CHAPTER 3 50 ABSTRACT Importance Patients with low-grade (grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis when compared to high-grade (grade 3) EC patients. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, it could be questioned whether molecular profiling is valuable in these patients. Objective To determine the prognostic relevance of molecular profiling within low-grade EC patients. Design In this cohort study, patients were diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9-years. Molecular subgroups were determined by next generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, cases were classified as: polymerase epsilon (POLE)-mutant, microsatellite instable (MSI), tumor protein 53 (TP53)-mutant and no-specific molecular profile (NSMP). Setting Retrospective multicenter international study. Participants Patients diagnosed with all histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC. Patients with early-stage EC (FIGO I-II) were only included with known lymph node status. Exposure Molecular testing of the four molecular subgroups. Main outcome and measure Disease-specific survival (DSS) within the molecular subgroups. Results A total of 393 European EC patients were included with a median age of 64.0 (31.0-86.0) years and median BMI 29.1 (18.0-58.3) kg/m2. Most patients presented with early-stage EC (73.8%), and low-grade EC (53.2%). Of all patients, 8.4% was classified as POLE-mutant, 19.8% as MSI, 18.3% as TP53-mutant and 53.4% as NSMP. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared to high-grade EC, varying between 90-100% vs. 41-90% (P<.001), respectively. Multivariable analysis in the entire
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