Breast cancer brain metastases (BCBrMs) remain a major clinical challenge, affecting up to 30 % of patients with metastatic breast cancer and associated with a poor prognosis. While genomic studies have revealed recurrent alterations in BCBrMs, translating these insights into effective therapies has been limited by the lack of high-fidelity preclinical models. We performed an integrated analysis of 16 published genomic datasets from 223 BCBrM patients to define recurrent alterations and actionable pathways. To functionally validate therapeutic strategies, we established the first expandable patient-derived organoid (PDO) models from three patients with BCBrMs. Organoids were characterized histologically and genomically, and then subjected to personalized drug sensitivity testing based on both the BCBrM-specific genomic landscape and individual mutation profiles. Genomic analysis revealed frequent alterations in HER2/EGFR, PI3K/AKT/mTOR, cell cycle, TP53, and DNA damage response pathways, with 11 out of the 12 most recurrently altered genes being clinically actionable. All organoids retained the histopathological and genomic fidelity of their primary tumors and were successfully expanded for in vitro drug testing. Functional screening showed that HER2 + organoids were sensitive to HER2/EGFR inhibitors (afatinib, pyrotinib), whereas HR+ /HER2- organoids responded to PI3K/AKT inhibitors. However, discrepancies between genomic alterations and drug response—such as the lack of efficacy of everolimus despite PI3K pathway alterations—underscore the limitations of genomics alone and the necessity of functional validation. Together, our study updated the genomic landscape of BCBrMs and developed the first highly efficient and expandable BCBrM-derived organoid platform. In addition, we demonstrated that integrating organoid-based functional assays with genomic profiling enables accurate prediction of therapeutic vulnerabilities. Our integrated approach provides a clinically relevant framework for precision therapy and a transformative platform for translational research in brain metastases.
Hu et al. (Sun,) studied this question.