Back to the future: The impact of oestrogen receptor profile in the era of molecular endometrial cancer classification

Purpose: The aim of this study is to evaluate the impact of the oestrogen receptor (ER) profile on oncologic outcomes in the new endometrial cancer (EC) risk classification. Methods: Immunohistochemistry (IHC) analyses were performed in a retrospectively reviewed large series of ECs to assess the presence/absence of oestrogen receptors (ER0\1+ or ER2+\3+) and other molecular factors (i.e. p53 mutation, p53mut; and mismatch repair mutational status, MMRd (mismatch repair deficient) versus MMRp (mismatch repair proficient)), histopathologic and clinical outcomes. ER status was correlated with molecular, histologic, clinical and prognostic data. Results: 891 EC patients were included in the study (211 ER0\1+ and 680 ER2+\3+). The ER0\1+ phenotype was associated with an unfavourable clinicopathological profile (i.e. grading, histotype, lymphovascular space invasion (LVSI), stages, etc.). Simple regression showed that risk class, p53mut, and ER0/1+ impacted on both disease-free survival (DFS) and overall survival (OS) (p < 0.05). In the ER0/1+ population, p53mut no longer influenced DFS and OS (p > 0.05). In multiple regression, age, high and advanced/metastatic risk classes influenced survival outcomes (p < 0.05), but lost significance in the ER0/1+ population (p > 0.05). ER-positivity retained a remarkable prognostic impact even after stratification of the population according to the European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology, and the European Society of Pathology (ESGO/ESTRO/ESP) 2021 risk classes and molecular classification. ER0/1+ intermediate, high-intermediate, high and advanced risk versus ER2+/3+ intermediate, high-intermediate, high and advanced risk classes showed statistically different OS and DFS (p< 0.001). ER0/1+ status was associated with a worse prognosis when associated with MMRp, MMRd and p53mut compared to the same molecular classes associated with ER2+/3 (p < 0.001). Conclusions: We demonstrated that ER status has a significant impact on oncologic outcomes, regardless of risk class and p53/MMR status. Based on our results, we recommend the inclusion of ER assessment in featured EC risk classification system.