Background: Anthracyclines and trastuzumab play a key-role in preoperative and adjuvant breast cancer (BC) treatment, and showed a significant survival benefit in several trials. Although acute cardiac toxicity is infrequent and usually reversible in a dose-dependent manner, published data evidenced a clinically relevant early late cardiac toxicity, with a chronic progressive deterioration of left ventricular ejection fraction (LVEF), up to congestive heart failure (CHF). Late toxicity occurs in most cases within the first year following chemotherapy completion, but an echocardiographic monitoring is strongly recommended even after a longer time. Recent studies highlighted that the evaluation of myocardial strain could be a refined predictive marker of early cardiac dysfunction after anthracyclines exposure. The aim of our study is to find out the best approach as cardiac toxicity prevention in non-metastatic BC patients undergoing anthracycline-based chemotherapy, with or without subsequent anti-HER2 therapy. Methods: This is a randomized phase III, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol (5 mg, twice daily), ramipril (5 mg, twice daily), or both drugs, compared to placebo, on anthracycline therapy induced LVEF dysfunction for non-metastatic disease. Cardioprotection is administered for one year, or until the end of trastuzumab (if HER2 positive). All patients undergo cardiac surveillance with echocardiogram and speckle tracking strain at baseline and every three months, until 2 years. Primary endpoint is maximum change in LVEF. Assuming a cardiac toxicity incidence of 40%, with a 15% reduction in both arms to reach the outcome, a sample of 120 patients per arm provides a 90% statistical power, for a total of 480 enrolled patients. The analysis is based on intent-to-treat. Exclusion criteria are: history of CTCAE (v.4) grade > 2 symptomatic CHF, previous myocardial infarction, significant symptoms (grade > 2) relating to LVEF dysfunction, valvular disease, cardiac arrhythmia (grade > 3). Clinical trial information: NCT2236806