PROFFi：一项在绝经后乳腺癌幸存者中评估非瑟酮（fisetin）与运动的II期随机对照研究

Background: Breast cancer treatment accelerates aging, particularly in post-menopausal women. Postmenopausal accelerated aging leads to physical functional decline that in turn results in loss of independence, falls, and death. Given the growing number of breast cancer survivors, there is a need to develop mechanism-based interventions to mitigate and, ideally, reverse chemotherapy-induced functional decline. One mechanism that is thought to underly chemotherapy-induced functional decline is cellular senescence. In preclinical studies, targeting senescence with fisetin (an oral flavonoid with senolytic activity) reduces muscle atrophy and improves strength. However, the ability of fisetin to reverse chemotherapy-induced functional decline in postmenopausal breast cancer survivors has not been tested. Methods: PROFFi is an ongoing multi-center Phase II randomized placebo-controlled 2x2 factorial trial designed to determine the effects of fisetin, with or without exercise, in frail postmenopausal breast cancer survivors. In this trial, N= 200 post-menopausal women with stage I-III breast cancer treated with neo/adjuvant chemotherapy and with functional decline, as measured using the 6-minute walk distance (6MWD), are randomized to 1 of 4 arms: fisetin alone, exercise alone, fisetin plus exercise, or control, for 16 weeks. Fisetin is given orally at 20 mg/kg/day on days 1-3 of each 14-day cycle. Exercise is administered using a tailored, structured, supervised program. The primary endpoint for the trial is the change in 6MWD from baseline to 16 weeks. Secondary endpoints include aging outcomes (physical, cognitive, psychological function) and cancer outcomes (survival, recurrence). Exploratory endpoints include blood-based markers of biological aging (senescence, SASP inflammation) and tissue-based measures of skeletal muscle health (muscle mass, strength, mitochondrial biogenesis). Discussion: To our knowledge, PROFFi is one of the first trials to apply a aging-guided strategy in oncology by directly intervening on therapy-induced biological aging to improve chemotherapy-induced functional decline. The trial will test whether fisetin and exercise, individually or synergistically, improve mechanistic aging biomarkers, increase muscle strength and mitochondrial biogenesis, and, ultimately, reverse chemotherapy-induced functional decline in postmenopausal breast cancer survivors. Moreover, this study will serve as a prototype for future trials that test senotherapeutics in cancer survivorship.