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Introduction: Immunohistochemical expression (IHC) of estrogen receptor (ER) and progesterone receptor (PR) are biomarkers for prognosis and response to hormonal therapy in endometrial cancer (EC). However, the presence of ER/PR is not inherently reflective of estrogen driven tumor growth. Previously, ER pathway activity score (ERPAS), a test to asses ER pathway, was shown to reflect estrogen driven tumor growth and to have additional prognostic and predictive value over ER and PR-IHC. Within the four molecular subgroups of EC, ER and PR-IHC are present in all subgroups. Yet, the relation of ERPAS with molecular subgroups is unclear. In this study we aim to identify estrogen driven tumor growth by application of ERPAS in the molecular subgroups. Methods: ER and PR-IHC expression, ERPAS testing and molecular analysis was available in 72 endometrial cancer cases. ER and PR-IHC expression was analyzed from formalin-fixed paraffin-embedded (FFPE) tumor sections using standard procedures. A cut-off value of 10% was defined as positive. ERPAS was performed using RT-qPCR analysis of the most relevant ER-related genes (www.philips.com/oncosignal). A Bayesian computational model was used to infer ERPAS that were normalized on a scale from 0 to 100. The cut-off value for an active ER pathway was 29.7, as previously defined. Molecular analysis was performed using Next Generation Sequencing with single-molecule Molecular Inversion Probes (smMIPs). Accordingly patients were grouped in the POLE-mutant, MSI high, TP53-mutant or no specific molecular profile, NSMP group. Results: The TP53-mutant-group had a worse outcome compared to other groups. ER pathway was active in 75% of POLE-mutant, 83.3% of MSI-high, 87.5% of NSMP and 38.9% of TP53-mutant cases. Similarly, PR-IHC expression was present in 100% of POLE-mutant, 72.2% of MSI-high, 81.3% of NSMP and 27.8% of TP53-mutant cases. The mean ERPAS was significantly higher in MSI-high and NSMP groups compared to the TP53-mutant group. Within the NSMP subgroup, an active ER pathway was significantly associated with improved disease-free survival and disease-specific survival in Kaplan-Meier analysis. Analysis in other subgroups was not possible due to limited number of cases. Conclusions: The majority of POLE-mutant, MSI-high and NSMP tumors showed an active ER pathway, indicating relevance of estrogen driven tumor growth in these groups. In the NSMP subgroup, ERPAS can be used to stratify patients for prognosis. Whether ER pathway is prognostic in the MSI-high and TP53-mutant subgroups needs to be evaluated in larger cohorts. If hormonal therapy is applied, we suggest to tailor it to patient with an active ER pathway. Citation Format: Willem Jan van Weelden, Stephanie Vrede, Louis van der Putten, Hans Bulten, Marc Snijders, Sanne Sweegers, Andrea Romano, Astrid Eijkelenboom, Anja van de Stolpe, Johanna Pijnenborg. The relevance of estrogen driven tumor growth within the molecular subgroups of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1962.