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. The gene discussed is ESR1; the disease is breast cancer.