Targeted therapies inhibiting pathways that have been shown in the current report to segregate with high mutation numbers, such as PI3K inhibitors and PARP inhibitors (most effective in cancer cells with homologous recombination deficiency), are candidates for development in combination with immune checkpoint inhibitors to sensitize ER-positive/HER2-negative breast cancers to immunotherapies and improve the mediocre results obtained in previous clinical trials. This evidence concerns the gene ESR1 and cancer.