Targeting cellular senescence to enhance skeletal muscle recovery in survivors of breast cancer: An ancillary study of the phase II randomized PROFFi clinical trial.

TPS12168 Background: Postmenopausal survivors of breast cancer frequently experience persistent physical function decline after chemotherapy. A key contributor is skeletal muscle dysfunction, leading to weakness, fatigue, and reduced physical activity. One potentially targetable mechanism of chemotherapy-induced skeletal muscle dysfunction is cellular senescence. Senescence is a state of terminal growth arrest that leads to a senescence-associated secretory phenotype marked by the secretion of pro-inflammatory cytokines. These cytokines worsen muscle dysfunction by impairing calcium handling and muscle fiber contractility. Emerging evidence suggests senolytics and exercise may reduce senescent cell (SnC) burden. Senolytics are agents that selectively eliminate Sncs and can improve physical function in non-cancer populations. Exercise not only enhances physical function but also reduces blood markers of senescence. Preclinical studies demonstrate a synergistic effect of senolytics and exercise on SnC reduction. However, no human studies have examined the independent or combined effects of senolytics and exercise on skeletal muscle function and senescence in cancer survivors. We hypothesize that fisetin plus exercise will produce independent and synergistic effects that enhance skeletal muscle recovery in survivors of breast cancer. Methods: This site-specific ancillary mechanistic study at UCLA is embedded within PROFFi (Prevention of Frailty with Fisetin), an ongoing phase II multicenter, randomized, placebo-controlled clinical trial evaluating fisetin and exercise in postmenopausal survivors of breast cancer. Eligible participants are within 12 months of completing neo/adjuvant chemotherapy and have reduced physical function as measured by a 6-minute walk distance of 400-480 meters. PROFFi uses a 2x2 factorial design, randomizing 200 participants 1:1:1:1 to exercise plus fisetin, exercise alone, fisetin alone, or placebo for 16 weeks. Fisetin is administered orally at 20mg/kg/day on days 1-3 every 14 days. Exercise is individually tailored and remotely supervised by an exercise physiologist and includes aerobic and resistance exercises. The ancillary study will enroll 84 of the 200 participants (21 per arm) to undergo additional muscle-specific assessments including Biodex strength testing, thigh magnetic resonance imaging (MRI), and vastus lateralis muscle biopsies. The primary objectives of the ancillary study are to evaluate the effects of fisetin and/or exercise on muscle strength (Biodex peak torque), muscle volume (on MRI), and muscle mitochondrial function (oxidative phosphorylation capacity). Secondary objectives include assessing changes in blood and muscle-specific markers of senescence from baseline to end of study. Enrollment to this study began July 2024 and is ongoing (NCT06113016). Clinical trial information: NCT06113016 .