HORMONAL BIOMARKERS AND MOLECULAR SUBGROUPS IN EC 149 6 profiling, perhaps as an result of using older archival tumor samples for DNA testing. Fourth, race or ethnicity has not been reported in our study. Although we fully agree that these patients’ information might be impact outcome in several diseases28, within Europe it is not routinely documented in patient files.29 Fifth, using patients between 1994-2019 could have biased the survival because of different treatment strategies over the time. However, the death caused by EC has not been reduced or increased over the 25 years in our study cohort (data not shown), therefore we believed this has not biased our results. Finally, according to the ProMiSe criteria the order of molecular subgroup allocation within the Vancouver cohort is different compare to the original TCGA cohort, in which MMRd testing is followed by POLE testing.11, 13 The distribution of MMRd that also include POLEmut varies, patients with POLEmut and MMRd have comparable prognosis to POLEmut.30 Therefore a different allocating order could bias the outcome. However, in the original ProMiSe cohort, no MMRd patients are present with also POLEmut. Within the cohorts from the ENITEC centers the order of molecular testing was in line with the original TCGA cohort.10, 11, 18, 19 This study demonstrates the prognostic importance of ER and PR biomarkers within the era of molecular profiling. Future prospective studies need to focus on response to hormonal treatment within the molecular subgroups. Currently, an international randomized control trial has been started to refine the adjuvant treatment in endometrial cancer based on molecular features (RAINBO trial), in which one arm includes patients with NSMP EC (ClinicalTrials.gov Identifier: NCT05255653). Patients with ER positive expression will receive RT and hormonal treatment. However, only the presence of ER expression is part of the inclusion criteria, and the cutoff for positivity is not specified. Furthermore, in order to increase response to hormonal treatment, a different cutoff for ER and PR might be indicated as suggested by a recent paper in which a cutoff of 50% was suggested.31 CONCLUSION Our study demonstrated the prognostic relevance of ER and PR expression within the molecular subgroups of patients with EC and that the use of a three-tiered risk classification refines prognostication. These data support incorporating routine evaluation of ER/PR expression in clinical practice.
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