Molecular Profiles of Brain Metastases: A Focus on Heterogeneity

SIMPLE SUMMARY: Precision cancer medicine depends on the characterization of tumor samples, usually by a single-tumor biopsy, to administer an optimal therapeutic. However, primary tumors and their metastases are often heterogeneous. A metastatic lesion may harbor a completely different genetic makeup to that of its parent tumor, and a single tumor sampling may be ineffective in selecting the most efficient therapy. Brain metastases, due to their low availability and specific microenvironment, pose a particular challenge for precision medicine. In this review, we highlight the genetic landscape of brain metastases, with a particular focus on their heterogeneity. To illustrate this problem, we present phenotypic alterations in brain metastases originating from lung cancer, breast cancer, and melanoma. This article may help clinicians better understand alterations in brain metastases and the relevance of their heterogeneity. ABSTRACT: Brain metastasis is a common and devastating clinical entity. Intratumor heterogeneity in brain metastases poses a crucial challenge to precision medicine. However, advances in next-generation sequencing, new insight into the pathophysiology of driver mutations, and the creation of novel tumor models have allowed us to gain better insight into the genetic landscapes of brain metastases, their temporal evolution, and their response to various treatments. A plethora of genomic studies have identified the heterogeneous clonal landscape of tumors and, at the same time, introduced potential targets for precision medicine. As an example, we present phenotypic alterations in brain metastases originating from three malignancies with the highest brain metastasis frequency: lung cancer, breast cancer, and melanoma. We discuss the barriers to precision medicine, tumor heterogeneity, the significance of blood-based biomarkers in tracking clonal evolution, the phylogenetic relationship between primary and metastatic tumors, blood–brain barrier heterogeneity, and limitations to ongoing research.