Patients with HER2+, ER+ BC tend towards later disease recurrence [51], have a higher frequency of bone metastasis [47], and have a poorer response to chemotherapy plus HER2-targeted therapies, when compared with HER2+, ER– BC [11, 17, 52, 53], suggesting the ER pathway acts as an escape mechanism promoting tumor survival under sustained HER2 inhibition [47, 54]. This evidence concerns the gene ESR1 and breast cancer.