T-DM1-induced thrombocytopenia in breast cancer patients: New perspectives

Purpose: Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-20% of patients with breast cancer. HER2 overexpression is the result of a genetic alteration and this marker is associated with poor clinical outcomes. HER2-targeted therapy can significantly improve the prognosis of patients with either early or advanced HER2-positive breast cancer. One such therapy is the antibody drug conjugate (ADC) trastuzumab emtansine (T-DM1), a combination of trastuzumab and the cytotoxic antimicrotubule agent DM1. After T-DM1 binds HER2, DM1 is subsequently released into the cell. T-DM1 is generally well tolerated and has a relatively low incidence of adverse events. However, there are clinical concerns regarding T-DM1-induced high-grade thrombocytopenia. Methods: Here, we summarize the incidence of thrombocytopenia from several clinical trials and review experimental studies to explore the causes for T-DM1-induced thrombocytopenia. Progress in several other ADCs targeting HER2-positive breast cancer was also reviewed. Conclusions: We conclude that T-DM1 uptake by megakaryocytes occurs through either Fc gamma receptor binding or through pinocytosis, and we suggest several methods through which these processes could be interrupted to potentially improve the clinical safety of T-DM1. More generally, we recommend that toxicity should be carefully addressed during the development of ADCs.