HORMONAL BIOMARKERS AND MOLECULAR SUBGROUPS IN EC 137 6 INTRODUCTION Historically, endometrial cancer (EC) was divided into two histopathological subtypes.1 Type 1 EC includes low-grade (grade 1 and 2) endometrioid EC (EEC), represents the majority (80%) of patients, and is associated with obesity and good prognosis. Type 1 EC is considered to be hormone driven with high expression of estrogen (ER) and progesterone receptors (PR).2 Type 2 EC represents high-grade tumors (grade 3 EEC and non-endometrioid EC (NEEC)), generally have low ER expression and an unfavorable prognosis.1, 3 Despite the overall good prognosis of type 1 EC, mortality in absolute numbers is higher in type 1 compared to type 2 EC.4 Hormone receptor expression (ER/PR) are prognostic biomarkers that predict lymph node metastasis (LNM) and outcome.5-7 The current used cutoff for ER/PR expression within EC is adopted from breast cancer studies, and most frequently considered positive if >1% or >10% expression.8, 9 In an earlier study we evaluated different cutoff values for ER/PR expression using the subgroups 0-10% with unfavorable outcome, 20-80% with intermediate outcome and 90-100% with favorable outcome. This revised three-tiered risk classification model was shown to improve prognostication over the mostly used cutoff of 10%.10 The Cancer Genome Atlas (TCGA) classified patients with EC into four important prognostic subgroups based on their genomic molecular signature: I) ultramutated tumors with polymerase epsilon (POLE) mutations, II) hypermutated tumors with microsatellite instability (MSI) , III) copy-number-high (CNH) tumors with frequent tumor protein (TP53) mutations, IV) copy-number-low (CNL) tumors (also known as no-specific molecular profile (NSMP)).11 The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) is a surrogate diagnostic algorithm using low cost clinically applicable immunohistochemistry (IHC); mismatch repair deficient (MMRd) instead of MSI and p53 instead of TP53.12, 13 The histopathological subtypes (type 1 and 2) are present within all molecular subgroups. Type 1 (EEC histology) is mainly represented by the POLEmut, MMRd and NSMP subgroup, with positive ER/PR expression. Type 2 (NEEC histology) is mainly represented by the p53mut subgroup, with generally negative ER/PR expression.11 In this era of molecular profiling, the relevance of hormonal biomarkers needs to be redefined. Earlier study demonstrated that ER status was still important for the outcome of EC patients regardless of risk class and p53 or MMR status.14 Within the NSMP subgroup loss of ER and/ or PR expression (<1% and <10%) was shown to be an important prognosticators for EC, but this was not found in the other molecular subgroups.15-17 So far, it has not been investigated whether the previously mentioned three-tiered ER/PR risk model10, has prognostic impact in the different molecular subgroups. Therefore, we studied the prognostic relevance of the
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