Mismatch repair status and recurrence in endometrial cancer: Prognostic implications

Purpose: Recent studies for endometrial cancer (EC) have demonstrated a divergence of outcomes based on mismatch repair (MMR) status, with MMR deficiency being an important predictor of recurrence and death (1). Further investigation is needed to validate these findings in additional patient populations to support the clinical significance of MMR status EC.

Methodology: We performed a single institution retrospective review at UMass Memorial Medical Center to identify EC patients who were tested for MMR status and to follow their clinical outcomes after definitive management (TAH/BSO with adjuvant chemotherapy and/or radiation therapy, as per NCCN guidelines). Querying the EPIC electronic medical record for all available years (2017-2021), we identified patients with ICD10 codes C54-C55. Of the total of 1884 cases, 374 had endometrioid histology with available MMR immunohistochemical results. Charts were reviewed longitudinally following completion of definitive management, and recurrences were assigned only if pathologically confirmed by tissue biopsy as malignancy of the same histological and/or immunohistochemical profile as tumor obtained at initial diagnosis.

Results: Of the 374 endometrioid EC patients, 88 (23.5%) were MMR-deficient, the majority of which were MLH1/PMS2 deficient. Of the 286 MMR-intact endometrioid EC patients, 98 have been analyzed to date. Of the 98, the majority of patients were early-stage, node-negative (92% Stage I, 4% stage II, 3% stage III, 1% stage IV) and eligible for upfront definitive management with TAH/BSO. The median follow-up for MMR-intact patients was 32 months with a recurrence rate for Stage I-III patients of 4%. Of the 88 MMR-deficient endometrioid EC patients, stage at diagnosis was as follows: 84% Stage I; 6% stage II; 7% stage III; 3% stage IV. The median follow-up for MMR-deficient patients was 30 months with a recurrence rate for stage I-III patients of 9%.

Conclusions: In our preliminary analysis, the MMR-deficient endometrioid EC cases were associated with more advanced stage at diagnosis and higher recurrence rates, although future analyses will need to be completed to determine if this reflects advanced stage, additional patient- and tumor-specific variables, and/or treatment variables that are different between the MMR-intact and MMR-deficient cases.

If MMR status is successfully validated to represent an independent prognostic biomarker for outcomes in these patients, it may serve as additional criteria to risk-stratify patients at initial workup. This in turn may inform tailoring treatment in these higher risk individuals, perhaps with the early utilization of immune checkpoint inhibitors given their activity level in multiple MMR-deficient disease settings.

References: 1. Cosgrove, Casey M., Floor J. Backes, David O’Malley, Kristin L. Bixel, Adrian A. Suarez, Jeffrey M. Fowler, Larry J. Copeland, Paul J. Goodfellow, and David E. Cohn. 2021. “Endometrial Cancer: Who Lives, Who Dies, Can We Improve Their Story?” The Oncologist, August. https://doi.org/10.1002/onco.13934.