Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma

Abstract

Brain metastases (BM) occur frequently in many cancers, particularly non-small cell lung cancer (NSCLC), breast cancer, and melanoma. The development of BM is associated with poor prognosis and has an adverse impact on survival and quality of life. Commonly used therapies for BM such as surgery or radiotherapy are associated with only modest benefits. However, recent advances in systemic therapy of many cancers have generated considerable interest in exploration of those therapies for treatment of intracranial metastases.This review discusses the epidemiology of BM from the aforementioned primary tumors and the challenges of using systemic therapies for metastatic disease located within the central nervous system. Cumulative data from several retrospective and small prospective studies suggest that molecularly targeted systemic therapies may be an effective option for the treatment of BM from NSCLC, breast cancer, and melanoma, either as monotherapy or in conjunction with other therapies. Larger prospective studies are warranted to further characterize the efficacy and safety profiles of these targeted agents for the treatment of BM.

Keywords: Brain metastases; blood-brain barrier; breast cancer; melanoma; non–small cell lung cancer.

Fig. 1.

Pathways across the blood-brain barrier, blood-cerebrospinal fluid barrier, and blood-tumor barrier. The blood-brain barrier (BBB) is a continuous layer of epithelial cells joined by high-resistance tight junctions surrounded by pericytes and sealed by astrocytic perivascular endfeet. ^, The blood-cerebrospinal fluid (CSF) barrier demarcates the space between the choroid plexus and CSF. Unlike the BBB capillaries, the functional unit of the choroid plexus is fenestrated, has no tight junctions, and thus facilitates molecular transport such as CSF bulk flow, metabolic inactivation, and transcapillary exchange. The blood-tumor barrier refers to a tumor’s vasculature that is a variously permeable barrier. Similar to the BBB, it is a major factor limiting the access of many therapeutic agents to brain tumors. The blood-tumor barrier consists of continuous, nonfenestrated capillaries (like those of normal brain), fenestrated capillaries, and interendothelial gaps. Expression of efflux transporters located at the blood-tumor barrier represents an additional mechanism that prevents intracellular penetration of anticancer drugs. (Brain with tumor adapted with permission under a Creative Commons Attribution License from OpenStax College, http://legacy.cnx.org/content/m45981/1.4/; blood-brain barrier reused with permission under a Creative Commons Attribution License from Kübelbeck A, https://commons.wikimedia.org/wiki/File:Blood-brain_barrier_transport_en.png; anatomy of tight junction adapted with permission under a Creative Commons Attribution License from Polakis P. J Cell Biol. 2008;183(3):371–373; blood CSF barrier adapted with permission under a Creative Commons Attribution License from Bhaskar S, et al. Part Fibre Toxicol. 2010;7:3; blood-tumor barrier adapted from Bredel M. Anticancer drug resistance in primary human brain tumors. Brain Res Brain Res Rev. 2001;35(2):161–204, with permission from Elsevier.)

Fig. 2.

Non–small cell lung cancer mutations. Although more than one-third of driver mutations in non–small cell lung cancer (NSCLC) are still unknown, approximately one-half of primary single mutations have been identified. The approval of targeted therapies for epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinomas has led to a better understanding of individual driver and resistance mutations upon tumor progression. ^, (Large pie chart adapted with permission. © 2016 American Society of Clinical Oncology. All rights reserved. ^, )

Fig. 3

Breast cancer mutations. Breast cancer can be categorized into 4 types based on histology and gene expression. The majority of breast cancers are categorized as luminal A, with triple-negative breast cancer the next most common. ^, According to the Catalogue of Somatic Mutations in Cancer (COSMIC) database, certain genes are frequently mutated in each subtype (as indicated next to each subtype). ^, (Adapted with permission under Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License from Kumar R et al. J Pharm Bioallied Sci. 2012. ^, )

Fig. 4.

Melanoma mutations. Mutations in v-Raf murine sarcoma viral oncogene homolog B (BRAF) account for almost half of the driving mutations in melanoma, with another 16% driven by mutations in neuroblastoma RAS viral (v-Ras) oncogene homolog (NRAS). Therapies designed to target these mutations have improved outcomes in patients with melanoma.