New research supports retesting for mismatch repair deficiency (MMRD) at uterine cancer recurrence, as patients who are MMR proficient in the primary setting may have MMRD at recurrence.1
Since MMRD can influence prognosis and benefit from certain therapies, current guidelines recommend that patients should be screened for MMRD when diagnosed with endometrial cancer.2 In addition, finding MMRD triggers further testing for Lynch syndrome in the patient and, potentially, the patient’s family members.
Retesting for MMRD at relapse has not been standard practice. However, new data suggest it may be appropriate, according to Rebecca A. Previs, MD, of Duke University Medical Center in Durham, North Carolina. Dr Previs presented these data at the SGO 2022 Annual Meeting on Women’s Cancer. 1
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Patients and Methods
For their study, Dr Previs and colleagues retrospectively identified 43 patients with a history of recurrent uterine cancer who had tissue available from diagnosis and recurrence. Eleven patients were excluded because of insufficient or unavailable tissue specimens.
Histologic slides from the remaining 32 patients were reviewed to confirm the diagnosis of primary and recurrent cancer. Immunohistochemistry (IHC) was performed using antibodies against MMR proteins, including MLH1, PMS2, MSH2, and MSH6, on formalin-fixed paraffin-embedded slides from the matched specimens.
Most patients (n=28) had stage I disease at diagnosis, endometrioid histology (n=27), and had grade 3 tumors (n=31). From diagnosis, the median recurrence-free survival was 18.3 months (range, 5.5-117.4 months), and the median overall survival was 70.7 months (range, 20.4-303.9 months).
MMRD in the Matched Specimens
Dr Previs reported that 6 primary tumors had MMRD, 5 of which had absent MLH1 and PMS2 expression. All patients who had MMRD primary tumors retained an identical MMR phenotype in the tissue obtained at recurrence.
However, 3 tumors that were MMR proficient in the primary setting showed MMRD at recurrence. In each case, there was loss of MLH1, and 2 had loss of PMS2. Two of the 3 patients who developed MMRD cancers had grade 1 epithelial tumors at initial diagnosis.
In total, 29 patients (91%) had concordance between the tissue specimens obtained from their primary and recurrent tumors, but 3 patients (9%) with initially intact MMR developed MMRD at recurrence.
Dr Previs advised that retesting for MMRD at recurrence should be considered in all patients with uterine cancer since clonal evolution can occur and MMRD is a biomarker with therapeutic implications.
Implications and Matters Worthy of Additional Study
Some oncologists might be cautious about drawing practice-changing conclusions from a retrospectively identified case series of matched histologic specimens from a single institution. In addition, inadequate tissue in 26% of the cases limited the volume of specimens that could be studied.
However, Dr Previs’s advice that retesting for MMRD should be considered in recurrent uterine cancer seems worthy of further evaluation and, potentially, implementation in practice.
It is “quite obvious we should retest,” said SGO discussant Matthew A. Powell, MD, of Washington University School of Medicine in St. Louis, Missouri.
Dr Powell also said that pathologists should report intratumoral heterogeneity in initial specimens from endometrial cancer patients. Subclonal loss of MMR proteins in the primary tumor could predict whether MMRD is likely when the tumor recurs and could be relevant to whether the patient should receive immune-targeted therapies at that time.
Another presentation at SGO 2022 suggested that the mechanism by which MMRD develops could be relevant to the choice of treatment at relapse.3 The presentation showed a correlation between MLH1 hypermethylation and poor response to single-agent immune-targeted therapy in recurrent endometrial cancer.
These results suggest that forthcoming clinical trials should stratify patients by the mechanism of MMRD, said presenter Lindsay Borden, MD, of the University of Oklahoma in Oklahoma City.
In their study, Dr Previs and colleagues did not specifically assess MLH1 promoter hypermethylation in either the primary tumor specimens or the specimens obtained at relapse.
It has been 9 years since the Cancer Genome Atlas Research Network investigators published the genomic characterization of endometrial cancer and promised a future of molecularly-guided clinical trials and drug development.4
From SGO 2022, it is apparent that their vision is being realized, and some of the initial issues that require resolution in endometrial cancer are coming into focus.
Disclosures: Dr Previs disclosed relationships with Myriad Genetics and Natera. Dr Powell disclosed relationships with Merck, Eisai, GSK/Tesaro, Roche/Genentech, Seagen, AstraZeneca, and Clovis Oncology. Dr Borden reported having no conflicts of interest.
References
1. Spinosa D, Wong J, Whitaker R, et al. To test or re-test, that is the question: Comparison of the mismatch repair deficiency between primary and metastatic sites of uterine cancers. Presented at SGO 2022; March 18-21, 2022. Abstract 88.
2. NCCN practice guidelines in oncology: Uterine neoplasms. Version 1.2022. Published November 4, 2021. Accessed April 6, 2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473
3. Borden L, Dvorak J, Barrett Z, et al. MLH1 hypermethylation predicts poor outcomes with pembrolizumab in recurrent endometrial cancer. Presented at SGO 2022; March 18-21, 2022. Abstract 87.
4. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497(7447):67-73. doi:10.1038/nature12113
