title: Breast Cancer Brain Metastases: Clonal Evolution in Clinical Context.
abstract: Brain metastases are highly-evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely-held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management.
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland 4029, Australia. j.saunus@uq.edu.au.|QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. j.saunus@uq.edu.au.
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Saunus
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland 4029, Australia. amy.reed@uq.edu.au.|QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. amy.reed@uq.edu.au.
authors.forename: Amy E
authors.initials: AE
authors.lastname: McCart Reed
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland 4029, Australia. m.lim@uq.edu.au.|QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. m.lim@uq.edu.au.
authors.forename: Zhun Leong
authors.initials: ZL
authors.lastname: Lim
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland 4029, Australia. s.lakhani@uq.edu.au.|Pathology Queensland, Royal Brisbane Women's Hospital, Herston, Queensland 4029, Australia. s.lakhani@uq.edu.au.|UQ School of Medicine, Herston, Queensland 4006, Australia. s.lakhani@uq.edu.au.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
mesh_terms: D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000473:pathology*; D060965:Clonal Evolution; D005260:Female; D006801:Humans; D008954:Models, Biological
keywords: brain metastases; breast cancer; clonal evolution