Abstract PS4-08-01: Overall Survival and Breast Cancer-Specific Survival in HER2-Low versus HER2-Zero Breast Cancer: A Single-Center Cohort Study

Abstract Background Human epidermal growth factor receptor 2 (HER2)-low breast cancer, defined as immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization (ISH), represents approximately 40-50% of all breast cancers. Despite growing therapeutic interest, the prognostic significance compared to HER2-zero (IHC 0) tumors remains controversial. This study aimed to explore the clinicopathologic data and compare survival outcomes between HER2-low and HER2-zero breast cancers. Methods This retrospective cohort study analyzed data from breast cancer patients treated at the National Cancer Center in South Korea. From 13,785 patients diagnosed with breast cancer between 2005 and 2023, a total of 7,281 patients were included after excluding those with no surgery, distant metastasis at presentation, ductal carcinoma in situ (DCIS), follow-up duration <1 year, missing HER2 data, or HER2 IHC 3+ expression. HER2 status was categorized as HER2-low (IHC 1+ or 2+ with ISH-negative) or HER2-zero (IHC 0). Outcomes included overall survival (OS) and breast cancer-specific mortality (BCSM), analyzed using Kaplan-Meier curves and Cox proportional hazards models, stratified by hormone receptor (HR) status. Interaction effects with Ki-67 and HR status were evaluated using restricted cubic spline modeling. Results HER2-low tumors demonstrated more favorable tumor biology than HER2-zero tumors, with higher rates of low histologic grade, low nuclear grade, and lower Ki-67 index (all p<0.001). Overall mortality was significantly lower in the HER2-low group (6.8% vs. 8.3%, p=0.031), although breast cancer-specific mortality was comparable (5.3% vs. 6.0%, p=0.091). Kaplan-Meier analysis showed no significant difference in OS between HER2 groups in the overall population (p=0.88). In HR-positive patients, HER2-low tumors retained favorable features and had lower all-cause (6.0% vs. 7.6%, p=0.034) and breast-cancer-specific mortality (4.2% vs. 4.8%, p=0.035), although OS was not significantly different (p=0.73). Conversely, in HR-negative patients, HER2-low tumors showed no biologic advantage, higher (non-significant) mortality (13.1% vs. 10.4%, p=0.170), and significantly worse OS (p=0.02). Restricted cubic spline analysis showed rising mortality risk with increasing Ki-67 in the overall cohort. No interaction between HER2 status and Ki-67 was observed in the overall or HR-positive groups. However, in HR-negative patients, HER2-low tumors exhibited a U-shaped association with Ki-67, with elevated mortality at both low and high levels (p<0.01). Conclusion HER2-low status is not an independent prognostic factor in the overall or HR-positive breast cancer population but is associated with worse survival in HR-negative patients. Although Ki-67 is widely used to reflect tumor proliferation and prognosis, its predictive value may be limited in HR-negative, HER2-low tumors, suggesting the need for tailored prognostic strategies and potentially more aggressive treatment approaches in this challenging subgroup. Citation Format: M. Lee, D. Choi, H. Chae, J. Kim, J. Hong, E. Lee, J. Han, S. Sim, S. Lee, K. Lee, H. Kang, H. Kim, S. Jung. Overall Survival and Breast Cancer-Specific Survival in HER2-Low versus HER2-Zero Breast Cancer: A Single-Center Cohort Study [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 PS4-08-01.