Endometrial cancer is the most common gynecologic malignancy in the United States. In 2023, an estimated 66,200 women will receive a new diagnosis of endometrial cancer, and 13,030 women will die from this disease [1]. Approximately 20% of new diagnoses of endometrial cancer occur among premenopausal women [2], and definitive surgical management can jeopardize fertility for these patients [3].

Improvements in fertility have occurred over the past decade, largely due to patient preferences and improvements in assisted reproductive techniques, which have led to a 67% increase in fertility among patients over 35 years of age [4]. For well-selected patients with atypical endometrial hyperplasia (AEH) or grade 1, apparent stage IA endometrioid adenocarcinoma who desire to retain their uterus to preserve fertility, continuous progestin-based therapy with close clinical follow-up may be considered [5,6]. Complete response (CR) to progestin-based therapy has been observed in 53% to 84% of patients, with recurrence rates ranging between 10% and 47% [[6], [7], [8]]. Identifying reliable pathologic and clinical variables to predict progesterone responsiveness or later recurrence is an area of active interest [6].

In 2013, a landmark study from The Cancer Genome Atlas (TCGA) identified distinct, prognostically relevant endometrial cancer molecular subtypes, including polymerase epsilon (POLE)-ultramutated, microsatellite instability-high (MSI-H), copy number-high (CN-H), and copy number-low (CN-L) subtypes [9]. The integration of molecular classification into diagnostic and treatment guidelines, including the 2021 joint consensus statement published by the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP), holds potential clinical implications for patients who opt for medical management of endometrial cancer [10,11]. While acknowledging the limited prognostic value of the TCGA classification in patients with low-risk, early-stage endometrial cancer, evidence suggests that mismatch repair-deficient (MMRd) tumors (as a surrogate for MSI-H tumors) and p53-abnormal tumors (as a surrogate for CN-H tumors) may be associated with poor response to progestin-based fertility-sparing treatments compared to CN-L or POLE-ultramutated tumors. Recently, the International Federation of Obstetrics and Gynecology (FIGO) included molecular subtypes in their new staging classification, highlighting the prognostic value of molecular subtypes even in stage I disease [12]. Given the limited number of studies in the literature [[13], [14], [15], [16]], we sought to investigate the association of molecular subtype with response to progesterone in patients who undergo medical management of early-stage endometrial cancer or AEH.