Impact of HER2-Low Expression on Clinical Outcomes in Metastatic Breast Cancer Treated with CDK4/6 Inhibitors

<b>Background:</b> The prognostic significance of low-level human epidermal growth factor receptor 2 (HER2) expression in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer remains unclear, particularly in patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). This study aimed to evaluate the impact of HER2-low status on treatment response and survival outcomes in this setting. <b>Methods:</b> This multicenter retrospective cohort study included patients with HR+/HER2- metastatic breast cancer who received first-line endocrine therapy combined with palbociclib or ribociclib between January 2018 and May 2025. HER2-low tumors were defined as immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, while HER2-zero tumors were classified as IHC 0. Treatment response, progression-free survival (PFS), and overall survival (OS) were compared between groups using Kaplan-Meier analysis and Cox regression models. <b>Results:</b> A total of 309 patients were analyzed, including 122 (39.5%) with HER2-low disease and 187 (60.5%) with HER2-zero disease. Baseline clinicopathological characteristics were well balanced between groups. The overall response rate was 75.4% in the HER2-low group and 72.7% in the HER2-zero group (<i>p</i> > 0.05). Median PFS was 23.9 months for HER2-low patients and 25.2 months for HER2-zero patients (log-rank <i>p</i> = 0.785). Median OS was 49.5 and 53.1 months, respectively, with no statistically significant difference (log-rank <i>p</i> = 0.649). HER2 status was not an independent predictor of PFS or OS in multivariable analyses. <b>Conclusions:</b> In patients with HR+/HER2- metastatic breast cancer treated with first-line endocrine therapy plus CDK4/6 inhibitors, HER2-low expression was not associated with differences in treatment response or survival outcomes. These findings suggest that HER2-low status does not have prognostic or predictive relevance in this endocrine-sensitive population.