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.

SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells

“…Micrometastasis to brain is detected in ~30% of mice within 1 month of xenografting DCIS cells induced to express high levels of SOX11. SOX11 is amplified and overexpressed in ~30% of brain metastases in a recent study of a small cohort of breast cancer patients that were profiled using an integrated genomic and transcriptomic analysis of fresh frozen tumour samples ( Saunus et al, 2017 ; Saunus et al, 2015 ) and highly expressed by ~30% of BCBM in another independent study ( Varešlija et al, 2019 ). Our finding that iSOX11 mammary tumours spontaneously metastasize to the brain is clinically relevant.…”

CRISPR Technology for Breast Cancer: Diagnostics, Modeling, and Therapy

“…The technical and clinical advantages and disadvantages of xenografts and genetically engineered mouse models as well as combinational breast cancer models have recently been reviewed by Holen et al Studies are also exploring the use of microfluidic devices for 3D breast tumor models to better mimic the physiological microenvironment in vitro . However, current breast cancer models are limited in that many do not account for the dynamic transformation of the cancer genome to include the spatiotemporal mutations and genomic rearrangements that inevitably arise as the breast cancer progresses through clonal evolution . Advances in CRISPR gene editing can not only be used to characterize and diagnose breast cancer, but also precisely mimic breast cancer progression at discrete intervals, thus enabling the development of more accurate preclinical models for breast cancer research.…”

Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases

“…131 However, it is not clear whether these data derived from mouse models adequately recapitulate the human disease in terms of drug delivery to brain tumors. 208 Recent data suggest that gadolinium-DTPAimpermeable cerebral breast metastases have significantly more proliferative nuclei compared to gadolinium-DTPA-permeable tumors in the mouse brain. 209 In contrast, another study showed that melanoma metastases having a permeable vasculature grow faster than those having an intact BTB.…”