Abstract Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) therapy to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in the non-cancer population is associated with CV disease, including atherosclerosis and coronary artery disease, which can be detected pre-clinically by myocardial perfusion imaging and coronary artery plaques. This, together with the CV morbidity associated with other aspects of BC treatment and future life-years of these women, warrants further investigation with the goal of identifying pre-clinical markers of myocardial compromise. We seek to do this with the following specific aims: 1. Characterize and quantify the extent of coronary microvascular injury and perfusion changes experienced during early NCED therapy. 2. Characterize and quantify the extent of structural and functional alterations to the aorta and left ventricle while on NCED therapy. 3. Identify potential biomarkers and additional risk factors for CV morbidity in patients receiving NCEDTrial Design: This is a federally funded (NHLBI) prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary outcome is myocardial perfusion reserve (MPR) as measured by CMR imaging stress studies. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors, including an emphasis on racial disparities, on study outcomes, and dynamic change in modifiable and treatment related risk factors. Statistical Methods: We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group) for Aims 1 and 2. Comparisons will be made using longitudinal mixed models to examine effects on outcomes measured. The second analyses, for Aim 3, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with MPR. The sample size allows 80% power to address specific aims for between and within group comparisons, including a between group difference of 2.8% in our primary outcome, MPR. Present Accrual: 0 Target Accrual: 90 Contact information: Emily Douglas, MD; edouglas@wakehealth.edu Table 1: Study Procedures Citation Format: Emily Douglas, Nathaniel O’Connell, Mary Hackney, Wendy Bottinor, John Grizzard, Igor Klem, Carolyn Park, Sujethra Vasu, Karl Richardson, Susan Dent, Ralph D’Agostino, Gregory Hundley, Jennifer Jordan, Alexandra Thomas. The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-05.