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Triple-Negative Breast Cancer Brain Metastasis: A Comprehensive Review of Epidemiology, Molecular Pathobiology, and
Hongli Yang1, Yang Zhao2, Yue Wang2
1Department of Radiation Oncology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China.
Abstract:
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.
Insights
Triple-negative breast cancer brain metastases (TNBC-BMs) are common due to limited drug penetration into the central nervous system (CNS). Management is shifting towards selective local therapies and CNS-active systemic treatments.
Area of Science:
- Oncology
- Neuro-oncology
- Cancer Metastasis
Background:
- Triple-negative breast cancer (TNBC) frequently metastasizes to the brain (BMs).
- The central nervous system (CNS) presents a therapeutic challenge due to limited drug accessibility.
- Brain metastases (BMs) in TNBC significantly impact patient prognosis and quality of life.
Purpose of the Study:
- To review recent advancements in understanding and managing triple-negative breast cancer brain metastases (TNBC-BMs).
- To explore biological mechanisms driving CNS tropism and treatment resistance.
- To evaluate current and emerging therapeutic strategies for TNBC-BMs.
Main Methods:
- Systematic review of current literature on TNBC brain metastases.
- Discussion of epidemiological data and prognostic factors.
- Analysis of biological mechanisms including molecular axes and microenvironment interactions.
- Evaluation of evolving clinical management strategies, including radiotherapy and systemic therapies.
Main Results:
- Key biological mechanisms of brain colonization identified, including the FOXC1-CXCR4 axis and ST6GALNAC5 interactions with the blood-brain barrier (BBB).
- Bidirectional crosstalk between metastatic cells and the brain microenvironment (astrocytes, microglia) is crucial.
- Clinical management is evolving from whole-brain radiotherapy (WBRT) to stereotactic radiotherapy (SRS) and CNS-penetrant systemic therapies.
Conclusions:
- Understanding TNBC-BM pathogenesis is critical for developing targeted therapies.
- Personalized treatment approaches integrating local and systemic therapies are emerging.
- Further research is needed to address evidence gaps in TNBC-BM management.
