SGLT2i Dapagliflozin in primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy +/- trastuzumab: rationale and design of the multicenter PROTECT trial.

Background: SGLT2i exerts several cardiometabolic benefits in heart failure with reduced and preserved ejection fraction through the systemic reduction of insulin, visceral fat, chemokines and growth factors involved in cardiovascular diseases. Anthracyclines are considered the principal culprit drugs behind chemotherapy-induced cardiotoxicity. The pathognomonic manifestation of anthracycline-induced cardiotoxicity is a hypokinetic cardiomyopathy progressively leading to heart failure. Anthracycline-induced cardiotoxicity is still a significant problem that compromises the quality of life and overall survival of breast cancer (BC) patients. Sequential therapy regimen of anthracyclines and HER-2 blocking agents is associated to higher risk of cardiotoxicity compared to monotherapy regimen. 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 patients with cancer and T2DM who were treated with anthracyclines. These data support the conducting of a randomized clinical trial testing Dapagliflozin in patients with breast cancer treated with anthracyclines+/- trastuzumab.

Objective: To evaluate the cardioprotective effects of the SGLT2 inhibitor Dapagliflozin in chemotherapy-naive patients with stage I-III breast cancer undergoing anthracycline-based treatment with or without trastuzumab, by assessing its ability to reduce the incidence of cardiotoxicity and improve systemic cardiometabolic markers.

Methods: Chemotherapy-naive patients (18-70 years) scheduled for antracycline +/- trastuzumab treatment in the [neo-]adjuvant setting for stage I-III breast cancer, will be randomized using a web-based system stratified by the use of trastuzumab to follow a chemotherapy regimen plus Dapagliflozin [10 mg/die] [active group] or chemotherapy regimen plus standard of care [control group]. During follow up period, if a patient develops 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 (NT-pro-BNP, hsTNI), CKD-EPI eGFR and systemic inflammation (hsCRP, chemokines, cytokines and growth factors).

Results: The study is ongoing. Results will be published when the study is completed.

Conclusion: The PROTECT trial is the first randomized clinical study designed to evaluate whether Dapagliflozin can reduce anthracycline- and/or trastuzumab-associated cardiotoxicity in patients with early-stage breast cancer. Beyond its established cardiometabolic effects, this trial will also provide insight into the systemic anti-inflammatory and metabolic benefits of SGLT2 inhibition in the oncology setting. Findings from this study may pave the way for novel cardio-oncology strategies aimed at improving both cardiac outcomes and quality of life in cancer patients.

Trial registration: ClinicalTrials.gov NCT06341842 [EudraCT Number 2022-003377-28]. Registered on 19 March 2024.