Breast cancer brain metastasis: mechanisms, emerging biomarkers, and therapeutic opportunities

Breast cancer brain metastasis (BCBM) is a clinically distinct form of metastatic breast cancer that causes substantial neurological morbidity and mortality. This review examines the biological bottlenecks that precede a detectable brain lesion: survival in the circulation, interaction with the cerebral endothelium, passage across the blood-brain barrier (BBB), persistence in neural tissue, and intracranial outgrowth. We emphasize how astrocytes, microglia, neurons, stromal cells, and the nutrient environment of the brain shape these events and influence treatment response. These biological features also shape disease assessment. Magnetic resonance imaging defines lesion burden but cannot reliably determine molecular status, whereas tissue sampling is invasive and plasma biomarkers may underrepresent disease confined to the central nervous system. We therefore examine the complementary roles and current limitations of tissue reassessment, blood- and cerebrospinal fluid-based liquid biopsy, molecular imaging, and artificial intelligence-assisted image analysis. Experimental evidence is interpreted according to the questions that individual models can answer. Spontaneous, intravascular, and intracranial models retain different stages of the metastatic cascade, while immunocompetent, patient-derived xenograft, and organoid systems differ in their ability to reproduce immune interactions and patient heterogeneity. Treatment is considered by subtype and clinical setting, including the need for immediate local control, intracranial disease burden, leptomeningeal involvement, previous therapy, and extracranial disease status. Clinical evidence is most developed for human epidermal growth factor receptor 2 (HER2)-positive BCBM, whereas treatment of hormone receptor-positive/HER2-negative disease and triple-negative breast cancer remains more dependent on local therapy and systemic indications derived from extracranial disease. Linking brain-specific mechanisms with biomarker selection, model interpretation, and subtype-guided treatment may improve the translation of experimental findings into clinically meaningful strategies.