The progesterone paradigm: Molecular prognostication in conservative management of endometrial cancer

Objective. While most cases of early stage endometrioid endometrial cancer (EEC) are treated surgically, progestin therapy is an alternative for patients who are not surgical candidates. This study aimed to evaluate a single institution's response rates to hormonal therapy and to identify clinical and molecular factors associated with response. Methods. We conducted a retrospective cohort study of patients with EEC and atypical hyperplasia (AH) managed with progestin (oral or IUD) from 01/1999 to 12/2020. Patients with a complete or partial pathologic response at 12 months were considered as responders. Immunohistochemical stains as well as next generation sequencing was performed on biopsy tissue to identify abnormal p53 expression, mismatch repair deficiency (MMRd), and POLE mutations. We measured association of response to clinical and molecular factors using Fisher's exact tests and t-tests. Results. 105 patients diagnosed with AH/EEC treated with IUD or oral progesterone were included. Mean BMI was 47.7 (SD: 16.7). At 12 months, overall response was 61.0%. Response rate was higher in patients with AH (73.1%, 30/ 41) than in grade 1-2 EEC (54.8%, 34/62). Sixty-four patients had molecular testing. Both patients with abnormal p53 expression and 3 of 4 MMRd were non-responders. Older age and myometrial invasion on MRI were associated with non-response to progesterone. Conclusions. Selecting candidates for nonsurgical management of endometrial cancer remains challenging. The association of myometrial invasion to response illustrates the importance of pretreatment imaging. Given non-response in 3 of 4 MMRd and both p53 mutated tumors, molecular testing should be considered in all these patients. (c) 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.