Dapagliflozin for the primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy: design of the multi-center phase II randomized PROTECT trial

Background: Their clinical effectiveness of anthracyclines may be thwarted by the development of cardiotoxicity progressively leading to heart failure (HF) and compromising the quality of life and overall survival of breast cancer (BC) patients. Sequential therapy regimen of anthracyclines and human epidermal growth factor receptor (HER2) blocking agents, such as trastuzumab, is associated to higher risk of cardiotoxicity compared to monotherapy regimen. Sodium glucose cotransporter 2 inhibitors (SGLT2i) exert several cardiometabolic benefits in HF with reduced and preserved ejection fraction through the systemic reduction of insulin, visceral fat, chemokines and growth factors involved in cardiovascular diseases. Recent studies in preclinical models of anthracycline-induced cardiotoxicity concluded that SGLT2i are able to prevent ejection fraction reduction and myocardial inflammation and fibrosis. A very recent retrospective study indicates that SGLT2i were associated with lower rate of cardiac events among diabetic patients with cancer treated with anthracyclines. Based on this background we sought to conduct a randomized clinical trial testing SGLT2i in patients with BC treated with anthracyclines+/- trastuzumab. Methods: PROTECT trial is a phase II “proof of concept”, multicentre, randomized 1:1, open label, parallel-groups study, designed to evaluate if the SGLT2i dapagliflozin reduces chemotherapy-induced cardiotoxicity in participants with BC treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab. Chemotherapy-naive patients (18-70 years) scheduled for antracycline +/- trastuzumab treatment in the (neo-)adjuvant setting for stage I-III BC will be randomized using a web-based system stratified by the use of trastuzumab to follow a chemotherapy regimen plus the SGLT2i Dapagliflozin (10 mg/die) (active group) or chemotherapy regimen plus standard of care (control group). During follow up period, patients developing asymptomatic or symptomatic systolic disfunction will be treated according to good clinical practice. From randomization, to the third, sixth, twelfth and eighteenth months, echocardiographic and cardiological visits will be performed associated to blood analysis for quantification of cardiotoxicity biomarkers, estimated glomerular filtration rate and systemic inflammation. Discussion: PROTECT study aims to reduce cadiovascular events in BC through the oral administration of SGLT2i Dapagliflozin and to investigate on its systemic cardio-metabolic benefits. Trial registration: ClinicalTrials.gov NCT06341842 (EudraCT Number 2022-003377-28). Registered on 19 March 2024.