As was reaffirmed in the ASCO/CAP guidelines in June 2023, human epidermal growth factor receptor 2 (HER2) status is defined by immunohistochemistry (IHC) and reflex in situ hybridization (ISH) testing, with HER2 positive defined as IHC 3+ or IHC 2+ with positive ISH.1 The publication of the DESTINY-Breast 04 trial in 2022 established the operational category of HER2 low, defined as IHC 1+ or IHC 2+ with ISH negative, and demonstrated improved survival with use of trastuzumab deruxtecan (T-DXd) compared to chemotherapy of physician’s choice.