CHAPTER 6 148 high-risk NSMP as high-grade EC and ER <1% expression with unfavorable outcome.16 Which confirms the relevance of ER within the NSMP subgroup. Our study revealed also the additional relevance of PR expression within the NSMP and p53mut subgroup, contrary to the other studies which might again by explained by the use of a three-tiered risk classification.15 Interestingly, patients with p53mut EC and PR 90-100% expression showed an excellent 5-year DSS of 100%, since all these patients had EEC histology, the importance of both morphology and IHC in addition to molecular subgroups within EC is illustrated. Patients within p53mut or NSMP EC and PR 0-10% show the worst outcome. Early studies indicated that PR <10% expression was predominantly present in the ‘advanced/metastatic’ ESGO risk group and predicting disease recurrence in patients and increased risk of death. This is in line with our findings in multivariable regression analysis, were PR expression 0-10% is more correlated with decreased DSS compared to ER expression 0-10%. Due to the used cutoffs for ER and PR of 1% or 10% the prognostic relevance within the molecular subgroups might have been underestimated when compared with the three-tiered ER/PR risk classification in our study.15, 17 In clinical practice generally both ER and PR IHC expression are determined, therefore, understanding the prognostic relevance of both ER/PR expression within the molecular subgroups is interesting. Early studies indicated that both ER/PR provide additional prognostic information, comparable with our study.5, 7, 10, 17 Combining ER+PR shows ER+PR 0-10% as an independent prognostic marker for reduced DSS and ER+PR 90-100% as an independent prognostic marker for improved DSS. Combining ER+PR expression within the three-tiered risk classification will create a remaining subgroup, in this paper classified as discordant. For clinical practice, when the ER+PR subgroup is discordant in patients with POLEmut, MMRd or NSMP EC, the prognosis is in line with an intermediate prognosis. Within p53mut, the prognosis is in line with decreased prognosis (comparable to high risk 0-10% expression). The strengths of this retrospective study are the large number of included cases from multiple centers, including ER and PR immunohistochemistry and representing all tumor grades and FIGO stages. Second, by including ER/PR expression both and combined these results are highly relevant for clinical practice Furthermore, this is the first study to analyze a three-tried ER/PR risk classification within all molecular subgroups. Some limitations need to be addressed. First, the mortality rate of POLEmut patients is low, possibly hampering interpretation on the impact of ER/PR expression within this specific subgroup. Second, technical allocation of the molecular subgroups differed slightly. However, either full NGS or use of ProMiSe criteria (combination of NGS and IHC) are repeatedly validated as comparable techniques and representative for the daily practice in Europe and Canada.26, 27 Third, a relative amount of patients were excluded due to unsuccessful molecular
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