Abstract Radiation therapy (RT) is a highly effective and widely used treatment for breast cancer, the most common female cancer worldwide. However, RT carries a significant risk of cardiovascular (CV) toxicity, limiting important gains in cancer control and survival. There are a number of fundamental questions related to the CV effects of modern-day proton and photon RT. Do changes in CV biomarkers and imaging markers with RT support the hypothesis that proton therapy is less cardiotoxic than photon therapy? Which RT dose-volume parameters are most strongly associated with changes in these markers? Can we use biologic and imaging markers to identify high CV risk subgroups? In order to address these questions, we propose a time-sensitive biomarker and imaging ancillary study to the ongoing Radiotherapy Comparative Effectiveness (RadComp) pragmatic clinical trial of breast cancer patients randomized to proton versus photon therapy (PCORI PCS-1403-12804; NCT02603341). The overall objectives of our proposal are to determine how early, subclinical measures of CV injury and dysfunction as detected by imaging (Aim 1) and biologic (Aim 2) markers differ according to RT type (proton versus photon); and which RT cardiac dose-volume parameters are most strongly associated with changes in these markers (Aim 3). To accomplish these objectives, we will build a longitudinal prospective cohort study of 150 RadComp participants from the 3 highest enrolling sites: Memorial Sloan Kettering Cancer Center (MSKCC), the University of Pennsylvania (Penn), and Northwestern Memorial HealthCare (NW). Our proposal addresses a research priority within the NHLBI Strategic Vision, NCI Symptom Management and Quality of Life Steering Committee, and NCI Radiation Research Branch.