Project Summary Highly effective breast cancer therapies, including anthracyclines and HER2+ targeted therapies are used widely and have led to important oncologic survival gains. However, these agents --- doxorubicin, trastuzumab (Herceptin®), and pertuzumab (Perjeta®) --- carry an established short-term cardiotoxicity (CTX) risk, within 1- 2 years after initiation of cancer therapy. Doxorubicin-induced CTX, defined primarily by left ventricular ejection fraction (LVEF) declines, cardiomyopathy, and heart failure (HF), occurs in 10-15% of patients at dosages of 240mg/m2. HER2+ targeted therapies such as trastuzumab and pertuzumab result in LVEF declines in 9-18% of treated patients. Doxorubicin and HER2+ targeted therapies in combination are associated with LVEF declines in up to 33% of individuals, and severe, symptomatic HF in 2-4%. The development of CTX in the short term results in dose interruptions, treatment delays, and worse oncologic outcomes. However, the long-term consequences of these therapies are poorly understood, as prior studies report inconsistent findings and are limited by external validity. Our application, directly responsive to NIH PA 19-111, comprehensively defines the incidence and severity of cancer-treatment related CTX in the long-term, with a focus on late effects. In this R21, we leverage the existent infrastructure within the prospective, longitudinal Penn CCT cohort study (R01 HL 118018, 2014-2020), which enrolled 611 breast cancer patients. We will define the effects of anthracyclines and/or HER2+ targeted cancer therapies in the long-term, over a maximum follow-up time of 10 years, through a detailed and comprehensive evaluation of the trajectories of cardiac remodeling and function. We focus specifically on late cardiac dysfunction, defined as the incidence at ≥5 years’ of followup in the 318 CCT participants with ≥5 years’ of followup. We also focus on cardiac recovery, defined as: 1) partial (LVEF increase >5% absolute points and >50%) or 2) full (LVEF increase to >55%). In Aim 1, we will comprehensively determine the late changes in cardiac remodeling and function in women with breast cancer receiving anthracyclines and/or HER2+ targeted therapy. In Aim 2, we will determine the clinical predictors of late LVEF declines and recovery. In Aim 3, we will determine the echocardiographic predictors of late LVEF declines and recovery. By addressing each of these Specific Aims, we will provide insight into the development of effective cardiac function monitoring and treatment strategies in this high CV risk population. Breast cancer therapy CTX is a significant problem, and decreasing this public health burden is a high priority in both cardiology and oncology. In this R21, we will build upon the early insights and unique resources of R01 HL118018 to gain new knowledge into late CV effects.