Abstract More than 40,000 women die each year of metastatic breast cancer. The majority of these tumors are hormone receptor positive (HR+) that are treated with a cyclin dependent kinase 4/6 (CDK4/6) inhibitor in combination with an aromatase inhibitor or fulvestrant. With these treatments, women with advanced breast cancer are living longer, but treatment related toxicities inevitably occur, and quality of life is limited by side effects of cancer treatment which may result in dose reductions and delays. Fatigue is the most commonly cited adverse side effect reported for women taking CDK4/6 inhibitors and mechanistically may be associated with inflammation. When unmanaged, fatigue is debilitating directly impacting both psychological and physical quality of life and a key driver in discontinuation of therapy. Lifestyle interventions targeting diet and exercise have evidence for improving fatigue in early stage breast cancer, however whether these strategies are efficacious for improving outcomes in women with advanced breast cancer remains unknown, with even less information for women from underrepresented backgrounds, who suffer disproportionately from breast cancer and its treatment. Research regarding the impact of these strategies on high grade fatigue induced by CDK4/6 inhibitors in advanced disease from a diverse patient population are needed. The prolonged overnight Fasting and/or Exercise on fatigue and other patient reported outcomes in women with hormone Receptor positive advanced breast cancer (FastER) study, will evaluate a phase II, 2 x 2 randomized controlled trial testing the effects of a prolonged overnight fasting (POF) intervention alone, moderate-intensity exercise alone, or in combination, on fatigue in 260 women with advanced breast cancer initiating treatment with hormonal therapy in combination with a CDK4/6 inhibitor. Participants would undergo assessment of fatigue and associated inflammatory biomarkers, as well as assessment of physical activity, diet, physical function, body composition and patient reported outcomes at baseline (prior to the initiation of CDK4/6 inhibitor) and 12 weeks (post-intervention), 6 and 12 months after study enrollment. The primary outcome of the study is to evaluate the impact of the interventions (vs control) on fatigue in women at 12 weeks. Secondary outcomes include inflammatory biomarkers, patient-reported outcomes, physical function and body composition. The FastER study will also explore the impact of the intervention on circadian rhythms, fatigue, sleep, depression, anxiety, quality of life, physical function and body composition. The overarching goal of the FastER study is to determine whether prolonged overnight fasting or moderate- intensity exercise alone or in combination can mitigate the adverse consequences of treatment and improve fatigue and other outcomes, in women with advanced breast cancer treated with CDK4/6 inhibitors to ultimately improve both quantity and quality of life for this growing population of women.

Project Narrative Women with advanced hormone receptor (HR)+ breast cancer being treated with endocrine therapy in combination with an inhibitor of cyclin dependent kinase 4/6 (CDK4/6) inhibitor are at risk for debilitating fatigue which can lead to poor quality of life and reductions or even discontinuation of the medication. Lifestyle interventions, particularly exercise and intermittent fasting, are well-tolerated and favorably impact fatigue, biomarkers of inflammation, physical function, patient reported outcomes and body composition in women with early-stage breast cancer, however, there have been few studies in women with advanced breast cancer. To address this gap, we propose a 2 x 2 trial in 260 women with advanced HR+ breast cancer initiating treatment with hormonal therapy in combination with a CDK4/6 inhibitor, to evaluate the impact of either prolonged overnight fasting intervention alone, moderate-intensity exercise alone, or in combination on fatigue and associated inflammatory biomarkers.