A phase II randomized placebo-controlled study of fisetin to improve physical function in breast cancer survivors: the TROFFi study rationale and trial design

Background: Postmenopausal breast cancer survivors treated with neo/adjuvant chemotherapy often experience persistent declines in physical function that fail to resolve after treatment. One mechanism thought to underlie this lasting impairment is cellular senescence(definition), a fundamental process of aging that contributes to frailty and functional decline. Chemotherapy induces senescence, and preclinical studies show that targeting senescent cells with senolytics(definition) can reduce inflammation and improve physical function. These findings have generated a strong interest in translating senolytic therapies to humans; however, no study to date has evaluated the effects of senolytics on physical function in postmenopausal breast cancer survivors. Objective: To evaluate the effects of targeting senescence with the oral senolytic agent fisetin on physical function in chemotherapy-treated postmenopausal breast cancer survivors. Design: A multicenter, phase II, randomized, double-blind, placebo-controlled trial. Methods and analysis: Eighty-eight postmenopausal women with early-stage, high-risk breast cancer who completed neo/adjuvant chemotherapy within the past 12 months and have diminished physical function, defined by a 6-minute walk distance (6MWD) <400 m, will be randomized 1:1 to receive either placebo or fisetin (20 mg/kg/day) on days 1-3 of a 14-day cycle for four cycles. The primary endpoint is the change in the 6MWD from baseline to end of treatment. Ethics: The study has been approved by the institutional review boards at participating sites. Discussion: This is one of the first studies to test whether targeting senescence with an oral senolytic agent, fisetin, can mitigate physical function decline in postmenopausal breast cancer survivors treated with neo/adjuvant chemotherapy. Promising results would provide the preliminary evidence needed to support a larger, confirmatory trial evaluating fisetin's efficacy in this population. If successful, this approach could fill an important unmet clinical need, as no pharmacological therapies currently exist to prevent or treat chemotherapy-related declines in physical function among postmenopausal breast cancer survivors. Trial registration: ClinicalTrials.gov NCT05595499.