Breast cancer brain metastasis: Emerging therapeutic strategies and challenges

To the Editor: Breast cancer brain metastasis (BCBM) remains a critical challenge due to its poor prognosis and limited treatment options. The median survival after diagnosis is typically only 7–8 months. This survival rate is heavily influenced by a range of factors. A significant hurdle in treating BCBM is the blood–brain barrier (BBB), which impedes the effective delivery of many therapeutic agents. Additionally, the inherent heterogeneity of breast cancer, particularly among its subtypes (e.g., human epidermal growth factor receptor 2-positive [HER2+] and triple-negative [TNBC]), complicates the development of one-size-fits-all treatment regimens. Each subtype exhibits distinct biological behaviors and responses to treatment, which can further limit therapeutic efficacy. Furthermore, the immune and metabolic characteristics of the brain environment create additional barriers; as compared with primary tumors, metastases can adopt different immune evasion strategies. The exclusion of patients with brain metastases from most clinical trials has historically hindered the development of personalized therapies. However, recent advancements have focused on developing subtype-tailored therapeutic strategies, targeting specific molecular pathways, and addressing preclinical-to-clinical translation challenges. This progress highlights the potential of precision medicine in overcoming several of the barriers associated with BCBM and improving patient outcomes. BCBM is a complex, multistep process that begins when primary breast cancer epithelial cells acquire mesenchymal characteristics. This transformation enables tumor cells to become invasive and penetrate the basement membrane where they enter the bloodstream. The primary tumor continuously generates new blood vessels, which support tumor cell proliferation and metastasis while also causing degradation of the surrounding extracellular matrix. Once in the bloodstream, tumor cells exist as circulating tumor cells (CTCs), interacting with stromal cells in the circulation, which aids their journey through the bloodstream to other organs. Brain metastasis involves the adhesion of tumor cells to brain endothelial cells, allowing them to cross the BBB. During this process, tumor cells must adapt to the unique immune microenvironment of the brain, form micrometastases, and eventually colonize the new microenvironment.[1] Crossing the BBB is a major hurdle in brain metastasis, requiring tumor cells to utilize a series of molecular mechanisms, such as selective adhesion, upregulation of invasiveness-related proteins, and alterations in vascular permeability, to successfully enter the brain [Supplementary Figure 1, https://links.lww.com/CM9/C589]. BCBM has specific molecular subtypes, influencing both BCBM risk and treatment outcomes [Supplementary Table 1, https://links.lww.com/CM9/C589]. The luminal A and luminal B subtypes are associated with a lower risk for BCBM than the HER2+ and TNBC subtypes, which are more prone to metastasis. For HER2+ BCBM, antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), have proven effective in clinical trials, such as DESTINY-Breast01 and DESTINY-Breast03. The ability of T-DXd to penetrate the BBB and target both tumor cells and surrounding cells contributes to its efficacy in treating both stable and active brain metastases. Additionally, tucatinib combined with trastuzumab and capecitabine in the HER2CLIMB trial increased median survival by 9.1 months for HER2+ BCBM patients. In contrast, patients with TNBC BCBM, particularly in those with BRCA1/2 mutations, benefit from therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors (e.g., talazoparib). The tumor associated calcium signal transducer 2 (TROP-2)-targeting ADC sacituzumab govitecan (SG) has shown promise in extending progression-free survival (PFS) for advanced TNBC patients, including patients with brain metastases, as demonstrated in the phase III ASCENT trial.[2] Other potential therapies for TNBC BCBM include ANG1005, a paclitaxel conjugate, which has shown efficacy in phase II trials. Moreover, targeted inhibitors of the PI3K/AKT/mTOR signaling pathway and fatty acid synthase inhibitors are being explored as treatments for TNBC brain metastasis. Although the Impassion130 trial revealed no benefit of immunotherapy for TNBC BCBM, preclinical studies suggest that combining radiotherapy with immunotherapy may have synergistic effects. Ongoing clinical trials, such as NCT03483012 and NCT03449238, are evaluating the effectiveness of this combination therapy. These findings highlight the importance of subtype-specific treatment strategies, emphasizing molecular drivers as crucial factors in shaping therapeutic approaches and improving outcomes for BCBM patients. The brain tumor microenvironment (TME), composed of astrocytes, microglia, and neurons, plays a pivotal role in the progression of BCBM. Astrocytes contribute to chemoresistance by sending survival signals, such as glutathione, via gap junctions to tumor cells, thus shielding them from the effects of chemotherapy. Targeting connexin 31 (Cx31) and focal adhesion kinase (FAK) to disrupt this communication has emerged as a promising strategy to sensitize tumors to treatment. Microglia, the resident immune cells of the brain, play various roles in BCBM.