Standard therapy of HER2-positive and triple negative metastatic breast cancer – present and future

TREATMENT OF HER2-POSITIVE METASTATIC BREAST CANCER The treatment of HER2-positive metastatic breast cancer (MBC) has been improved. The HER family consists of four transmembrane receptors that mediate in a complex network of signaling pathways (1). HER1, HER2, and HER3 are all implicated in the development and progression of cancer (2, 3). The HER1 and HER2 receptors are perhaps the best known HER family members. The HER3 receptor is gaining increasing importance in cancer research. The role of the HER4 receptor in breast cancer is unclear (4). Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and the part of HER family of growth factor receptors. However, there is no known ligand for HER2. After dimerization, intracellular signaling is activated through transphosphorylation reactions by the tyrosine kinase located at the cytoplasmic domain. HER2 plays a key role in the regulation of normal cell survival, proliferation, and differentiation (5-8). HER2 is a very significant to target therapy. Overexpression of the HER2 protein, usually as a result of HER2 gene amplification, can result in malignant transformation of cells and it is seen in about 18%-20% patients with breast cancer (7). Women with HER2positive breast cancer usually have tumors that are more aggressive, shorter time to relapse at all stages of the disease, and a poor prognosis (9). HER2 positivity is a negative prognostic marker (10). HER2 positive patients have lower survival rate. Breast cancer patients have different disease profiles, which are categorized by HER2 and HR status. Subgroups of patients with breast cancer have different disease prognosis. About 50% of HER2-positive patients are also HR-positive, and have a better prognosis. Patients with HER2-positive/HR-positive disease have a better prognostic outcome regarding time to distant metastasis and overall survival in comparison to HER2-positive/HR-negative patients. HER2 overexpression in patients with breast cancer is associated with an increased risk of disease progression and death. Treatments that suppress HER2 signaling improve disease control in patients with HER2-positive metastatic breast cancer. HER2-targeted therapy contributes to a more favorable treatment outcome in HER2-positive patients with metastatic breast cancer (9). Paul Ehrlich (1854-1915), Nobel Prize Winner (1908), introduced the word chemotherapy and set the concept of “magic bullet” which was the basis for target therapy. Today many opportunities exist to target the HER2 receptor and downstream pathways: on extracellular domain there are monoclonal antibodies (i.e. trastuzumab, per tuzumab, T-DM 1), and on intracellular domain there are tyrosine kinase inhibitors like (lapatinib, neratinib, afatinib) and downstream inhibitors (i.e. everolimus, mTOR, BKM120, BEZ-235). Trastuzumab is the first oncogene-targeted therapy that changes the prognosis of HER2-positive BC. The effect of trastuzumab is achieved through four mechanism of action: – Activation of ADCC – Prevention of the formation of p95, a truncated but very active form of HER2, – Inhibition of cell proliferation, and – Inhibition of HER2-regulated angiogenesis