In conclusion, while definitive evidence will require prospective clinical evaluation of PARPi and/or ICB and/or CDK 4/6 inhibitor combinations in cohorts of patients with HRD-high and HRD-low vs BRCA1/2-mutated ER + breast cancer, our results could have important implications for translational research and/or the design of future clinical trials and highlight possible novel biological differences among ER + /HER2- breast cancer related to their ability to respond to DNA-damaging agents and ICB. Here, ESR1 is linked to breast carcinoma.