Breast cancer brain metastasis: from molecular insights to therapeutic innovation

Breast cancer is the most common malignancy in women and a major cause of cancer-related mortality. While early-stage disease is often curable, many patients ultimately develop distant metastases, with the brain representing one of the most devastating sites. Breast cancer brain metastasis (BCBM) is particularly prevalent in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes, leading to severe neurological symptoms, diminished quality of life, and poor prognosis. Despite progress in systemic therapy for primary tumors, outcomes for patients with BCBM remain poor, and these patients are frequently excluded from clinical trials. The pathogenesis of BCBM involves complex interactions between tumor cells and the central nervous system microenvironment. Crossing the blood-brain barrier and adapting to the brain niche requires tumor-stroma crosstalk, including signaling with astrocytes and microglia, which promotes immune evasion, therapeutic resistance, and metastatic outgrowth. Although advances in preclinical models and molecular profiling have provided valuable insights, critical mechanisms remain incompletely understood. Systemic therapies are increasingly important, with HER2-targeted agents, tyrosine kinase inhibitors, and subtype-specific regimens showing activity. Novel approaches, including poly (ADP-ribose) polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidylinositol 3-kinase inhibitors, and antibody-drug conjugates, are under evaluation. This review synthesizes epidemiology, molecular mechanisms, and emerging therapies of BCBM, underscoring advances achieved and highlighting the urgent need for novel targeted strategies and inclusive clinical trials.