Prognostic role of HER2-low expression in HR +/HER2- metastatic breast cancer treated with CDK4/6 inhibitors

The low expression of human epidermal growth factor receptor 2 (HER2) in hormone receptor positive (HR +) metastatic breast cancer has become a novel area of interest, particularly after the demonstration that it can be targeted with antibody–drug conjugates (ADCs). This study aimed to describe the clinicopathological characteristics and real-world survival outcomes associated with HER2-low status in HR + /HER2 negative (-) metastatic breast cancer patients treated with cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy. A retrospective cohort study was conducted including 140 patients treated with CDK 4/6 inhibitors and endocrine therapy for HR + /HER2- metastatic breast cancer. Patients were stratified based on HER2 expression levels assessed by immunohistochemistry (IHC): HER2-zero (IHC score 0) and HER2-low (IHC score 1 + or 2 + /fluorescence in situ hybridization (FISH) negative). Appropriate statistical tests were used to evaluate the association between clinicopathologic variables and HER2 subgroups. Kaplan–Meier survival curves and log-rank tests were applied to assess differences in progression-free survival (PFS) and overall survival (OS) between the groups. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors associated with PFS and OS. The median age of the patients was 51 years (interquartile range (IQR): 43–64 years), and the median follow-up period was 29.9 months (95% confidence interval (CI): 27.2–32.6 months). HER2-low expression was identified in 40 (28.6%) patients. Among patients with HER2-low expression, 26 had an IHC score of 1 + , and 14 had a score of 2 + /FISH-negative. The median PFS was 11.3 months (95% CI: 3.1–19.6 months) in the HER2-low group and 34.3 months (95% CI: 25.1–43.6 months) in the HER2-zero group (p = 0.018). This difference did not remain statistically significant in the multivariate analysis. Independent predictors of shorter PFS included liver metastases, recurrent disease, high Ki-67 index, and low ER expression. This study does not provide sufficient evidence to support HER2-low status as an independent prognostic factor in HR + /HER2- metastatic breast cancer. Prospective studies with larger cohorts are warranted to further clarify this association.