Open questions, current challenges, and future perspectives in targeting human epidermal growth factor receptor 2-low breast cancer.

Approximately 60% of traditionally defined human epidermal growth factor receptor 2 (HER2)-negative breast cancers express low levels of HER2 [HER2-low; defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization (ISH)-]. HER2-low breast cancers encompass a large percentage of both hormone receptor-positive (up to 85%) and triple-negative (up to 63%) breast cancers. The DESTINY-Breast04 trial established that HER2-low tumors are targetable, leading to the approval of trastuzumab deruxtecan (T-DXd) as the first HER2-directed therapy for the treatment of HER2-low breast cancer in the United States and Europe. This change in the clinical landscape results in a number of questions and challenges-including those related to HER2 assessment and patient identification-and highlights the need for careful assessment of HER2 expression to identify patients eligible for T-DXd. This review provides context for understanding how to identify patients with HER2-low breast cancer with respect to sample types, scoring and reporting HER2 status, and testing methods and assays. It also discusses management of important T-DXd-related adverse events. Available evidence supports the efficacy of T-DXd in patients with any history of IHC 1+ or IHC 2+/ISH- scores; however, future research may further refine the population who could benefit from T-DXd or other HER2-directed therapies and identify novel methods for patient identification. Because HER2 expression can change with disease progression or treatment, and variability exists in scoring and interpretation of HER2 status, careful re-evaluation in certain scenarios may help to identify more patients who may benefit from T-DXd.