Mechanisms of Resistance to Trastuzumab and Novel Therapeutic Strategies in HER2-Positive Breast Cancer

HER2-positive breast cancers have poorer prognosis and are prime candidates for molecular-targeted therapy because they are driven by the unique mechanism of HER2 oncogene addiction. While anti-HER2 agents such as trastuzumab and lapatinib are integral to the treatment of HER2-positive breast cancer, intrinsic and secondary resistance pose a significant challenge, underscoring the need to develop novel anti-HER2 therapies. In recent years, an array of promising and novel anti-HER2 therapeutic agents and their combinations have entered various stages of clinical development. However, questions remain on the optimal sequences of HER2-directed therapies and selection of patients for the most appropriate drug or combinations; incompletely defined mechanisms of trastuzumab action and resistance have also dampened the progress of more successful biomarker-driven treatment approaches. This paper summarizes existing preclinical and clinical evidence on the mechanisms of trastuzumab action and resistance and provides an up-to-date overview of novel HER2-directed therapies in clinical development.