Prognostic impact of HER2-low versus HER2-zero expression by hormone receptor status in early breast cancer: a retrospective cohort study

HER2-low breast cancer, defined as immunohistochemistry (IHC) 1 + or 2 + without ERBB2 amplification, has uncertain long-term prognostic significance compared with HER2-zero breast cancer (IHC 0), particularly according to hormone receptor (HR) status. Recent therapeutic advances targeting HER2-low disease have increased interest in understanding its biological and prognostic characteristics in early breast cancer. However, despite increasing recognition of HER2-low breast cancer as a distinct therapeutic entity, its prognostic significance in early-stage breast cancer remains controversial, with inconsistent findings reported across studies, particularly according to HR status. In this study, we aimed to evaluate the prognostic relevance of HER2-low expression in early-stage breast cancer, stratified by HR status. We retrospectively analyzed data from 7,281 patients with HER2-negative early breast cancer treated between 2005 and 2023 at a single institution. Clinicopathological characteristics and long-term survival outcomes were compared between the HER2-low and HER2-zero subgroups according to HR status. Long-term overall survival (OS) and breast cancer-specific mortality were assessed according to HR status using survival analyses. HER2-low tumors demonstrated more luminal-like biological characteristics, including higher hormone receptor positivity, lower histologic grade, and lower Ki-67 expression, although they also showed relatively higher tumor and greater nodal stage involvement. However, HER2-low status was not associated with improved OS in the overall cohort. Among HR-positive patients, survival outcomes were comparable between HER2-low and HER2-zero tumors. Among HR-negative patients, HER2-low expression demonstrated a trend toward poorer survival outcomes; however, this association did not remain statistically significant after multivariable adjustment. A significant interaction between HER2 status and Ki-67 expression was observed in HR-negative disease, with HER2-low tumors demonstrating particularly poor outcomes among patients with low Ki-67 expression. HER2-low expression demonstrates distinct prognostic implications according to HR status, supporting the biological heterogeneity of HER2-negative breast cancer. These findings suggest that the prognostic impact of HER2-low expression is modified by both HR status and proliferative activity, identifying a potentially high-risk subgroup of HR-negative, HER2-low tumors with low Ki-67 expression. Further studies are warranted to clarify the biological mechanisms underlying the differential prognostic effects of HER2-low expression across HR subgroups.