Targeting the Human Epidermal Growth Factor Receptor Family in Breast Cancer beyond HER2

Currently, the dichotomous definition of human epidermal growth factor receptor 2 (HER2)-positive versus HER2-negative disease undergoing a change through inclusion of the identification of the HER2-low category, for which new therapeutic compounds in the form of potent antibody drug conjugates (ADC) may be effective. In addition, resistance to HER2-directed targets has become a clinical challenge and, therefore, strategies to bypass the HER2 receptor are of high interest. These are new HER2 ADCs and tyrosine kinase inhibitors, such as tucatinib or neratinib. The underlying mechanisms of resistance to anti-HER2 therapies and compensatory pathways are complex and a wide range of mechanisms of resistance may coexist in the same cell. Therefore, the combined treatment with agents that interact with HER2-associated downstream signaling pathways like the phosphoinositide-3-kinase (PI3K) and the serine/threonine kinases AKT and mTOR might overcome HER2 resistance. In addition, targeting other members of the HER family is a promising approach to improve outcomes in breast cancer patients. This review gives an overview of treatment strategies in targeting HER2 and other members of the HER family, not only in HER2-positive breast cancer, but also in HER2-low expressing tumors, and of approaches to overcome HER2 resistance.