Brain metastasis: The next steps for translational research

As the global incidence of cancer has increased, brain metastases now appear in 8%–10% of all cases. Major advances in neuroimaging have led to increased detection of brain metastases in patients. Yet, brain metastases indicate poor prognosis, will likely result in exclusion from clinical trials, and cause serious neurological deficits that affects patients' lives profoundly. Radiation and neurosurgery are the only existing therapies, while chemotherapeutic options are limited. Targeted therapies have significantly improved management of systemic diseases, however poor bioavailability in the brain has increased its potential as a repository of metastatic disease. In this special of issue of Cancer Reports, we present current advances in both the clinical and molecular biology of brain metastasis. As a whole, Breast cancer metastasizes to the brain in about 40% of patients who have a tumor that is Her2 (>30% of tumor cells stain for the tyrosine kinase receptor erbB2) or are negative for estrogen/ progesterone/Her2 receptors (referred to as triple negative; TN). Ninety percent of patients with these breast cancer subtypes will die of brain metastases. The survival of breast cancer patients is improving, but brain metastases have been identified as a major limiting factor for those with advanced disease. In this issue, Zimmer et al review the landscape of Her2 breast to brain metastasis. Furthermore, the review by Contreras-Zarate et al examines how estrogens and androgens influence brain metastatic colonization and progression. Traditionally metastatic spread was thought to occur as a late event occurring long after primary tumor had progressed locally. While this may still be the case for some tumors, recent evidence also suggests parallel progression of primary and metastatic cancers. Even before tumors develop, metastatic cancer cells with a fewmolecular alterations can spread to organs, remain dormant for a long period of time, and then suddenly awaken to form aggressive, deadly brain metastases. Through the perspective of circulating tumor cells, Klotz et al examine in the current issue how tumor cells disseminate to brain tissues and establish brain metastasis. The central nervous system (CNS) is one of the most complex biological systems, poses unique challenges, but is also ripe for discovery. Metastasis to the brain is caused by successful interplay between tumor cells and newly encountered brain microenvironments. The cornerstone of reliable neural signaling within the CNS is a highly regulated milieu. Thus, the CNS must be protected from external influences at interfaces where blood and cerebral spinal fluid (CSF) come into close contact with neural elements. Intriguingly, Herrera et al describe how cortisol, a stress hormone, promotes breast to brain metastasis through the blood–CSF barrier. Moreover, Remsik et al demonstrate that breast and lung tumor cells adopt a two-phenotypic state in in leptomeningeal disease when they have spread to the CSF. Finally, given the global impact of COVID-19 on cancer patients, this special issue would be a remiss if it failed to address how it impacts patients with brain metastases. Mummundi et al discuss approaches oncologists need to consider when managing patients during the COVID-19 pandemic. This special issue of Cancer Reports, which focuses on brain metastasis provides new insights into how cancer cells spread to this last frontier—with the goal of opening new avenues for developing innovative treatment strategies to treat patients with brain cancer metastases.