It is postulated that the enhanced efficacy of neratinib in HR+/HER2+ breast cancer in the ExteNET trial may be explained by interruption of crosstalk between the ER and HER2 pathways given that >90% of patients with HR+ disease in ExteNET received concurrent adjuvant ET along with extended adjuvant neratinib. Here, ESR1 is linked to breast carcinoma.