Background: Molecular classification of endometrial cancer (EC) proposed by The Cancer Genome Atlas in 2013 has improved prognostic assessment of patients. PORTEC-3 assessed these molecular markers in early-stage high risk patients. We examine the prognostic value of these markers in a real-world data (RWD) cohort of early-stage high risk patients and extend the analysis to intermediate and low risk patients to inform treatment decisions across disease risk levels.

Methods: We performed a retrospective study (2016-2022) of EC patients from the Tempus de-identified, multimodal RW database. Stage I-III patients who received total hysterectomy with bilateral salpingo-oophorectomy and next generation sequencing (NGS) Tempus xT assays were stratified into high, intermediate, and low risk disease levels based on tumor characterization and categorized into POLE mutated (POLEm), mismatch repair-deficient (dMMR), p53-abnormal (p53abn), or no specific molecular profile (NSMP) PORTEC-3 subtypes. Recurrence-free survival (RFS), defined as time from surgery to earliest disease recurrence, progression, metastasis or death, was assessed using Kaplan-Meier methods for the combination of risk level and molecular subtype. We compared RFS trends across molecular subtypes at 5-years in PORTEC-3 and 18-months in RWD due to limited follow-up.

Results: Of the 740 eligible RWD patients, 546 (74%), 110 (15%) and 84 (11%) were high, intermediate, and low risk and 286 (39%), 250 (34%), 180 (24%) and 24 (3%) were P53abn, NSMP, dMMR and POLEm, respectively. Similar to RFS trends at 5 years in PORTEC-3, the p53abn subtype consistently had the lowest 18-month RFS, although the degree of separation from other subtypes varied across risk levels. NSMP and dMMR subtypes had 18-month RFS within 4% of each other for high and low risk levels, consistent with PORTEC-3. The POLEm subtype had 100% 18-month RFS across risk levels, but low prevalence.

Conclusions: Marker prognostic ranking was consistent between the PORTEC-3 high risk cohort and all risk levels in RWD despite absolute RFS differences likely due to differences in baseline characteristics and outcome assessments. The consistent poor prognosis of p53abn patients, good prognosis of POLEm albeit with limited power, and moderate prognosis of NSMP and dMMR patients in RWD support use of these markers to inform treatment decisions across disease risk levels in an early EC setting.

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