Role of HER2 signaling pathway in breast cancer: biology, detection and therapeutical implications

Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20–30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Therapies targeting HER2 receptor are effective in adjuvant treatment and in metastatic disease. Several agents have demonstrated promising activity in HER2 metastatic breast cancer, either as monotherapy or in combination therapy, including the tyrosine-kinase inhibitors lapatinib and neratinib, and the anti-HER2 monoclonal antibodies trastuzumab, pertuzumab and trastuzumab-DM1/T-DM1/. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from the agents because of inherent resistance. In addition, many patients who achive an initial response eventually acquire drug resistance. Several mechanism of resistance have been described, including mutations in other signalling pathways, expression of a truncated form of HER2, receptor crosstalk, and autophagy.