HER2 expression in breast cancer: evidence gaps and challenges

The classification of breast cancer (BC) based on HER2 expression is undergoing significant changes. While traditional approaches have focused on HER2-positive and HER2-negative categories, emerging evidence highlights varied therapeutic responses depending on the level of HER2 protein expression. Breast cancers are now immunohistochemically (IHC) scored into five subgroups, which define two primary therapeutic groups: HER2-positive (IHC 2+ amplified and 3 + ) and HER2-negative (IHC 0, 1 + , and 2+ non-amplified). Recent advances, particularly in antibody-drug conjugates (ADCs), have led to further subclassification of HER2-negative BC into HER2-Low and HER2-null (IHC 0). Also, for HER-positive subgroups, a differential response to HER2-targeted therapies is seen. This evolving landscape challenges the traditional use of HER2 as a diagnostic marker and underscores the need for a deeper understanding of HER2 biology. This review addresses these complexities, focusing on the emerging HER2-Low and Ultralow subtypes, and evaluates the distinct therapeutic responses across the spectrum of HER2 expression in different BC subtypes.