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.

Beta blockers have been used to treat ischemic heart disease due to their negative chronotropic and inotropic properties thus inducing a decrease in myocardial consumption of oxygen and nutrients allowing better balance between nutritional needs and blood flow. Recent studies have proved that not all beta blockers have equal effect as their intercellular mechanisms of action are different. Beta blockers have shown a cardioprotective effect against chemotherapy induced- cardiotoxicity.

Nebivolol is a third-generation beta blocker. It is highly selective to B1- adrenergic receptors. It also has peripheral vasodilating effect due to its effect on L-arginine/ nitric oxide pathway in the endothelium of blood vessels. Nitric oxide is a paracrine factor derived from the endothelial cells and alleviate ROS mediated oxidative damage. Nebivolol activates the endothelial nitric oxide system and increases nitric oxide release through activation of the beta 3 adrenergic receptors in endothelium cells. The release of nitric oxide causes peripheral vasodilation, an increase in the myocardial compliance and an inhibition of inotropic effect of sympathetic stimulation. Nebivolol also decreases the nitric oxide break down and increases its bioavailability. All these effects of nebivolol on nitric oxide lead to a decrease in cardiac load, an enhanced cardiac filling and a protection of myocardium.

In a meta-analysis of 12 clinical trials, it was found that there was a great decrease in reactive oxygen species (ROS) concentration in endothelial cells exposed to oxidative stress in patients who were taking nebivolol in comparison to other patients who were receiving other beta blockers. Besides, it was found that the decrease of basal and stimulated nitric oxide because of oxidative stress is less in patients taking nebivolol compared to other patients. This all shows that nebivolol has antioxidant properties which reduce oxidative stress and affects organs damage.

The animal study which is conducted in 2018 to assess the Protective effect of nebivolol on doxorubicin-induced cardiotoxicity in rats. The specimens were examined using H + E and Masson's trichrome, caspase 3, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and tumor necrosis factor factor-α (TNF-α). The mean area percentage of collagen fiber content, caspase-3, eNOS, iNOS and TNF-α immunoactivities was measured. Doxorubicin-treated group showed marked myocyte distortion and fragmentation, congestion and cytoplasmic lysis in most fibers. These changes were less intense in the nebivolol-treated group. The study concluded that nebivolol exerted a significant protective effect from doxorubicin toxicity. The protective effect appears to be mediated mainly through caspase-3, eNOS, iNOS and TNF-α modulation.

Cochera and his colleagues conducted a study in 2018 to assess the effect of nebivolol treatment in the prevention of anthracyclines induced cardiotoxicity. The dose of nebivolol given in the study was 5mg/day for the entire period of the study. Echo was done for all patients to determine the changes of left ventricular ejection fraction in patients in the treatment group and control group. The study concluded that nebivolol prevented the occurrence of anthracycline induced cardiotoxicity.

the current study will be the first clinical trial to evaluate the cardioprotective effect of nebivolol on trastuzumab-induced cardiotoxicity in breast cancer patients.

Aim of the work

Evaluation of the effect of Nebivolol on trastuzumab - induced cardiotoxicity in non-metastatic breast cancer patients by assessment of:

• Left ventricular ejection fraction.
• Cardiac biomarkers (troponin- Pro- BNP).
• Treatment safety.
• Patient quality of life (Using fact-B questionnaire)