The Prognostic Impact of MLH1 Promoter Hypermethylation in Stage I-II Endometrial Cancer Treated with Adjuvant Radiotherapy

Purpose/Objective(s)

To examine the impact of MLH1 promoter hypermethylation (MLH1ph) on prognosis and recurrence patterns in stage I-II endometroid endometrial cancer (EEC) treated with adjuvant radiotherapy.

Materials/Methods

In a retrospective multi-institutional cohort study, patients with stage I-II EEC status post-surgical resection with known mismatch repair (MMR) status were included. Tumors with MSH2, MSH6, MLH1 or PMS2 mutations were classified as somatic deficient MMR (sdMMR), while tumors with epigenetic silencing of the MLH1 promoter were classified as MLH1ph. Recurrences were classified into 3 categories: vaginal, pelvic or distant (including para-aortic lymph nodes). Recurrence-free survival (RFS) and overall survival (OS) were calculated by the Kaplan Meier method. Univariate and multivariate analyses (UVA/MVA) were performed via Cox proportional hazard models. Statistical analyses were conducted using statistical software.

Results

A total of 823 patients were included with a median age at diagnosis of 65 (IQR = 58-71). Most patients had grade 2-3 disease (59.5%), ≥ 50% depth of myometrial invasion (56.4%), absence of lympho-vascular space invasion (57.5%), and no cervical stromal involvement (77.5%). Vaginal brachytherapy (VBT) was the most common adjuvant radiation modality for 643 (78.1%) patients, while 180 (21.9%) patients received external beam radiation (EBRT) +/- VBT. After a median follow up (MFU) of 38.2 months, OS and RFS for the entire cohort were 93.8% and 87.5%, respectively. MMR was proficient in 550 (66.8%) patients and deficient in 273 (33.2%) patients, most of which were MLH1ph (n = 171, 62.6%), while 93 (34.1%) were sdMMR; 9 could not be classified. The following prognostic factors were associated with decreased RFS on UVA and maintained significance on MVA: age ≥ 65 (P = 0.008, HR = 1.7), grade 2-3 (P = 0.046, HR = 1.6), and MMR status (P < 0.001, HR = 2.1). At MFU, patients with MLH1ph had inferior RFS compared to sdMMR and pMMR (73.5% vs 86% vs 92%, respectively, P < 0.001), but there was no difference in OS (92%, 92%, and 96%, respectively, P = 0.57). Of the 117 recurrences overall, the most common site of recurrence was distant regardless of MMR status, with overall breakdown as follows: 20 (2.4%) vaginal, 19 (2.3%) pelvic, and 78 (9.5%) distant. Patients with MLH1ph had a higher proportion of pelvic (28.2%) and vaginal (20.5%) recurrences, with only 51.3% distant recurrences compared to pMMR (73.2%) and sdMMR (76.5%) (P = 0.04).

Conclusion

This large multi-institutional study highlights the importance of MLH1 promoter hypermethylation testing when analyzing MMR status for patients with early-stage EEC treated with adjuvant radiotherapy. While MMR status did not impact OS, patients with MLH1ph dMMR had worse RFS and a higher proportion of locoregional recurrences compared to the pMMR and sdMMR patients which could hypothesize a need for escalation in locoregional therapy in patients with MLH1ph.