Molecular Mechanisms Driving the Formation of Brain Metastases

Simple Summary Brain metastases are the most common brain tumor in adults and are associated with poor prognosis. The propensity of different solid tumors to metastasize varies greatly, with lung, breast, and melanoma primary tumors commonly leading to brain metastases, while other primaries such as prostate rarely metastasize to the brain. The molecular mechanisms that predispose and facilitate brain metastasis development are poorly understood. In this review, we present the current data on the genomic landscape of brain metastases that arise from various primary cancers and also outline potential molecular mechanisms that drive the formation of distant metastases in the brain. Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies; however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain.