Abstract PS5-01-21: Prognostic Significance of Circulating Tumor Cell Subtypes in HER2+ Metastatic Breast Cancer with Central Nervous System Metastases

Abstract Background: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) are at increased risk for developing central nervous system (CNS) metastases, presenting a significant clinical challenge and a major cause of morbidity and mortality in this population. Circulating tumor cells (CTCs) offer a noninvasive tool for disease monitoring; however, the prognostic significance of CTC subtypes in the context of CNS involvement remains unclear. This study examines the association between CTC subtypes and CNS progression and outcomes in patients with HER2+ MBC and detectable HER2+ CTCs. Methods: This retrospective cohort study examined patients with MBC who had CTCs collected from blood samples between 2016-2024 under an IRB-approved protocol (NU16B06) at Northwestern University Robert H. Lurie Comprehensive Cancer Center. CTC enumeration was performed via CELLTRACKS (Menarini). Patients with CTC samples collected within 6 months prior to radiographic detection of CNS metastases, defined as parenchymal brain metastases (PBM) or leptomeningeal disease (LMD), were included. Early CNS disease was defined as detection of CNS metastases within 12 months of metastatic diagnosis. Patients with at least one HER2+ CTC were analyzed. The relative proportion of CTCs was assessed by including both HER2+ and non-HER2+ CTC counts in multivariable models to capture the distinct contributions of each subtype. Results: 26 patients with HER2+ CTCs who developed CNS metastases were identified. The median age at diagnosis of CNS metastases was 54 years (interquartile range [IQR]: 46-64); 18 (75%) were White, 4 (17%) African American, and 2 (8.3%) Asian. At radiographic detection, 21 (80.8%) had PBM, 3 (11.5%) had LMD, and 2 (7.7%) had both. Median total CTC count was 15 (IQR: 5-108), and median HER2+ CTC count was 6 (IQR: 2-59). Following CNS detection, 13 (50%) received HER2-targeted therapy, 8 (31%) received non-HER2 therapy, and 5 (19%) received no therapy. Median overall survival (OS) was 13.0 months with HER2-targeted therapy versus 7.0 months with non-HER2 therapy (p=0.32), while median progression-free survival (PFS) was 2.6 vs. 2.0 months, respectively (p=0.98). After adjusting for extracranial disease burden, receipt of radiation, and CTC counts, HER2-targeted therapy was not associated with differences in OS (HR 0.50, 95% CI 0.16-1.50, p=0.2) or PFS (HR 1.89, 95% CI 0.55-6.47, p=0.3). Similarly, after multivariable adjustment, HER2+ CTC count was not associated with OS (HR 1.006 per CTC, 95% CI 0.99-1.02, p=0.5) or PFS (HR 0.997 per CTC, 95% CI 0.98-1.01, p=0.7), and non-HER2+ CTC count was not associated with OS (1.007 per CTC, 95% CI 0.10-1.02, p=0.2) or PFS (HR 1.004 per CTC, 95% CI 0.99-1.02, p=0.4). After multivariable adjustment, HER2+ CTC count was not associated with early (<12 months) versus late (>12 months) CNS progression (OR 1.00, 95% CI 0.97-1.03, p=0.9), whereas higher non-HER2+ CTC count was significantly associated with early CNS progression (OR 1.02 per CTC, 95% CI 1.00-1.07, p=0.041). Conclusion: In this real-world cohort of patients with HER2+ CTCs and CNS metastases, higher non-HER2+ CTC burden, included to capture total CTC burden while isolating the effects of HER2+ CTCs, was associated with early CNS progression. HER2+ CTC counts and HER2-targeted therapy were not associated with survival or progression outcomes. These findings suggest that CTC heterogeneity, particularly the presence of non-HER2+ subpopulations, may reflect a biologically aggressive or treatment-resistant phenotype in patients with HER2+ MBC and CNS involvement. The lack of association between HER2+ CTCs and outcomes may reflect the limited cohort size and treatment heterogeneity, highlighting the need for larger studies to clarify the prognostic value of HER2+ CTC burden in this population. Citation Format: D. Jaber, S. Marini, N. Raptis, N. K. Heater, Y. Ma, S. Warrior, L. Flaum, R. Stein, P. Robinson, H. Liu, Y. Zhang, R. Chen, Q. Zhang, L. C. Platanias, W. Gradishar, P. U. Kumthekar, J. Lu. Prognostic Significance of Circulating Tumor Cell Subtypes in HER2+ Metastatic Breast Cancer with Central Nervous System Metastases [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 PS5-01-21.