Targeting senescence to reverse chemotherapy-induced muscle aging in breast cancer survivors: An ancillary study of the TROFFi Trial

Background: Breast cancer chemotherapy accelerates biological aging, particularly in postmenopausal women, leading to skeletal muscle decline, impaired physical function, and increased risk of frailty, falls, and loss of independence. Cellular senescence is a key mechanism underlying therapy-induced aging, contributing to chronic inflammation, mitochondrial dysfunction, and muscle atrophy. Preclinical studies demonstrate that fisetin, an oral flavonoid with senolytic activity, reduces senescent cell burden, improves mitochondrial function, and restores muscle strength. However, the mechanistic effects of senolytic therapy on skeletal muscle and mitochondrial health in breast cancer survivors have not been studied in humans. Methods: This ancillary mechanistic study is embedded within TROFFi (Treatment of Frailty with Fisetin; NCT05595499), an ongoing multicenter, randomized, placebo-controlled phase II trial evaluating fisetin in frail postmenopausal breast cancer survivors. TROFFi enrolls 88 women with stage I-III breast cancer treated with neo/adjuvant chemotherapy and evidence of functional decline, defined by reduced 6-minute walk distance (6MWD). Participants are randomized to fisetin (20 mg/kg/day orally on days 1-3 of each 14-day cycle) or placebo for up to 16 weeks. In a mechanistic subset (n=20), assessments at baseline and end of treatment include isokinetic muscle strength testing, thigh muscle volume (MRI), and vastus lateralis muscle biopsies. Muscle tissue analyses assess mitochondrial respiration, mitochondrial genome integrity, fiber composition, and histochemical markers of muscle health. Circulating biomarkers of senescence and the senescence-associated secretory phenotype are also evaluated. Results: This study will determine whether senolytic therapy with fisetin improves skeletal muscle mass, strength, and mitochondrial function in breast cancer survivors with chemotherapy-induced functional decline and will estimate effect sizes linking biological aging biomarkers to functional outcomes. Conclusions: TROFFi represents one of the first aging-guided interventional strategies in oncology to directly target therapy-induced biological aging. This ancillary study provides critical tissue-level mechanistic insight into how senolytic therapy may reverse chemotherapy-related muscle aging and functional decline. Findings will inform future precision survivorship trials targeting fundamental aging processes to improve long-term health and resilience in cancer survivors.