Evaluation of the Cardioprotective Effect of Nebivolol on Trastuzumab-Induced Cardiotoxicity in Breast Cancer Patients

Breast cancer is one of the most common malignancies that affect females around the world. According to the WHO, the number of females who were diagnosed with breast cancer in 2020 in Egypt was 22038 females. This number represents 32.4% of all women malignancies and 16.4% of all malignancies in Egypt (men and women).

Breast cancer can be managed using chemotherapy, endocrine therapy and biological therapy. Treatment is determined and specified according to the characteristics of the tumor including overexpression of the human epidermal growth factor receptor (HER2). Previously patients who were diagnosed with HER2 positive breast cancer were considered of poor survival but after the discovery of trastuzumab, disease free survival among these patients was improved significantly.

Trastuzumab is a humanized monoclonal antibody that was approved to treat HER2 positive breast cancer. Studies have shown that trastuzumab has improved the survival, reduced the mortality, reduced the recurrence and metastases rates in patients with HER2 positive breast cancer. Trastuzumab perform its tumor suppressive actions through different mechanisms that include activation of antibody-dependent cell-mediated cytotoxicity, inhibition of HER2 extracellular domain cleavage, disruption of HER2 receptor homodimerization and heterodimerization, abrogation of oncogenic cellular signaling and downregulation of angiogenesis and DNA repair pathways.

Though trastuzumab has made great improvement in the treatment of breast cancer, it was identified to possess a major side effect which is cardiotoxicity. Cardiotoxicity that occurs with anticancer agents is usually manifested as left ventricular dysfunction (LVD) and overt heart failure (HF). LVD was defined as a decrease in cardiac LV ejection fraction (LVEF), that is either global or more severe in the septum, symptoms of congestive heart failure (CHF), associated signs of CHF including but not limited to S3 gallop, tachycardia or both and decline in LVEF of at least 5% to below 55% with accompanying signs or symptoms of CHF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms.

According to a study conducted by Mohan et al in 2016, It was shown that treatment with trastuzumab leads to inhibition of HER2 signaling and phosphorylation of HER1-Y845/HER2-Y1248 and the activation of Erk. All this consequently leads to upregulation of the mTOR-Ulk1 pathway to mediate inhibition of autophagy in cardiomyocytes. This was clearly shown by the decrease in expression levels of LC3 I/II and increase in p62 after trastuzumab treatment. Studies has shown that inhibition of autophagy by autophagy inhibitor (3-methyladenine) leads to accumulation of damaged mitochondria and increase the concentration of mitochondrial ROS and thus accumulation of toxic reactive oxygen species (ROS) in human cardiomyocytes which can lead to oxidative damage and cardiotoxicity.