image: Tumor cells from the primary lesion undergo EMT and invade the bloodstream. Once in the circulatory system, these CTCs enter a dormant state to evade immune surveillance. Dormant tumor cells are transported to the brain via blood circulation, where they penetrate the BBB and undergo MET. Following this, tumor cells remodel the brain microenvironment and establish co‐colonization with various brain cells, ultimately leading to the formation of BCBrM.
Credit: Suling Liu
A team of researchers led by Dr. Suling Liu from The First Affiliated Hospital of Zhejiang University has published a comprehensive review on breast cancer brain metastasis (BCBrM), a devastating complication with limited treatment options and poor prognosis. The article, co-authored by Jing Feng, Yuwei Tao, and Fengkai Li, systematically analyzes the biological mechanisms, preclinical models, and therapeutic innovations in BCBrM.
BCBrM occurs in approximately 5–20% of breast cancer patients and is especially common in HER2-positive and triple-negative subtypes. As systemic therapies improve survival, the incidence of BCBrM is rising, underscoring the urgent need for effective brain-targeted treatments.
The review outlines the metastatic cascade, beginning with local invasion and intravasation, followed by circulation, BBB extravasation, and colonization in the brain. Key molecular pathways, such as TGF-β, Wnt/β-catenin, PI3K/AKT, Notch, HER2-HER3, and JAK/STAT, orchestrate these processes, enabling tumor cells to adapt to the neural niche and evade immune surveillance.
A major focus is placed on the brain microenvironment, where astrocytes, microglia, and neurons interact with metastatic cells through gap junctions, cytokine signaling, and metabolic coupling. These interactions create a supportive niche that promotes tumor survival and resistance to therapy.
The authors also evaluate current preclinical models, including intracardiac injection, orthotopic brain injection, patient-derived xenografts, and organoids, and highlight their strengths and limitations in recapitulating human BCBrM. Emerging approaches such as humanized mouse models and advanced imaging techniques are paving the way for more translational research.
On the therapeutic front, the review discusses the limited efficacy of conventional treatments and the promise of CNS-penetrant agents like tucatinib, neratinib, and antibody-drug conjugates such as trastuzumab deruxtecan. Immunotherapy, nanoparticle-based delivery, and focused ultrasound are also explored as strategies to overcome the blood-brain barrier.
Finally, the authors call for cross-disciplinary collaboration, innovative clinical trial designs, and personalized treatment strategies to improve outcomes and quality of life for patients with BCBrM.
See the article: Breast Cancer Brain Metastasis: Bridging Biological Mechanisms to Therapeutic Innovations
https://doi.org/10.1002/mog2.70043
Journal
MedComm – Oncology
Article Title
Breast Cancer Brain Metastasis: Bridging Biological Mechanisms to Therapeutic Innovations
Article Publication Date
24-Oct-2025