Abstract Background: The Central nervous system (CNS) is a frequent and clinically significant site of progression in advanced HER2-positive (HER2+) breast cancer. Identifying patients at high risk for CNS progression could inform more personalized surveillance and therapeutic strategies. Prior work has demonstrated the prognostic value of the HER2DX ERBB2 mRNA score in this setting (NPJ Breast Cancer 2025; SABCS 2024). In addition, the HER2DX metastatic prognostic score—an integrated model combining ERBB2 with additional molecular signatures—was developed to predict overall survival (SABCS 2025, submitted). Here, we report the development and validation of the HER2DX CNS progression score, a distinct genomic tool specifically designed to predict the risk of brain metastasis. Methods: Transcriptomic data were analyzed from 215 patients with HER2-positive advanced breast cancer treated with first-line trastuzumab, pertuzumab, and chemotherapy (THP), including 93 cases from Spain and 122 from Poland. All tumor samples were profiled using the standardized HER2DX gene expression platform. Biological features associated with CNS progression were explored in the combined cohort, and a genomic score was developed using key signatures. Coefficients were derived in the Spanish cohort, and the final score was validated in the Polish cohort. Associations with CNS progression and overall survival were estimated using Cox models and Kaplan-Meier curves. Results: In the combined cohort (n=215), the median follow-up was 37.1 months. A total of 53 patients (24.8%) developed brain metastases. No significant differences in CNS progression rates (27.2% and 23.0%) or time to CNS progression (hazard ratio HR 0.90, 95% CI 0.51-1.56, p=0.70) were observed between cohorts. Clinical variables associated with CNS progression included younger age and having ≥3 metastatic sites. In contrast, hormone receptor status, HER2 IHC (3+ vs other), menopausal status, biopsy site (primary vs. metastatic), bone disease, and best overall response to THP were not associated with brain metastasis.HER2DX assay identified 3 main genomic patterns associated with CNS progression: (1) HER2DX ERBB2 expression and lower time to CNS progression, (2) HER2DX luminal score and longer time to CNS progression, and (3) a new HER2DX immune-related signature associated with longer time to CNS progression. In the Spanish set, the 3-year cumulative incidence of CNS progression was 42.8% in the HER2DX CNS progression high-risk group vs. 24.9% in the intermediate-risk group vs. 15.5% in the low-risk groups (HR between low vs high 0.32, 0.11-0.90, p=0.032); in the Polish set, the 3-year cumulative incidence of CNS progression was 39.2% in the HER2DX CNS progression high-risk group vs. 13% in the intermediate-risk group vs. 4.3% in the low-risk groups (HR between HER2DX low vs high groups of 0.11, 0.02-0.83, p=0.033). Importantly, the HER2DX CNS progression score was not associated with PFS or OS, confirming its specificity for CNS progression. Conversely, the HER2DX metastatic prognostic score (submitted to SABCS 2025) was not associated with CNS progression, and the two scores were uncorrelated (Pearson r=-0.049). Conclusions: The HER2DX CNS progression score is a novel, biology-informed genomic tool that independently predicts brain metastasis in HER2+ advanced breast cancer treated with first-line THP. These findings support its potential integration into clinical workflows to personalize CNS surveillance and treatment strategies. Citation Format: R. Sanchez-Bayona, S. Cobo, M. Kubeczko, J. Soberino, M. Rey, B. Pycinski, E. Chmielik, J. Montes, F. Pardo, V. Sirenko, P. Galván, A. Lesniak, M. Oczko-Wojciechowska, I. Monge, M. Gonzalez, I. Garcia-Fructuoso, F. Schettini, G. Villacampa, T. Pascual, L. Paré, F. Brasó-Maristany, E. Ciruelos, A. Prat, M. Jarzab. Development of the HER2DX Predictor of Brain Metastasis in Advanced HER2-Positive Breast Cancer Treated with First-Line THP 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 PS5-01-08.
Sánchez-Bayona et al. (Tue,) studied this question.