Abstract 3828: Understanding the molecular underpinnings of breast cancer brain metastases: implications for early detection and treatment

Abstract Brain metastases (BrM) are a major cause of morbidity and mortality among patients with metastatic breast cancer. Women with metastatic HER2-positive (HER2+) and triple-negative breast cancer (TNBC) have a particularly high propensity to develop BrM, with up to half developing BrM during their lifetime. Currently, apart from assignment of risk by breast cancer subtype, risk factors for the development of BrM are lacking. Given that BrM are associated with a poor prognosis, particularly among patients with TNBC, there is a critical need for biomarkers to identify patients at high risk of BrM for whom future screening and/or prevention strategies can be employed. In this study we performed whole transcriptomic profiling of 53 brain metastases in triplicate with spatial resolution using Bruker’s Digital Spatial Profiler, Whole Transcriptome Assay. Patients with breast cancer BrM who were treated with surgery, whole brain radiotherapy (WBRT) and/or stereotactic radiosurgery (SRS) between 2008 and 2018 were selected, representative sections of tumor were cored and microarrayed prior to spatial transcriptomic profiling of the tumor and tumor microenvironment. Across both HER2+ and TNBC subtypes, spatial deconvolution revealed a high proportion of CD4+ and CD8+ naïve T-cells in the tumor compartments compared to the tumor microenvironment whereas macrophages were the most abundant immune cell type irrespective of subtype in the tumor microenvironment. Differential gene expression analysis demonstrated that higher expression levels of known HER2 mediated genes including MED1, STARD3 and GRB7 were present in the HER2+ brain subtypes. Markers for stem cell features were more prevalent within tumor compartments of TNBC BrM compared to HER2+ BrM. In conclusion, this study characterized the tumor and tumor microenvironment of breast cancer BrM using spatial transcriptomics, identifying molecular underpinnings that may be targeted for BrM prevention and/or treatment. Citation Format: Melanie Spears, Megan Hopkins, Rania Chehade, Italo Fernandes, Vida Talebian, Jane Bayani, Katarzyna Jerzak. Understanding the molecular underpinnings of breast cancer brain metastases: implications for early detection and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3828.