ABSTRACT Currently, there are 3.5 million breast cancer survivors in the United States and this number is expected to increase dramatically. Early stage breast cancer survivors are more likely to die of cardiovascular disease (CVD) than breast cancer. Exposure to chemotherapy may exacerbate existing CVD risk factors or may lead to acute and long-term cardiovascular toxicity. Studies on the cardiovascular impact of chemotherapy have typically focused on acute cardiotoxic effects. However, the vascular impact of chemotherapy, which may have longer term consequences, is not well characterized. Recently, there is increasing evidence that chemotherapy may cause endothelial dysfunction, a key early event in CVD development which leads to loss of atheroprotection and independently predicts CVD events and progression. Therefore, strategies to prevent CVD in breast cancer patients undergoing chemotherapy are clinically important. Aerobic exercise is considered safe during breast cancer chemotherapy and may be an effective strategy for guarding against cardiovascular toxicity but there are limited data in humans and no randomized controlled trials. Acute chemotherapy-induced side effects (e.g., fatigue, muscle weakness, balance problems, increased risk of falls) present unique challenges that may influence the feasibility and tolerability of exercise, and in turn its efficacy. We have recently developed an all- extremity non-weight-bearing exercise (ANE) intervention which is a promising novel and innovative exercise approach for breast cancer patients during chemotherapy and may be superior to other widely recommended forms of exercise. Our central hypothesis is that ANE will be feasible and will lead to greater cardiovascular protection during breast cancer chemotherapy and will be better tolerated than walking. The aims of this exploratory/developmental R21 application are to investigate in patients with primary non-metastatic breast cancer who are undergoing chemotherapy: 1) the effect of ANE, treadmill exercise (TE) and usual care (UC) on endothelial and cardiac function; and 2) the feasibility, tolerability and safety of ANE compared with TE. Breast cancer patients will be randomly assigned to receive 12 weeks of supervised ANE, TE or UC during chemotherapy. Exercise training will be supervised, and exercise prescription will be personalized to their initial fitness level and will gradually progress to 70% of peak heart rate, 50 min/session, 3 days/week. The primary focus will be on endothelial function assessed by brachial artery flow-mediated dilation via high-resolution ultrasonography and global longitudinal strain assessed by speckle tracking echocardiography. Cardiovascular assessments and other study measures will be completed before initiation of chemotherapy and after the intervention. Feasibility, tolerability, and safety will be monitored throughout the intervention. This exploratory/developmental R21 will provide early evidence on whether...