Triple-Negative Breast Cancer Brain Metastasis: A Comprehensive Review of Epidemiology, Molecular Pathobiology, and Therapeutic Frontiers

Triple-negative breast cancer (TNBC) is associated with a high risk of brain metastases (BMs). Although systemic therapies have improved extracranial disease control, the central nervous system (CNS) remains less accessible to numerous agents. As a result, this limited drug penetration makes brain metastases (BMs) remain common in TNBC, which are a leading cause of serious symptoms. This review summarizes recent key advances in triple-negative breast cancer brain metastases (TNBC-BMs), including epidemiology, prognostic stratification, biological mechanisms of CNS tropism and treatment resistance, and evolving management strategies. We discuss potential mechanisms of brain colonization, including the FOXC1-CXCR4 axis, ST6GALNAC5-related interactions with the blood–brain barrier (BBB), and the bidirectional crosstalk between metastatic cells and the brain microenvironment, particularly astrocytes and microglia. Furthermore, we evaluate the evolving clinical management, emphasizing the transition from whole-brain radiotherapy (WBRT) toward more selective local approaches such as stereotactic radiotherapy (SRS) and hippocampal sparing techniques. Concurrently, we examine the integration of CNS active systemic therapy across specific molecular subsets. This review systematically distinguishes standard-of-care interventions from investigational strategies, ultimately underscoring critical evidence gaps within the TNBC-BM landscape.