Andrea Neilson

Co-existent endometrial and ovarian carcinoma: molecular and pathological features define low risk entity

Most co-existent endometrial and ovarian carcinomas are clonally related and exhibit an indolent disease course. Pathologic assignment and clinical management of this entity vary greatly. The International Federation of Gynecology and Obstetrics (FIGO) 2023 endometrial carcinoma staging/risk stratification system introduced a new substage for co-existent endometrial and ovarian carcinomas that meet strict pathologic criteria (stage IA3, distinct from IIIA1). Our aim was to validate if FIGO IA3 identifies a subset of co-existent endometrial and ovarian carcinomas at very low risk of recurrence and determine whether further refinement, through molecular features and expanded ovarian pathologic criteria, could improve prognostic discernment and direct more patients for consideration of de-escalation. Clinicopathologic, molecular, and outcome data were collected on patients with co-existent endometrial and ovarian carcinoma, extracted from pathology archives and molecularly classified endometrial carcinoma cohorts. Among the 154 co-existent endometrial and ovarian carcinoma patients, higher recurrence rates were observed with the p53abn (2/6, 33%), mismatch repair deficiency (MMRd) (7/34, 21%) or no specific molecular profile (NSMP) estrogen receptor (ER) negative-low (2/15, 13%) molecular sub-types, compared with patients with POLEmut or NSMP ER strong positive tumors. Thirty-two patients met FIGO IA3 criteria, with one recurrence and death event (MMRd). Eliminating patients with adverse molecular features (p53abn or MMRd endometrium or ovary, or NSMP ER negative-low endometrium) and expanding criteria to include any POLEmut or cases with bilateral ovarian involvement, intra- or pre-operative ovarian rupture, or ovarian surface involvement significantly improved risk stratification (p = .008) and added 48 co-existent endometrial and ovarian carcinoma patients (>2-fold increase) with no recurrence events (mean follow-up: 6 years). There was 91% concordance of molecular sub-type assignment between endometrial and ovarian tumors. FIGO IA3 criteria identify a subset of co-existent endometrial and ovarian carcinomas with excellent outcomes. However, incorporating molecular features into the definition enables greater prognostic discernment and supports the inclusion of patients with a broader range of pathologic features with indolent disease (increased from 20% to 49% of the cohort, 0 recurrences) who may be candidates for treatment de-escalation.

The Progesterone Challenge Test as a Functional Biomarker of Endometrial Cancer Risk: Results from a Prospective Feasibility Study

Abstract Endometrial cancer incidence continues to increase globally, driven mainly by obesity. Current diagnostic pathways rely on symptom presentation; no validated approach exists to identify asymptomatic individuals who may benefit from targeted prevention. The progesterone challenge test (PCT) is a physiologic assessment of endometrial hormonal responsiveness that could pragmatically guide endometrial cancer prevention interventions. The RESToRE study (NCT05651282) prospectively assessed the feasibility of the PCT as a community-based risk-stratification tool for endometrial cancer prevention in British Columbia, Canada, between 2023 and 2024. Asymptomatic postmenopausal participants, defined by the absence of vaginal bleeding, with body mass index ≥34.9 kg/m2 and an intact uterus, completed a 10-day course of oral medroxyprogesterone acetate (MPA) 10 mg daily. Feasibility, tolerability, and acceptability were evaluated. Of 96 eligible individuals, 68 enrolled, 53 initiated, and 51 completed the PCT. Sixteen participants experienced withdrawal bleeding (+PCT; 30.2% of those with evaluable results). All +PCT individuals were referred to a gynecologist for standard-of-care evaluation, including an endometrial biopsy. Among the 15 who underwent biopsy, two had a proliferative endometrium, and one had simple hyperplasia. Participants and providers found the test acceptable, citing its simplicity and low administrative burden. Side effects of the PCT were mild (median severity ≤three of 10), resulting in 3.8% (two of 53) of participants discontinuing the MPA. The PCT was feasible, well-tolerated, and acceptable among higher-risk postmenopausal individuals, supporting its use as a physiologic, functional biomarker of endometrial responsiveness. These findings provide early evidence for a scalable, low-cost strategy to identify individuals likely to benefit from targeted endometrial cancer prevention. Prevention Relevance: This study demonstrates that the PCT is feasible and acceptable as a functional biomarker associated with the risk of endometrial cancer in asymptomatic postmenopausal individuals with obesity. As a low-cost, scalable, community-deliverable approach, our findings support validation of this test in the context of endometrial cancer precision prevention.