Two Niches, One Disease: Brain and Leptomeningeal Metastases in Breast Cancer: A Narrative Review

Central nervous system (CNS) metastasis is an increasingly important challenge in advanced breast cancer, yet brain parenchymal metastases (BM) and leptomeningeal metastases (LM) are often considered within a single framework despite occupying biologically distinct CNS compartments. In this narrative review, we synthesize breast cancer-specific mechanistic and clinical evidence to examine how these two forms of CNS disease differ in metastatic entry, local adaptation, molecular evolution, biomarker representation, and therapeutic vulnerability. Parenchymal BM primarily arise through haematogenous dissemination and subsequent adaptation to a neurovascular, neural, and immune-rich environment, where successful colonization requires more than blood–brain barrier traversal and is supported by reciprocal tumour–host interactions and metabolic plasticity. By contrast, LM develops within a fluid-dominated, CSF-facing compartment characterized by distinct meningeal and blood–CSF interfaces, constrained resource availability, and dynamic immune conditions. C3–C3aR-mediated barrier remodeling and LCN2–SLC22A17-dependent iron acquisition are supported mainly by experimental LM models and selected patient-derived observations, including mixed-cancer cohorts, and require broader breast cancer-specific clinical validation. Genomic and phenotypic studies further indicate that BM and LM can share metastatic ancestry while undergoing branched and compartment-associated evolution, although observed divergence may also reflect pre-existing heterogeneity, treatment selection, elapsed time, and sampling effects. Therapeutic efficacy therefore depends not only on CNS drug access but also on target expression, tumour state, niche support, disease geometry, and prior treatment. By integrating metastatic dissemination, niche adaptation, molecular evolution, biomarker representation, and therapeutic vulnerability within a single comparative framework, this review links compartment-associated biology to molecular sampling, experimental modeling, and clinical trial design. Clinically, this framework may inform compartment-specific molecular sampling and trial stratification by BM treatment status and LM presentation, although its utility for individual treatment selection requires prospective validation. Future studies combining paired multi-compartment sampling, lineage-resolved models, and serial CSF and plasma profiling will be needed to distinguish shared ancestry from niche-associated adaptation and treatment-driven evolution.