[3] Evans et al[4] reported that through latent Dirichlet allocation (LDA) analysis, microglia can be divided into three groups on the basis of their immune response: The secretion, interferon (IFN), and antigen-presentation (AP) groups. These cells play crucial roles in immune surveillance and the antitumor response. Proinflammatory microglia activate immune-related pathways such as those associated with antigen presentation and IFN responses, and targeting these pathways may enhance immune responses against BCBM. Notably, microglia in TNBC and HER2+ breast cancer have distinct functions in the early stages of brain metastasis. In TNBC, microglia interact with astrocytes and form sheath-like structures around blood vessels, whereas in HER2+ breast cancer, microglia encase tumor cells in a different structure that is isolated by the extracellular matrix. These structural differences trigger various Alzheimer’s disease-associated microglial (DAM) responses. In TNBC, the microglial response peaks in the early phase and is associated with high levels of cytokines, such as TNF-β and IL-β, promoting tumor growth, angiogenesis, and vascular permeability. In contrast, an antitumor AXL receptor tyrosine kinase (AXL) signaling pathway is activated in microglia during the later DAM phase in HER2+ breast cancer models.[5] These insights underscore the critical role of microglia in the immune response to BCBM and suggest their potential as therapeutic targets. Furthermore, neuronal signaling contributes to BCBM by allowing tumor cells to bypass the BBB and invade leptomeninges, where they interact with resident macrophages to secrete glial cell-derived neurotrophic factor (GDNF), which supports tumor growth.[6] Additionally, breast cancer cells are influenced by sensory dorsal root ganglion (DRG) neurons, which release substance P (SP), inducing tumor cells to release single-stranded RNA (ssRNA). These ssRNA molecules engage toll-like receptor 7 (TLR7) on cancer cells, increasing the expression of genes that promote metastasis, tumor growth, and invasion.[7] Together, these findings highlight the intricate interactions between tumor cells and brain components, underscoring the therapeutic potential of targeting TME elements to improve BCBM treatment outcomes. Despite promising preclinical advances, the clinical translation of therapies for BCBM faces several significant challenges. One of the primary hurdles is BBB penetration. Only ~5% of systemic drugs can reach therapeutic concentrations within the central nervous system (CNS), limiting the effectiveness of many treatments. Innovative strategies such as nanoparticles and ultrasound-mediated BBB disruption, such as the use of lipid-based ultrasound microbubbles (LIPU/MBs), have been proposed to improve drug delivery to the brain, with some studies showing encouraging results.[8] Additionally, the TME significantly contributes to therapy resistance. Astrocytes induce autophagy, which protects tumor cells from chemotherapy, whereas microglia upregulate PD-L1, inhibiting immune responses. To overcome these challenges, dual-targeting strategies that target both tumor cells and TME components, such as C-X-C chemokine receptor type 4 (CXCR4) inhibitors, are under investigation to disrupt the protective microenvironment and improve treatment efficacy.[9] Another critical barrier to effective BCBM treatment is the lack of subtype-specific trials. Most clinical trials exclude patients with BCBM, especially those with TNBC, a subtype with a particularly poor prognosis. The METIS trial (NCT02831959), which evaluates tumor-treating fields (TTFields) in BCBM, represents an effort to bridge this gap and includes patients with brain metastases, offering hope for more inclusive and relevant clinical studies for BCBM patients. Notably, currently employed preclinical models for studying BCBM face significant limitations, particularly in their ability to replicate the complexity and heterogeneity of human disease. Traditional models, including mouse xenografts and cell line-based models, often fail to accurately represent the diversity observed in human tumors. Considering the limitations of traditional models, the Clustered regularly interspaced short palindromic repeat (CRISPR)-edited CTC-derived model may represent an important breakthrough for tracking the metastatic cascade in real time, offering critical insights into the stepwise genetic dependencies of metastasis. Bailey et al[10] employed an in vivo CRISPR screening technique in CTC xenografts to identify key genetic drivers across metastatic stages, including intravasation and organ adaptation, identifying potential therapeutic targets, such as plk1. A CRISPR screen in TNBC models further revealed metabolic dependencies that drive lung metastasis, demonstrating how lipid metabolism alterations promote immune evasion and metastatic niche formation.[11] These findings highlight the potential of CRISPR-based approaches to reveal metastatic mechanisms, refine targeted therapies, and improve prognostic strategies for aggressive cancers. In conclusion, significant progress has been made in the treatment of BCBM in recent years. However, challenges such as crossing the BBB, adaptive changes in the TME, and drug resistance remain. Future research should focus on optimizing drug delivery technologies, such as nanocarriers and ultrasound-mediated drug permeation, that enable drugs to cross the BBB. It is also necessary to further analyze the subtype-specific molecular mechanisms of BCBM to develop precise treatment strategies. Moreover, efforts should be made to promote the application of CRISPR and single-cell sequencing technologies to explore in depth the relationship between drug resistance and the microenvironment. Additionally, the inclusiveness of clinical trials should be enhanced, and the strategies of combination therapies should be optimized to improve the survival benefits and treatment accessibility for patients with BCBM. Conflicts of interest None. Funding This work was supported by the Support Program of Innovation Research Project from 0 to 1, Sichuan University (No. 2023SCUH0071), the National Natural Science Foundation of China (No. 82173280), the Support Program of Science & Technology Department of Sichuan Provincial (No. 2025ZNSFSC0694), and the Fundamental Research Funds for the Central Universities (No. SCU2024ZLYJ-8).

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