Resistance to Trastuzumab

One of the most impactful biologics for the treatment of breast cancer is the humanized monoclonal antibody, trastuzumab, which specifically recognizes the HER2/neu (HER2) protein encoded by the ERBB2 gene. Useful for both advanced and early breast cancers, trastuzumab has multiple mechanisms of action. Classical mechanisms attributed to trastuzumab action include cell cycle arrest, induction of apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). Recent studies have identified the role of the adaptive immune system in the clinical actions of trastuzumab. Despite the multiple mechanisms of action, many patients demonstrate resistance, primary or adaptive. Newly identified molecular and cellular mechanisms of trastuzumab resistance include induction of immune suppression, vascular mimicry, generation of breast cancer stem cells, deregulation of long non-coding RNAs, and metabolic escape. These newly identified mechanisms of resistance are discussed in detail in this review, particularly considering how they may lead to the development of well-rationalized, patient-tailored combinations that improve patient survival.