The Prognostic Impact of MLH1 Promoter Hypermethylation in Stage I-II Endometrial Cancer Treated With Adjuvant Radiation Therapy: A Multi-Institutional Retrospective Study.

PURPOSE: To assess the impact of MLH1 promoter hypermethylation (MLH1ph) on prognosis and define the patterns of recurrence in stage I or II endometroid endometrial cancer (EEC) treated with adjuvant radiation therapy.

METHODS AND MATERIALS: In a retrospective, institutional review board-approved, multi-institutional cohort study, 814 patients with stage I or II EEC with known mismatch repair (MMR) status were included. Tumors with MSH2, MSH6, MLH1, or PMS2 mutations were classified as somatic deficient MMR (sdMMR), whereas tumors with epigenetic silencing of the MLH1 promoter were classified as MLH1ph. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method. Univariate and multivariate analyses (UVA/MVA) were performed via Cox proportional hazards. Statistical analyses were conducted using SPSS version 27.

RESULTS

The median age at diagnosis was 65 years (IQR, 58-71), and most patients had grade 2 or 3 disease (59.2%), ≥50% myometrial invasion (56.0%), and absence of lymphovascular space invasion (58%). Vaginal brachytherapy was delivered to 643 (78.1%) patients, and 180 (21.9%) patients received external beam radiation (EBRT) ± vaginal brachytherapy (VBT). MMR was proficient in 550 (67.6%) patients and deficient in 264 (32.4%) patients. Of the patients with dMMR, most patients harbored MLH1ph (n = 171, 66%), and 93 patients (35.2%) had somatic dMMR. Tumor size ≥ 3.8 cm [hazard ratio (HR), 2.2; P = .003], MMR deficient versus proficient (HR, 2.7; P < .001), and EBRT ± VBT versus VBT alone (HR, 1.9; P = .032) were associated with decreased RFS on MVA. On subgroup analysis including patients with dMMR only, patients with MLH1ph had worse RFS compared with patients with sdMMR (HR, 1.9; 95% CI, 1.1-3.6; P = .025). Distant recurrence was the most common recurrence site, regardless of MMR status. Patients with MLH1ph had significantly higher proportion of vaginal (5% vs 0% vs 2%) and pelvic (5.3% vs 3.2% vs 0.5%) recurrences compared with sdMMR and pMMR, respectively (P = .038).

CONCLUSIONS

Patients with MLH1ph had worse RFS, which may be attributed in part to a higher proportion of locoregional recurrences compared with the pMMR and sdMMR patients.