Background: Among patients with breast cancer undergoing radiation therapy (RT), post-treatment cardiovascular disease and worsened quality of life (QOL) are leading causes of morbidity and mortality. To overcome these negative RT effects, this prospective, randomized clinical trial pilots a 12-week Stay on Track exercise and diet intervention for overweight patients with non-metastatic breast cancer undergoing whole-breast RT. Methods: The intervention group (n=22) participated in three personal exercise and dietary counseling sessions, and received three text reminders/week to adhere to recommendations. The control group (n=22) was administered a diet/exercise information binder. All patients received a Fitbit, and at baseline, 3, and 6 months, measurements of biomarkers, dual-energy X-ray absorptiometry scans, quality of life and physical activity surveys, and food frequency questionnaires were obtained. A satisfaction survey was administered at three months. Results: Stay on Track was well received, with high rates of adherence and satisfaction. The intervention group showed an increase in self-reported physical activity and preserved QOL, a decrease in BMI and visceral fat, and higher ACS/AICR dietary adherence. The control participants had reduced QOL, anti-inflammatory markers, and increased metabolic syndrome markers. Both groups had decreased overall body mass. These changes were within group effects. When comparing the intervention and control groups over time, there were notable improvements in dietary adherence in the intervention group. Conclusions: Targeted lifestyle interventions during RT are feasible and could decrease cardiovascular comorbidities in patients with breast cancer. Larger-scale implementation with longer follow-up can better determine interventions that influence cardiometabolic health and QOL.

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