Abstract Background:. Up to 75% of breast cancer patients have tumors expressing the predictive biomarker estrogen receptor alpha (ER) and are consequently offered endocrine therapy. Approximately one third eventually relapse in their disease with the majority still expressing ER but resistant to one or several types of endocrine-based therapies. Molecular studies of ER-signaling suggest several potential factors influencing endocrine response such as ER structural and functional domains, posttranslational modifications and unbalanced receptor and co-regulator activity with alterations in downstream signaling pathways. However, the mechanism behind endocrine resistance is elusive and tumor cell expression of ER is the only clinically utilized biomarker for endocrine therapeutic response. This calls for a broader understanding of the resistance process in order to develop novel tools for therapy prediction and treatment alternatives. This study aims to improve our understanding of the underlying mechanism behind endocrine resistance and to identify biomarkers for an individualized approach to cancer therapy. Materials and methods:. A cohort comprising verified endocrine-resistant early breast cancer diagnosed in 2005-2006 and 2008-2014 at the Karolinska University Hospital, Stockholm, Sweden was retrospectively collected. Patients with ER+ and human epidermal growth factor receptor 2 (HER2)- primary breast cancer who had an ER+/HER2- relapse tumor during ongoing endocrine therapy (<5 years from diagnosis) were included as cases, with both primary tumors (n=68) and relapse tumors (n=67). A control cohort was selected consisting of patients with ER+/HER2- early breast cancer diagnosed in 2005, without relapse or disease progression at 10 years of follow-up (n=78), and matched to cases (2:1 ratio) by age and tumor stage. To determine the transcriptomic and genomic profiles, RNA and DNA were extracted from archived formalin-fixed paraffin-embedded tumor tissue. RNA samples were analyzed using Affymetrix DNA Microarray with Clariom D Chip and assessed through Transcriptome Array Console and R. DNA was analyzed through panel sequencing (GMCK gene panel consisting of 370 genes and a size of 2,4 Mb intended for genetic screening of solid tumors) with following assessments in R. Results:. The preliminary transcriptomic analysis showed several differentially expressed pathways and specific genes that differentiate both the primary tumors of cases that eventually relapse during endocrine therapy compared to controls, as well as between the cases’ relapses and their corresponding primary tumors. Intrinsic analyses show upregulation in tumor-driving pathways such as PI3K signaling pathway, androgen receptor and cell adhesion pathways in primary tumors of cases versus controls. This has further been investigated by gene analysis where genes such as PIK3CA, PTEN, CDK4/6 and ESR1 were upregulated between the groups. In the analysis of relapses compared to their primary tumors, pathways involving apoptosis and response to hypoxia were downregulated as well as specific genes such as IGF1R, whereas pathways including immune response were upregulated. Conclusion:. Our study suggests that endocrine resistant tumors are associated with distinct genomic and transcriptomic profiles that potentially could be utilized as predictive and prognostic markers for endocrine resistant breast cancer. These preliminary results can guide further investigations deciphering the mechanisms of endocrine resistance in breast cancer. This trial is a non-interventional study set up as a research collaboration between Karolinska Institutet and Novartis Sweden AB. Citation Format: Caroline Schagerholm, Stephanie Robertson, Barbro Holm, Karolina Lindberg, Emmanouil Sifakis, Linnea Hases, Cecilia Williams, Johan Hartman. Endoresist: Prognostic and predictive gene profiles in endocrine-resistant breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-07.