Project Summary Our overarching goal is to identify and characterize cancer patients at risk of developing cancer treatment- related cardiotoxicity and to mitigate cardiovascular dysfunction while optimizing cancer outcomes. Advances in early detection and treatment of cancer has improved 5-year survival. However, multi-modal cancer treatment often leads to cardiotoxicity. Cardiovascular disease (CVD) events during treatment can interfere with its delivery and thus lead to sub-optimal cancer outcomes and increased downstream morbidity, cost, and mortality. American Heart Association (2019) guidelines recommend primary prevention with anti- hyperlipidemic and anti-hypertensive medication in high-risk individuals, based on atherosclerotic cardiovascular disease (ASCVD) risk. However, it’s uncertain if primary prevention in cancer patients improves long-term CVD outcomes. American Society of Clinical Oncology (ASCO) (2017) guidelines has categorized high-dose anthracyclines, targeted therapy, and certain combinations of these, as cardiotoxic regimens. The impact of primary prevention in patients on such cardiotoxic regimens is unknown. To evaluate these questions, we will create a unique dataset by merging Kaiser Permanente (KP)’s electronic medical records with KP’s SEER cancer registry, KP’s medical financial assistance program, and Social Security Administration’s supplemental income, disability, and mortality data, in a cohort of 17,000+ breast cancer patients followed longitudinally for 5+years. We will risk stratify breast cancer patients on ASCVD risk and evaluate the effect of primary prevention using advanced causal inference models exploring treatment effect heterogeneity from policy and decision-making perspectives. The study aims are Aim 1: Compare effectiveness of primary prevention pharmacological therapy on 1) cancer and CVD outcomes during chemotherapy and 2) cancer and CVD outcomes post- chemotherapy in adults with breast cancer. Aim 2: Evaluate the impact of primary prevention pharmacological therapy on financial toxicity and disability in adults with breast cancer. Aim 3: Evaluate the incremental medical expenditure and cost-effectiveness of primary prevention pharmacological therapy in adults with breast cancer using a net-benefit regression framework. Completion of this proposal will answer crucial questions to improve patient outcomes (1) Does primary prevention prevent future CVD events, improve/optimize cancer treatment and outcomes, reduce financial toxicity, disability, and cost? (2) How many patients need to be treated to avoid one adverse cardiovascular or cancer outcome? (2) What are the long-term effects of primary prevention? (3) Is primary prevention cost-effective or should society invest its resources elsewhere?