With a median survival of 4 months, the development of breast cancer leptomeningeal metastasis (BCLM) is devastating for patients. Investigating this often occult disease process is hampered by the difficulty of accessing leptomeningeal tumour material. Here, we utilise cerebrospinal fluid as a source of both cell-free DNA (cfDNA) and disseminated tumour cells, to explore the evolution of BCLM and heterogeneity between leptomeningeal and extracranial sites. CSF cfDNA sequencing detected

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... le somatic alterations in 81% (17/21) of BCLM cases. Further genomic characterisation identified frequently altered genes involved in cell adherens junctions and cytoskeleton/chemotaxis pathways. Patient-derived organoids established from CSF tumour cells allowed profiling of this rarely available biological material, in addition to therapeutic testing and generation of in vivo models. Together these data reveal the development of BCLM is associated with the acquisition of a lobular-like breast cancer phenotype, and highlight potential approaches for tackling this hard-to-treat form of metastatic disease.