Evaluating Patient-Derived Tumour Xenografts as Translational Models of Breast Cancer Brain Metastases: Molecular Characterisation and Therapeutic Exploration

Brain metastases occur in 20–40% of patients with metastatic breast cancer and are linked to a poor prognosis. Current treatment options primarily include surgical resection, stereotactic radiosurgery, whole-brain radiotherapy, chemotherapy, and targeted therapy. However, there is an urgent need for more effective therapies for breast cancer brain metastases (BCBM).
In this study, we established patient-derived tumour xenograft (PDTXs) models and characterised their in vivo growth. Comparison of PDTX models with matched patient tumours using mRNAseq, immunohistochemistry, and immunofluorescence showed overall molecular concordance, except for a striking reduction in cyclin D2 (CCND2) expression in xenografts. Alongside a literature-based analysis, I identified cell cycle dysregulation as a hallmark of BCBM, with 16.6% of the most frequently mutated genes involved in the G1/S phase, implicating targeting of the cell-cycle machinery through the inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) as a promising therapeutic approach.
Pharmacokinetic study confirmed that palbociclib can access BCBM. The efficacy of orally administered palbociclib and abemaciclib was analyzed in two different PDTX models (ER-/PR-/Her+ BCBM2 and ER+/PR+/Her2+ BCBM6 models) by quantifying Ki67 expression, which demonstrated a decrease in cancer cell proliferation following 5 days of drug administration. While palbociclib prolonged survival in the BCBM2 model, it exhibited only cytostatic effects, failing to induce tumour regression. No further improvement in survival was observed when combining palbociclib with irradiation. While neither drug altered FOXM1 expression nor induced apoptosis, palbociclib reduced MHC class I expression in the BCBM6 model, which could potentially compromise anti-tumour immunity in immunocompetent hosts.
Cell cycle dysregulation is a hallmark of BCBM. However, current CDK4/6 inhibitors fail to induce tumour regression due to limited intracranial drug penetration and low cytotoxicity. Combining CDK4/6 inhibitors with immune-targeting therapies and developing next-generation inhibitors with improved brain penetration and cytotoxic efficacy offer promising strategies for advancing BCBM treatment.