Background: Modern treatment for breast cancer (BC) has led to improved survival; however, this improvement can be offset by an increase in cancer therapy-related morbidity and mortality. Over one-third of early stage BC patients treated with cancer therapy experience CV injury, left ventricular (LV) dysfunction, exercise intolerance, or fatigue. CV disease is a leading cause of mortality in BC survivors. There is limited information on the time course and long-term CV health of BC survivors. UPBEAT, a multicenter study, will prospectively evaluate CV risk factors and outcomes in early stage BC patients,treated with modern cancer therapies. This will facilitate evaluation of primary CV prevention strategies in this patient population. Methods: This is a prospective cohort study of 840 patients with early stage (I-III) BC treated with chemotherapy +/- radiation and 160 controls. Baseline and serial longitudinal measures will examine the influence of cancer treatment on CV function, exercise capacity and fatigue, and future development of CV events. The comprehensive assessment of factors includes ascertainment of cardiac biomarkers, CV risk factors, comorbidities, functional status (e.g., disability measures, Expanded SPPB), neurocognitive tests, behavioral risk factors, socio-demographics, and quality of life at baseline, 3-, 12-, and 24-mos. Outcomes measured at the same time points, include a deep phenotyping of CV dysfunction (via cardiac MRI assessing LV end diastolic volume, LV end systolic volume, LV ejection fraction, myocardial strain, strain rate, left atrial volumes and mass, and aortic stiffness), exercise intolerance (submaximal as 6-minute walk test and maximal as VO₂peak via cardiopulmonary exercise test), fatigue (via FACT-F). Eligibility criteria are: age >18 years; ECOG 0-2, able to walk without symptoms; and for BC patients, treatment with chemotherapy. 143 participants are accrued and currently enrolling through ECOG and NCORP sites. Participants will be followed for 9 years with active surveillance of CV events, i.e., heart failure, myocardial infarction, stroke, all-cause and CV death. Clinical trial information: NCT02791581