Resistance of HER2-expressing breast cancer patients treated with trastuzumab: Underlying mechanisms of resistance and reversals

Breast cancer has been marked as one of the most prevalent cancers among women and a leading cause of death in women with cancer. The subtype of HER2-positive breast cancer consists of HER2 overexpression/amplification and accounts for greater than 20% of breast cancers. The standard care for HER2 breast cancer is trastuzumab, a monoclonal antibody directed against the HER2 receptor. Binding of trastuzumab to HER2 inhibits downstream signaling pathways involved in proliferation and invasion and mediates in vivo antibody-dependent cellular cytotoxicity (ADCC). In the adjuvant setting, trastuzumab is administered in combination with chemotherapy or radiotherapy. However, there is a high rate of resistance, both innate and adaptive, to trastuzumab. Several mechanisms have been reported to underlie the mechanisms of resistance. These include the lack or weak expression of HER2, alteration of the extracellular domain and binding site of HER2, HER2 mutations, expression of the membrane glycoprotein mucin 4, immune suppression, resistant cancer stem cells, hypoxia, redundant signaling pathways, etc. Hence, to overcome resistance, new trastuzumab-drug conjugates were developed, namely, trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Both consist of humanized trastuzumab bounded with a microtubule inhibitor (emtansine) or a topoisomerase inhibitor (deruxtecan), respectively. These have improved the overall survival rate in patients with metastatic breast cancer. Like trastuzumab, resistance to these drug conjugates has also been observed. Thus, to overcome the resistance, several novel targeted therapies have been developed that are being investigated clinically, alone or in combination with other agents, along with the development of prognostic biomarkers.