PROJECT SUMMARY Aging is a major risk factor for breast cancer and 80% of breast cancer cases are diagnosed after age 50. Currently in the US, there are more than 3.8 million breast cancer survivors, and this number is expected to increase dramatically due to the aging of the population. Chemotherapy is a highly effective treatment for breast cancer but is associated with acute and long-term cardiovascular toxicity that may accelerate cardiovascular aging, thus setting the stage for premature development of cardiovascular disease (CVD). Aerobic exercise is recommended for CVD prevention, however, evidence on the optimal exercise prescription in breast cancer survivors is limited. Breast cancer survivors often suffer from long-lasting cancer therapy-related side effects (e.g., physical dysfunction, severe fatigue, muscle weakness, peripheral neuropathy, and balance impairments) that may be compounded by age-related frailty and mobility issues (50% of breast cancer survivors are older than age 60). These unique challenges may limit exercise feasibility, adherence, and in turn efficacy. High- intensity interval training (HIIT) is attracting increasing attention as a time-efficient and potentially superior aerobic exercise strategy for CVD prevention compared to moderate-intensity continuous training (MICT) in clinical populations. We have recently adapted HIIT and MICT on an all-extremity non-weight-bearing exercise (ANE) ergometer that eliminates balance concerns and distributes work between the upper and lower extremities, compensating for weakness and fatigue. Our HIIT-ANE and MICT-ANE regimens are novel and innovative exercise interventions for breast cancer survivors. Our central hypothesis is that HIIT-ANE will result in greater and more durable improvements in endothelial and cardiac function compared with MICT-ANE and usual care (UC) in breast cancer survivors who have recently completed chemotherapy. The aims of this application are to conduct a randomized controlled trial to investigate: 1) the short-term and prolonged effects of HIIT-ANE, MICT-ANE and UC on endothelial and cardiac function; and 2) the durability of the endothelial and cardiac effects of HIIT-ANE vs. MICT-ANE. Women, 50 years of age and older, who have completed chemotherapy within the past 6 months for primary, invasive, non-metastatic, stage I-III breast cancer will be randomized to 1 of 3 groups: HIIT-ANE, MICT-ANE or UC. Exercise training will be performed 3 days/week over 12 weeks under supervision. The primary focus will be on endothelial and cardiac function assessed by flow- mediated dilation and global longitudinal strain, respectively. Assessments will be performed at baseline, after the 12-week exercise intervention and after a 12-week observation period. To gain mechanistic insight, we will investigate circulating blood biomarkers and key biomarkers in endothelial cells harvested using a state-of-the- art endovascular technique. This exploratory/developmental R21 will provide early evidence on whether our promising HIIT-ANE is more effective in mitigating CVD risk than MICT-ANE and UC following breast cancer chemotherapy. Our findings will lay the foundation for designing a rigorous full-scale clinical trial.

NARRATIVE Aging is a major risk factor for breast cancer and due to the aging of the U.S. population, the number of breast cancer survivors is expected to increase dramatically. Chemotherapy is a highly effective treatment for breast cancer but is associated with cardiovascular toxicity which may accelerate cardiovascular aging setting the stage for premature cardiovascular disease. The proposed research aims to build the evidence base for optimizing exercise prescription for cardiovascular disease prevention in breast cancer survivors by investigating two novel and innovative exercise regimens.