ESR1 and breast cancer: This manuscript: (1) explains our recent findings regarding the association between ER status and the defective DNA repair phenotype, controlling for different variables including HER2 receptor status [38,39], (2) outlines potential mechanisms behind what we found for future mechanistic studies, and (3) proposes how our findings could form the basis for a new combination of biomarker testing that may better characterize BC tumors, which could improve diagnostic, prognostic, and therapeutic efforts.