Potential Ameliorating Role of Spironolactone in Trastuzumab-induced Cardiotoxicity: A Narrative Review

Abstract

Background: Around 20% of breast cancers (BCs) overexpress Human Epidermal Growth Factor Receptor 2 (HER-2). HER-2 overexpression is associated with increased tumor aggressiveness and poor prognosis. Trastuzumab (an anti-HER2 monoclonal antibody) has been reported to improve overall survival in early-stage and metastatic BCs, but at the expense of increasing cardiac morbidity. In the current review study, we aims to discuss the pathogenesis of trastuzumab-induced cardiotoxicity and the potential ameliorating role of spironolactone in this regard. Methods: The search strategy aimed to identify both published and unpublished studies. First off, we identified keywords and index terms, including trastuzumab, cardiotoxicity, heart failure, and spironolactone to conduct a broad search in PubMed, Embase, Scopus, and Web of Science, using the aforementioned keywords either individually or in combination. Lastly, the reference list of all identified articles was also evaluated. Our study included observational and interventional studies, case-reports, and systematic reviews and meta-analyses. Results: Trastuzumab could deteriorate mitochondrial function and subsequently leads to the accumulation of Reactive Oxygen Species (ROS) in cardiomyocytes. Published clinical studies offered conflicting results regarding the efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in respect of trastuzumab-induced cardiotoxicity. On the other hand, spironolactone was found to have both antioxidant and anti-inflammatory properties. Recent in-vivo studies supported the cardioprotective effect of spironolactone through maintaining mitochondrial ultrastructure and reducing ROS production. Conclusion: Although spironolactone mitigates oxidative stress and mitochondrial dysfunction, there is a lack of clinical evidence to support the effectiveness of spironolactone in trastuzumab-induced cardiotoxicity. Design and implementation of clinical trials are recommended to determine the potential beneficial effects of spironolactone on trastuzumab-induced cardiotoxicity.