Background: PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancers and are associated with endocrine resistance. The combination of the PI3Kα inhibitor alpelisib and fulvestrant significantly improves progression-free survival (PFS) in this patient population, as demonstrated by the SOLAR-1 trial. However, treatment-induced hyperglycemia, observed in over 60% of patients, can not only compromise cardiovascular health but also promote cancer progression through compensatory hyperinsulinemia and reactivation of the PI3K/AKT pathway. Retrospective clinical data suggest that co-administration of SGLT2 inhibitors may mitigate these effects, prolonging time on treatment and potentially improving PFS. This study aimed to investigate the direct cardiotoxic effects of alpelisib and fulvestrant on human cardiomyocytes under hyperglycemic conditions (25 mM glucose), and assess whether dapagliflozin, an SGLT2 inhibitor, provides cardioprotection in vitro, under co-treatment condition. Methods : Human iPSC-derived cardiomyocytes were exposed to alpelisib and fulvestrant under hyperglycemic conditions (50 mM) to simulate the clinical metabolic milieu of treated breast cancer patients. Dapagliflozin was introduced either concomitantly. Cellular viability, mitochondrial membrane potential, ROS and markers of cardiotoxicity and apoptosis (BNP, troponin I, caspase-3) were quantified. Transcriptomic analysis was performed to explore cardiometabolic signaling pathways. Results: Dapagliflozin significantly attenuated cardiotoxic responses induced by alpelisib/fulvestrant, including preservation of mitochondrial function, reduction in ROS, and inhibition of apoptotic signaling. Transcriptomic analysis revealed suppression of pro-inflammatory and insulin-related stress pathways. Conclusion : These in vitro data support the potential clinical utility of SGLT2 inhibitors in minimizing cardiotoxic risk and improving treatment tolerance in HR+/HER2− PIK3CA-mutant breast cancer patients.
Associazione Nazionale Medici Cardiologi Ospedalieri
