The current treatment landscape for patients with HER2-low metastatic breast cancer

HER2 overexpression has been a therapeutic target in breast cancer (BC) for many years and the development of anti-HER2 therapies has markedly improved the outcome of patients exhibiting high levels of HER2 expression. In this, the HER2 status of patients was traditionally defined in a binary fashion, in which patients with high levels of HER2 expression were classified as HER2-positive, while all the rest were denominated as HER2-negative. Despite being classified as HER2-negative; the majority of these BCs do express some level of HER2. Until recently, however, these low levels of HER2 expression did not have any therapeutic implications. This has changed with the publication of the DESTINY-Breast04 (DB-04) study in which trastuzumab deruxtecan (T-DXd) was shown to significantly improve the progression-free (PFS) and overall survival (OS) of patients with HER2-low metastatic BC. These findings require a recalibration of the treatment paradigm for patients with advanced BC. Furthermore, the increased interest in HER2-low BC led to questions on the biology, epidemiology, heterogeneity, and prognostic relevance of HER2-low disease and confronts physicians with the challenge of incorporating the treatment of HER2-low disease in the rapidly evolving treatment landscape for patients with hormone-receptor-positive (HR+) and triple-negative BC (TNBC).