Human epidermal growth factor receptor 2 (HER2) is overexpressed in around 20–30% of breast cancer tumors. It is associated with a more aggressive disease, higher recurrence rate, and increased mortality. Trastuzumab is a HER2 receptor blocker that has become the standard of care for the treatment of HER2 positive breast cancer. The effectiveness of Trastuzumab has been well validated in research as well as in clinical practice. The addition of Trastuzumab to standard of care chemotherapy in clinical trials has been shown to improve outcomes for early stage as well as metastatic HER2 positive breast cancer. The most clinically significant side effect of Trastuzumab is the risk of cardiac myocyte injury, leading to the development of congestive heart failure. The emergence of patterns of resistance to Trastuzumab has led to the discovery of new monoclonal antibodies and other targeted agents aimed at overcoming Trastuzumab resistance and improving survival in patients diagnosed with HER2 positive breast cancers. 1. Introduction Human epidermal growth factor receptor HER2 overexpression is present in approximately 20–30% of breast cancer tumors. HER2 overexpression is associated with a more aggressive disease, higher recurrence rate, and shortened survival [1–4]. Trastuzumab is a humanized monoclonal antibody targeting the HER2 receptor, which was approved for use in 1998. The mechanisms of action of Trastuzumab have not been clearly defined, but likely include extracellular mechanisms involving antibody-dependent cellular cytotoxicity (ADCC), and intracellular mechanisms involving apoptosis and cell cycle arrest as well as inhibiting angiogenesis, and preventing DNA repair following chemotherapy-induced damage [5, 6]. Trastuzumab has been shown to be effective in combination with chemotherapy, for the treatment of early stage and metastatic HER2 positive breast cancer. 2. Biology HER2 is part of the epidermal growth factor (EGF) family, along with 3 other receptors: epidermal growth factor receptor (HER1, erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). The HER2 gene is located on the long arm of chromosome 17 and encodes a 185-kDa transmembrane protein [7–9]. The HER2 receptor extracellular domain has no identifiable ligand, unlike the other EGF family receptors. It is present in an active conformation and can undergo ligand-independent dimerization with other EGF receptors [6, 10, 11]. The most active and tumor promoting combination is thought to be the HER2/HER3 dimer [12–15]. The mechanism of action of Trastuzumab is perceived to be through both
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