ESR1 and breast carcinoma: Notably, gene expression profiling has revealed that ~30% of HR+/HER2+ breast cancers, as identified by the PAM50 assay, are classified as the HER2-enriched (HER2-E) intrinsic subtype.11,12 This subtype is characterized by robust activation of the ERBB2 pathway, coupled with relative suppression of ER signaling, correlating with enhanced sensitivity to HER2-targeted therapies such as trastuzumab, pertuzumab, and tyrosine kinase inhibitors (TKIs) like lapatinib and pyrotinib.