For intermediate risk endometrial cancer, multiple clinical trials have established the use of clinicopathologic risk factors including age, stage, grade of tumor, myometrial invasion and lymphovascular space invasion for recommendation of adjuvant radiation treatment.1-3 However, these trials predated the standardized use of molecular testing.
In 2013, the Cancer Genome Atlas Research Network classified endometrial cancers into four molecular subtypes, including the microsatellite instability high (MSI-H) group.4 This group accounts for 20-40% of endometrial cancer and has been shown to have worse clinical outcomes.5,6 The deficient mismatch repair (dMMR) group encompasses multiple etiologies, including sporadic defects in MMR genes (sdMMR), germline mutations, and hypermethylation of the MLH1 promoter (MLH1ph), which each have distinct implications for prognosis.5-7
Many ongoing clinical trials focus on the integration of molecular testing, including MMR status, into adjuvant therapy decision-making for early-stage endometrial cancer. Still, an additional question that remains is how to weigh molecular testing vs. clinicopathologic risk factors. On September 28, 2025, “Impact of MMR Status vs. Clinicopathologic Risk Factors on Locoregional Recurrence in Stage I Endometrioid Endometrial Cancer Treated with Brachytherapy Alone,” was presented at the ASTRO Annual Meeting.
Out of 484 patients in this retrospective cohort, 155 (32%) were dMMR, and all patients were treated with adjuvant vaginal brachytherapy alone. The only prognostic factor associated with worse locoregional recurrence-free survival was MMR status. MLH1ph status had significantly worse recurrence-free survival at three years. Specifically, the incidence of locoregional recurrences at three years was 16% in MLH1ph, 7% in sdMMR and 2% in pMMR. dMMR patients were significantly more likely to have nodal recurrences compared to pMMR (7.8% vs 0.3%), but not vaginal recurrences (1.8% vs 1.9%). Clinicopathologic risk factors were not significant.
Dr. Hathout, the lead author of this study, commented earlier,“In this large multi-institutional cohort study, patients with MLH1 promoter hypermethylation were older, had more grade 2-3 tumors and were more often high-intermediate risk. MLH1ph was associated with increased pelvic and distant recurrences, reinforcing its relevance as a distinct prognostic subset of early-stage endometrioid endometrial cancer.”
These results suggest that dMMR status, particularly MLH1ph, has potential to drive differential management for endometrial cancer. What remains unknown is the proper strategy for escalation of therapy in dMMR patients with a higher risk of locoregional recurrence, particularly considering previous data showing limited efficacy of the addition of chemotherapy to radiation in this population.8 Capitalizing on the dMMR status with immunotherapy is an intriguing possibility. Previous trials, including RUBY and GYO18, have shown the benefit of immune checkpoint inhibitors in dMMR recurrent or advanced EC, but these trials did not evaluate the role of radiation or include patients with intermediate risk EC.9,10 NRG-GYO20, which is a phase III trial assessing the role of pembrolizumab with or without radiation in early-stage high-intermediate risk dMMR EC, has recently completed accrual.11
Overall, the results of this study underscore how molecular testing, including MMR status, will impact practice in adjuvant therapy for endometrial cancer.
Abstract 121 - Impact of MMR Status vs. Clinicopathologic Risk Factors on Locoregional Recurrence in Stage I Endometrioid Endometrial Cancer Treated with Brachytherapy Alone, was presented during the SS 04 - GYN 1: Molecular and Precision Medicine for Gynecologic Cancers in Diverse Resource Settings session of the 67th ASTRO Annual Meeting.
1. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(3):744-751.
2. Creutzberg CL, Nout RA, Lybeert MLM, et al. Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. Int J Radiat Oncol Biol Phys. 2011;81(4):e631-e638.
3. Nout RA, Smit VTHBM, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010;375(9717):816-823.
4. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
5. Russo AL, Lee LJ, Wo JY, et al. Effect of mismatch repair status on outcome of early-stage grade 1 to 2 endometrial cancer treated with vaginal brachytherapy. Am J Clin Oncol. 2022;45(1):36-39.
6. Hathout L, Sherwani ZK, Alegun J, et al. Prognostic effect of mismatch repair status in early-stage endometrial cancer treated with adjuvant radiation: A multi-institutional analysis. Int J Radiat Oncol Biol Phys. 2024;119(4):1158-1165.
7. Sherwani ZK, Damast S, Fields EC, et al. The prognostic impact of MLH1 promoter hypermethylation in stage I-II endometrial cancer treated with adjuvant radiation therapy: A multi-institutional retrospective study. Int J Radiat Oncol Biol Phys. Published online May 14, 2025. doi:10.1016/j.ijrobp.2025.05.004
8. León-Castillo A, de Boer SM, Powell ME, et al. Molecular classification of the PORTEC-3 trial for high-Risk Endometrial Cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncol. 2020;38(29):3388-3397.
9. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
10. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
11. Study Details. Accessed August 24, 2025. https://clinicaltrials.gov/study/NCT04214067
