Prognostic Impact of Mismatch Repair Deficiency in High- and Low-Intermediate Risk, Early-Stage Endometrial Cancer Following Vaginal Brachytherapy

Abstract

Mismatch repair deficiency (dMMR) is found in approximately 25% of endometrial cancers (EC), yet it remains unknown how this information should be incorporated into adjuvant treatment paradigms. Ongoing trials are investigating the potential use of immunotherapy in conjunction with radiotherapy for the adjuvant treatment of dMMR patients with high-intermediate risk (HIR) features. We hypothesized that dMMR status is associated with higher rates of recurrence in both low-intermediate risk (LIR) and HIR subgroups. We examined the impact of dMMR status on prognosis among patients with early-stage endometrioid EC treated with vaginal brachytherapy (VB).We performed a retrospective review of 198 patients who were treated with adjuvant VB for FIGO stage I or II endometrioid EC and had known MMR status. Both LIR and HIR patients (per GOG 249 criteria) were included. Patients with non-endometrioid and mixed histologies and patients treated with pelvic radiotherapy were excluded. Patient, tumor, and treatment characteristics were compared between patients with proficient mismatch repair (pMMR) and dMMR using c2 tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards regression.Patients with dMMR compared to pMMR were more likely to have grade 2-3 tumors (75% vs. 57%, P = 0.012), lympho-vascular invasion (40% vs. 25%, P = 0.023), and HIR classification (65% vs. 49%, P = 0.038). There were no other differences in clinicopathologic or treatment characteristics. Median follow-up time for dMMR and pMMR patients was 37.5 and 37 months, respectively. Three-year RFS was inferior for dMMR compared to pMMR patients (75% vs. 96%, P = 0.001). dMMR patients compared to pMMR had similarly reduced 3-year RFS both within the LIR (74% vs. 100%, P = 0.026) and HIR (75% vs. 91%, P = 0.038) subgroups. Three-year OS was excellent across all categories and was not different between dMMR/pMMR patients (98% vs. 97%, P = 0.653) or HIR/LIR patients (97% vs. 97%, P = 0.999). On multivariable Cox regression, dMMR status was the only significant prognostic variable for RFS (HR 3.774, CI 1.495-9.526, P = 0.005), though it was not significant for OS. While failures were more likely in the dMMR cohort, salvage rates were high, and treatment included surgery (29.4%), pelvic RT (41.2%), chemotherapy (70.6%), and immunotherapy (47.1%).Following VB, patients with dMMR have poorer RFS compared to pMMR patients regardless of HIR/LIR risk classification. Increased monitoring for early salvage intervention and/or expansion of eligibility to clinical trials incorporating immune checkpoint inhibitors should be considered for both HIR and LIR patients with dMMR.