Clinical Outcomes of CDK4/6 Inhibitor Therapy in HR+/HER2− Metastatic Breast Cancer: A Multicenter Comparison of HER2‐Low and HER2‐Zero Subgroups

<b>Background:</b> The clinical impact of HER2-low status on the efficacy of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Therapy in patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC) remains unclear. <b>Methods:</b> We conducted a multicenter, retrospective analysis including 212 female patients with HR+/HER2-MBC treated with CDK4/6is between 2018 and 2022. Patients were classified as HER2-zero or HER2-low based on immunohistochemistry results. Progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were compared between the two groups. <b>Results:</b> Median PFS was 16.0 months in the HER2-low group and 13.9 months in the HER2-zero group (<i>p</i>=0.40). In first-line therapy, PFS was numerically longer in the HER2-low group (18.6 vs. 14.9 months; <i>p</i>=0.26) although this was not statistically significant. ORR was 71.4% in HER2-low and 62% in HER2-zero patients, and DCR was 86.6% and 82%, respectively (both <i>p</i> > 0.05). Subgroup analyses showed that within the HER2-low group, patients with ≥ 2 metastatic sites had significantly shorter PFS compared with those with a single site (14.1 vs. 20.2 months; <i>p</i>=0.02), and the presence of visceral metastases was associated with poorer PFS (<i>p</i>=0.003). Overall survival (OS) data were immature, with only 24.6% of the patients deceased at the time of analysis. <b>Conclusion:</b> HER2 status did not significantly impact treatment outcomes with CDK4/6i in HR+/HER2-negative MBC patients. However, subgroup analyses indicated that metastatic burden, particularly the number of metastatic sites and the presence of visceral disease, may adversely influence PFS. These findings highlight the need for further validation in larger prospective studies.