ESR1 and breast cancer: There are two reasons that this approach should be considered: 1) the vast diversity in mechanisms of acquired endocrine and CDK4/6 clinical resistance mechanisms makes it challenging to target tumors effectively, and 2) as the two major molecularly targeted pathways in breast cancer, there is a continuous pipeline of newer ER and HER2 inhibitors that may be potentially viable for endocrine-resistant HER2-low tumors.