Molecular Classification Guides Fertility-Sparing Treatment for Endometrial Cancer and Atypical Hyperplasia Patients

Objectives: The objective of this study was to investigate the significance of molecular classification in guiding treatment decisions for patients with endometrial cancer (EC) or atypical hyperplasia (AH) undergoing fertility-sparing treatment (FST), particularly for those with non-NSMP subtypes. Methods: We conducted a retrospective cohort study involving EC/AH patients undergoing FST and molecular classification using next-generation sequencing at Peking University People’s Hospital between June 2020 and September 2023. Results: A total of 118 EC/AH patients were included, including 92 cases with NSMP, 11 with MMRd, 11 with POLEmut, and 4 with p53abn. (1) Of the 11 patients with MMRd, 6 achieved a complete response (CR) with 1 case receiving progestin, 3 cases showed insensitivity to the initial progestin before transitioning to a combined regimen of progestin and a PD-1 inhibitor, and 2 cases initially received progestin plus a PD-1 inhibitor. There were no significant differences in the cumulative CR rates between the MMRd and NSMP subgroups but a trend of a lower relapse-free-survival (RFS) rate for the MMRd subgroup (p = 0.074). (2) Of the 11 cases with POLEmut, 10 achieved CR but 4 relapsed. There was also a trend for a lower RFS rate in the POLEmut patients (p = 0.069) compared with the NSMP subgroup. (3) Three of the four patients with p53mut achieved CR after treatment with the GnRHa plus LNG-IUS regimen. Conclusion: The selection of appropriate regimens may improve FST outcomes in EC/AH patients with molecular classification of non-NSMP subtypes. Immunotherapy is an effective fertility-preserving approach for patients with MMRd.