OBJECTIVE: The prognostic relevance of hormonal biomarkers in endometrial cancer (EC) has been well-established. A refined three-tiered risk model for estrogen receptor (ER)/progesterone receptor (PR) expression was shown to improve prognostication. This has not been evaluated in relation to the molecular subgroups. This study aimed to evaluate the ER/PR expression within the molecular subgroups in EC. METHODS: A retrospective multicenter cohort study was performed and data from the European Network for Individualized Treatment centers and Vancouver, Canada were used. ER/PR immunohistochemical expression was grouped as: ER/PR 0-10 %, 20-80 % or 90-100 %. Molecular subgroups were determined with full next-generation sequencing or combined with immunohistochemistry: POLEmut, mismatch repair deficient (MMRd), p53mut and no-specific molecular profile (NSMP). RESULTS: A total of 739 patients were included (median follow-up 5.0 years). Tumors were classified as POLEmut in 9.1 %(N = 67), MMRd in 27.6 %(N = 204), p53mut in 20.8 %(N = 154) and NSMP in 42.5 %(N = 314). Among all molecular subgroups, patients with ER/PR 90-100 % expression revealed the best disease-specific survival (DSS). Within p53mut, PR 90-100 % expression showed a 5-year DSS of 100.0 %. ER expression is prognostic more relevant in MMRd and NSMP tumors while PR expression in p53mut and NSMP tumors. Across all molecular subgroups, PR 0-10 %, p53mut, lympho-vascular space invasion and FIGO stage III-IV remained independently prognostic for reduced DSS Whereas PR 90-100 % and POLEmut remained independently prognostic for improved DSS. CONCLUSION: We demonstrated that ER/PR expression remain prognostically relevant within the molecular subgroups, and that a three-tiered cutoff refines prognostication. These data support incorporating routine evaluation of ER/PR expression in clinical practice.

Angelo Nocivelli' Institute of Molecular Medicine Division of Obstetrics and Gynecology ASST Spedali Civili di Brescia University of Brescia Brescia Italy

Biomedical Research Group in Gynecology Vall Hebron Institute of Research Universitat Autònoma de Barcelona CIBERONC Barcelona Spain

Department of Gynecology and Obstetrics Division of Gynecologic Oncology University of British Columbia Vancouver Canada

Department of Health Evidence Radboud university medical center Nijmegen the Netherlands

Department of Obstetrics and Gynecology and GROW School for Oncology and Developmental Biology Maastricht University Medical Center Maastricht the Netherlands; Department of Obstetrics and Gynecology Radboud University Medical Center Nijmegen the Netherlands

Department of Obstetrics and Gynecology Canisius Wilhelmina Hospital Nijmegen the Netherlands

Department of Obstetrics and Gynecology Medical Center University of Freiburg Freiburg Germany

Department of Obstetrics and Gynecology Radboud University Medical Center Nijmegen the Netherlands

Department of Obstetrics and Gynecology Radboud University Medical Center Nijmegen the Netherlands; Department of Obstetrics and Gynecology Canisius Wilhelmina Hospital Nijmegen the Netherlands

Department of Obstetrics and Gynecology University Hospital Brno and Masaryk University Brno Czech Republic

Department of Pathology and Laboratory Medicine University of British Columbia and BC Cancer Agency Vancouver Canada

Department of Pathology and Molecular Genetics and Research Laboratory Hospital Universitari Arnau de Vilanova University of Lleida IRBLleida CIBERONC Lleida Spain

Department of Pathology Canisius Wilhelmina Hospital Nijmegen the Netherlands

Department of Pathology Radboud university Medical Center Nijmegen the Netherlands

Department of Pathology University Hospital in Brno and Masaryk University Brno Czech Republic

Department of Pathology University of Turku Turku Finland

Department of Radiation Oncology Radboud University Medical Center Nijmegen the Netherlands

Gynecological Department Vall Hebron University Hospital CIBERONC Barcelona Spain; Biomedical Research Group in Gynecology Vall Hebron Institute of Research Universitat Autònoma de Barcelona CIBERONC Barcelona Spain

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