Heterogeneous Blood–Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer

Abstract

Purpose: Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain.Experimental Design: Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy.Results: Analysis of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14 C-paclitaxel and 14 C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset ($10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with overexpression of the pericyte protein desmin.Conclusions: This work shows that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. Clin Cancer Res; 16(23); 5664-78. Ó2010 AACR.Historically, brain metastases occurred in 10% to 20% of patients with disseminated breast cancer after the development of systemic lung, liver, and bone metastases. In such patients, treatment has been primarily palliative, with brain metastases rarely being the cause of death (1, 2). In recent years, however, the rate of brain metastasis has increased, approaching or exceeding 35% in subpopulations of metastatic breast cancer patients, particularly those with Her2 þ or "triple-negative" (estrogen and progesterone receptor negative, Her2 normal) tumors (3-5). The causes for this increase may be multiple, including improved systemic therapy, more frequent imaging, and the "sanctuary site" status of the brain. The net effect is that the patient experience is changing (6), with brain metastases more commonly presenting in patients who are responding to systemic therapy or have stable disease, and patients are succumbing to brain metastases (7). Clearly, a proportion of breast cancer patients are doing well systemically when brain metastases occur and need effective treatments for central nervous system (CNS) disease. Cur...

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