding MMR Deficiency
When a report indicates “MMR-deficient,” “MSI-high,” or both, the terminology may seem unclear. Dr. Turashvili clarified that these terms represent two distinct methods for detecting the same underlying issue.
Cells maintain a DNA mismatch repair system involving four proteins (MLH1, MSH2, MSH6, and PMS2) that correct minor DNA replication errors. If any of these proteins malfunction, errors accumulate in repetitive DNA sequences known as microsatellites.
Clinicians can identify this issue through two approaches: MMR testing employs immunohistochemistry, while MSI testing uses DNA-based assays. Since absent MMR proteins often result in unstable DNA, MMR-deficient tumors are frequently MSI-high, Dr. Turashvili explained.
Guidelines from the College of American Pathologists (CAP), the Association for Molecular Pathology, and the Society for Immunotherapy of Cancer strongly endorse MMR immunohistochemistry over MSI testing for assessing immunotherapy eligibility, Dr. Turashvili noted.
An MMR-deficient finding does not definitively indicate Lynch syndrome, an inherited condition linked to raised risks of endometrial, colorectal, and other cancers. The National Cancer Institute (NCI) estimates Lynch syndrome contributes to roughly 5% of endometrial cancers.
The NCI recommends Lynch syndrome testing for all women diagnosed with endometrial cancer. The pattern of missing MMR proteins can hint at the cause. If MLH1 and PMS2 are absent, a methylation test is typically ordered. Methylation findings often negate Lynch syndrome concerns, Dr. Turashvili stated.
Lynch Syndrome Testing
If methylation is undetectable or other MMR proteins are missing, patients are referred for germline genetic testing. This examines inherited genetic changes using blood or saliva samples rather than tumor tissue.
A positive result may prompt additional screening for other Lynch-related cancers, such as routine colonoscopies. Discussions may also cover risk-reduction strategies and family communication. Each biological child and sibling has a 50% chance of inheriting the mutation, Dr. Turashvili emphasized. She encourages siblings to consider testing even without symptoms, as Lynch syndrome does not manifest until cancer develops.
A genetic counselor can assist in identifying at-risk family members and guiding them through the process. The care team may also discuss strategies for discussing results with relatives and encouraging their participation in genetic testing.
Molecular subtype findings help clinicians predict cancer behavior and guide treatment. Researchers are refining subtype-specific treatment approaches. For example, MMR-deficient cancers are particularly responsive to immunotherapy, Dr. Avila noted.
Two clinical trials in uterine cancer—RUBY and NRG-GY018—showed improved outcomes for patients with MMR-deficient tumors receiving immunotherapy alongside chemotherapy. These findings led to multiple U.S. Food and Drug Administration (FDA) approvals:
Jemperli (dostarlimab) combined with chemotherapy received FDA approval in 2023 for advanced or recurrent MMR-deficient/MSI-high endometrial cancer. In 2024, this approval expanded to include all primary advanced or recurrent cases.
Tailoring Treatment Options
POLE mutations may signal eligibility for reduced treatment intensity. Dr. Avila stated that studies indicate patients with POLE tumors achieve excellent outcomes post-treatment, suggesting adjuvant therapy may be unnecessary. Ongoing trials explore safe, less-intensive treatment options, potentially omitting chemotherapy and/or radiation.
Results may also influence treatment beyond molecular subtypes. Approximately one-third of serous endometrial cancer patients exhibit HER2 overexpression, a more aggressive form. If HER2-positive, targeted therapy like Herceptin (trastuzumab) may be added to chemotherapy. In 2024, the FDA approved Enhertu (trastuzumab deruxtecan) for HER2-positive (IHC 3+) solid tumors post-treatment.
Molecular data now impact cancer staging. Under the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system, POLE tumors may be downstaged, while some p53-abnormal cases may be upstaged.
Patients uncertain about their molecular subtype should request a review with their care team to understand treatment implications. Results may appear in the primary pathology report or as a separate addendum/supplement issued later.
Dr. Turashvili suggests checking the patient portal for a second pathology entry dated days to weeks after the initial report. To confirm testing, look for sections labeled Immunohistochemistry, Special Stains, Molecular Pathology, or Molecular Studies. Additional documents may include Addendum, Supplemental Report, or Genomic Profiling Report, with terms like MLH1, PMS2, MSH2, MSH6, mismatch repair, MMR-deficient, MSI-high, MSS, POLE, p53, or next-generation sequencing. Common labs include FoundationOne, Tempus, Caris, Myriad, and Guardant. Absence of these terms may indicate pending results or no testing ordered. Dr. Turashvili recommends directly asking the team about testing completion and requesting copies of reports.