HR+/HER2+ breast cancers exhibit considerable biological heterogeneity, driven by the intricate and dynamic crosstalk between ER and HER2 signaling pathways, which represents a crucial area of research.13–16 This complicated signaling interaction not only contributes to the oncogenic potential of HR+/HER2+ tumors but also plays a central role in resistance to HER2-targeted therapies, posing significant challenges in clinical management. The gene discussed is ESR1; the disease is breast cancer.