In this regard, though it mechanistically made sense that anti-HER2 agents could have clinical applications beyond HER2-positive BC, this was never achieved in the first two decades of experience with HER2-targeted monoclonal antibodies (trastuzumab and pertuzumab), anti-HER2 vaccine (nelipepimut-S), and the first anti-HER2 antibody-drug conjugate (ADC) (trastuzumab–emtansine) [18,28,29,30]. This evidence concerns the gene ERBB2 and breast cancer.