Abstract PS1-11-04: Her2-low expression is associated with inferior progression-free survival in hr-positive metastatic breast cancer treated with CDK4/6 inhibitors

Abstract Background: CDK4/6 inhibitors have become a standard treatment option for patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. However, there remains a need for reliable biomarkers to predict treatment response. Recently, tumors classified as HER2-low have emerged as a distinct subgroup, exhibiting unique biological characteristics compared to traditional HER2-negative disease. This study aimed to investigate the impact of HER2 immunohistochemical expression levels on progression-free survival (PFS) in HR+ metastatic breast cancer patients treated with CDK4/6 inhibitors. Methods: This multicenter, retrospective study aimed to evaluate the impact of HER2 immunohistochemical (IHC) expression on PFS in patients with HR+, HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors (ribociclib or palbociclib). Patients were classified as HER2-negative (IHC 0) or HER2-low (IHC 1+ or 2+/ISH−) based on IHC scores. The primary endpoint was PFS, defined as the time from initiation of CDK4/6 therapy to radiological or clinical progression or death. Survival outcomes were analyzed using the Kaplan-Meier method and compared with the log-rank test. Factors associated with PFS were further evaluated using univariate and multivariate Cox regression analyses. Results: A total of 344 patients were included in the study. The mean age was 58.7 ± 12.3 years, and 70.6% of the patients were postmenopausal. The median follow-up duration was 20.0 months (IQR: 11.4-34.4). The progression rate was 38.3% in HER2-negative patients (IHC 0) and 52.5% in HER2-low patients (IHC 1+ or 2+/ISH−). According to Kaplan-Meier analysis, the median progression-free survival (PFS) was 36.4 months (95% CI: 27.1-45.7) in the HER2-negative group and 20.4 months (95% CI: 8.5-32.2) in the HER2-low group (log-rank p = 0.028). In univariate analysis, shorter PFS was significantly associated with high tumor grade (G3), PR-negativity, HER2-low expression, presence of visceral metastasis, and involvement of multiple metastatic sites at treatment initiation. In multivariate analysis, HER2-low expression (p = 0.041), visceral metastasis (p = 0.001), and PR-negativity (p = 0.003) were identified as independent predictors of inferior PFS. Conclusion: In HR+ metastatic breast cancer patients treated with CDK4/6 inhibitors, HER2-low expression was associated with shorter progression-free survival compared to HER2-negative disease. These findings suggest that HER2-low tumors may represent a biologically distinct subgroup with prognostic implications. HER2 expression levels should be considered when assessing prognosis, and further prospective studies are warranted to validate these observations. Citation Format: F. Kemik, B. Koylu, C. I. Kikili, N. Demir, B. Guney, A. K. Guren, E. Karanci, D. Tunali, S. Lacin, D. Tural, R. U. Gursu, O. Kostek, D. Kivrak Salim, F. Selcukbiricik, S. Gunduz. Her2-low expression is associated with inferior progression-free survival in hr-positive metastatic breast cancer treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-11-04.