For intrinsically aggressive breast cancers such as HER2-enriched tumors, therapeutic resistance is common, as evidenced by the progression of unresponsive tumors.23, 24, 25, 26 Similar to lapatinib and trastuzumab, it is likely that resistance mechanisms will impact the newer classes of HER2/EGFR inhibitors, such as neratinib.50 Therefore, a better understanding of the molecular drivers of resistance could enable the identification of effective drug combinations to improve clinical efficacy. The gene discussed is ERBB2; the disease is breast carcinoma.