Rationale and design of the: breast cancer, fitness and exercise for heart health (BE-FITTER trial)

As breast cancer (BC) survivorship improves, cardiovascular disease (CVD), has become the leading cause of non-cancer death in older survivors. This risk is driven by cardiotoxic treatments, underlying CVD risk factors, and sedentary deconditioning. Despite the established benefits of exercise training, older, long-term BC survivors—the population at greatest CVD risk—remain underrepresented in research. This randomized controlled trial will enroll 60 female BC survivors (aged ≥ 60 years, ≥ 1-year post-cardiotoxic therapy), randomizing them to 12 weeks combined aerobic and resistance training ( n = 30) or a stretching and yoga control ( n = 30). Comprehensive assessments at baseline and 12 weeks include cardiopulmonary (VO 2 peak) exercise testing, magnetic resonance imaging to measure whole-body VO₂ and its Fick determinants, and maximal plantar flexion exercise to measure lower leg blood flow, oxygen extraction, VO 2 , and mitochondrial oxidative capacity. We will also measure calf muscle composition, aerobic endurance (6-minute walk), physical function (SPPB), Framingham CVD risk score, and quality of life (FACT-B). The primary outcome is exercise arterio-venous oxygen difference. Analyses will follow intention-to-treat principles; the primary comparison will use ANCOVA adjusting for baseline outcome and stratification factors, with sensitivity analyses including per-protocol and multiple imputation for missing data. Adherence will be tracked via session attendance and trainer logs. The trial was registered with prior to enrollment and approved by the University of Alberta institutional review board. This is the first randomized controlled trial to investigate if a structured exercise program can improve whole-body and peripheral determinants of VO 2 peak, enhance skeletal muscle composition, and improve physical function and quality of life and reduce CVD risk in older, long-term BC, a high-risk and understudied population. NCT06595147