Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies

Abstract

Central nervous system (CNS) or brain metastasis is an emerging area of interest in organ-specific metastasis research. Lung and breast cancers are the most common types of primary tumors to develop brain metastases. This disease complication contributes significantly to the morbidity and mortality of both of these common cancers; as such, brain metastasis is designated an unmet medical need by the US Food and Drug Administration. Recently, an increase in incidence of CNS disease has been noted in the literature for breast cancer, while it has been an ongoing major complication from lung cancer. Progress in treating brain metastases has been hampered by a lack of model systems, a lack of human tissue samples, and the exclusion of brain metastatic patients from many clinical trials. While each of those is significant, the major impediment to effectively treating brain metastatic disease is the blood-brain barrier (BBB). This barrier excludes most chemotherapeutics from the brain and creates a sanctuary site for metastatic tumors. Recent findings on the biology of this disease and translational leads identified by molecular studies are discussed in this article. Clinical OverviewBrain metastasis is the most common form of adult CNS tumors, outnumbering primary brain tumors by 10:1 (1). While multiple primary tumor sites metastasize to the brain, 40-50% of brain lesions originate from lung cancer and 20-30% from breast cancer (2). The natural history of the disease is very different for these two primary tumor types. Lung cancer patients develop brain metastases early -within the first two years -after primary tumor diagnosis while breast cancer patients tend to recur in the CNS after the development of systemic metastatic disease and multiple rounds of chemotherapy. Regardless, brain metastasis is a major cause of morbidity and mortality. Tumors in the CNS strongly affect patient quality of life, impairing sensory and motor neural functions and inducing headaches (24-48%), nausea, vomiting, and seizures. The mainstay of treatment is radiation therapy, which can add additional morbidity, particularly neurocognitive complications from whole brain radiotherapy.The incidence of brain metastatic disease appears to be rising as a result of multiple factors. First, there is an increase in the aging population. Second, improvements in systemic Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.

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