HORMONAL BIOMARKERS AND MOLECULAR SUBGROUPS IN EC 147 6 and within POLEmut, MMRd and NSMP subgroup, the patients grouped as ‘discordant’, showed comparable outcomes as patients with ER+PR 20-80% expression, Within p53mut EC the outcome was in line with the outcome of ER+PR 0-10% expression. (Supplementary Figure S2A-E). Across all molecular subgroups and ER+PR risk groups, ER+PR 0-10%, p53mut, lymphovascular space invasion (LVSI) and FIGO stage III/IV remained independent prognostic factors for reduced DSS. ER+PR 90-100% and POLEmut were independent prognostic factors for improved DSS (Supplementary Table S2). DISCUSSION In this large retrospective multicenter cohort study we confirmed the relevance of using a three-tiered ER/PR risk classification that refined the prognostic relevance across the molecular subgroups. Among all molecular subgroups, patients with ER/PR 90-100% expression revealed the best 5-year DSS. Interestingly, patients with PR 90-100% and with p53mut EC revealed an excellent 5-year DSS. In multivariable analyses, PR 0-10% was an independent prognostic factor for reduced DSS and PR 90-100% an independent prognostic factor for improved DSS. Combining ER+PR, 0-10% ER+PR expression was an independent prognostic factor for reduced DSS, while ER+PR 90-100% for improved DSS. In EC, numerous studies have already shown the importance of ER and PR expression in relation to predicting LNM and outcome, regardless of risk class.5-7, 14, 25 However, no uniform cutoff is applied within EC. In an earlier study, we defined a three-tiered risk classification for ER/PR expression to improve prognostication specifically in patients with EC.10 The current study confirmed the additional value of using this three-tiered risk classification when compared to the commonly used cutoff of 1% or 10%. The relevance of ER/PR expression within all molecular subgroups was not fully elucidated until this study. Comparable to our data, early studies observed higher PR expression within the NSMP subgroup and low PR expression in p53mut tumors.11, 17 In addition, our study shows the relevance of hormonal biomarkers within the MMRd, p53mut and NSMP subgroups. Vermij et al. confirmed the significance of ER status within the NSMP high-risk EC. Comparable to our study, patients with ER expression <10% showed the worst outcome compared to ER >10%. Contrary to our findings, they found no prognostic impact of ER in the other molecular subgroups (especially MMRd) which might be explained by their cut-off of 1-10%.15 Jamieson et al. used ER and tumor grade to subclassify the NSMP subgroup. Low-risk NSMP was identified as low-grade EC and ER >1% with favorable outcome, and
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