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.

Seven Glycolysis-Related Genes Predict the Prognosis of Patients With Pancreatic Cancer

“…Expression of DSC2 is significantly correlated with the survival time of high-grade colorectal cancer patients ( Knösel et al, 2012 ). In addition, Saunus et al (2017) . Studied brain metastasis samples including lung cancer, breast cancer, esophageal cancer and melanoma, and found that the mutation rate of DSC2 is very high, and it may be a new marker in the development of brain metastasis.…”

Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases

“…Historically, interpretation of clinical trials failed to adequately consider the pathophysiological context of each treatment, and there was a disproportionate focus on the BBB as an immutable obstacle to effective systemic therapy. However, it has become clear that the barriers to successful treatment are different in early and later stages of brain metastasis development [46], and it is crucial that future designs establish the disease entity being targeted to ensure success. From a biological point-of-view, the goals of immuno-/oncologic therapy could be broadly divided as follows:Specifically target subclinical deposits with an intact BBB: to prevent outgrowth in patients at high risk of brain relapse who are undergoing first-line treatment.…”

“…Brain metastasis is an inefficient process marked by high rates of cellular attrition, and impacted by a myriad of selection pressures that drive clonal evolution. This includes requirements intrinsic to the metastatic cascade (capabilities for “metastatic fitness” are indicated in horizontal tracks) as well as extrinsic factors that drive the selection of particular tumor cell clones able to successfully establish brain metastases (vertical tracks; e.g., chemotherapy, radiotherapy or surgery) (adapted from [46]).…”

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

Figure 4.The blood–tumor barrier. The vasculature of the growing tumor forms the BTB.

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