Published OnlineFirst June 18, 2019; DOI: 10.1158/1078-0432.CCR-18-1624 Review Clinical Cancer Research The Evolving Modern Management of Brain Metastasis Peter E. Fecci1,2, Cosette D. Champion1,2, Jacob Hoj3, Courtney M. McKernan3, C. Rory Goodwin1,2, John P. Kirkpatrick1,2,4, Carey K. Anders5, Ann Marie Pendergast3, and John H. Sampson1,2 Abstract The incidence of brain metastases is increasing as cancer antitumor immune response. Better understanding of the therapies improve and patients live longer, providing new above mechanisms will allow for development and delivery challenges to the multidisciplinary teams that care for these of more effective therapies for brain metastases. In this review, patients. Brain metastatic cancer cells possess unique charac- we outline the molecular mechanisms underlying develop- teristics that allow them to penetrate the blood–brain barrier, ment, survival, and immunosuppression of brain metastases. colonize the brain parenchyma, and persist in the intracranial We also discuss current and emerging treatment strategies, environment. In addition, brain metastases subvert the innate including surgery, radiation, disease-specific and mutation- and adaptive immune system, permitting evasion of the targeted systemic therapy, and immunotherapy. Introduction pies to suffer. Finally, we outline the most current treatment strategies, including surgery, radiation, and systemic therapies. Brain metastases are the most common intracranial tumors in adults, and portend significant morbidity and mortality (1). Depending on the primary tumor, median survival ranges from Molecular Pathways Favoring Brain just 2 to 27 months (2). The most common cancers metastasizing to brain include lung (50%), breast (15%–20%), melanoma Metastasis (5%–10%), kidney (7%), and colon (4%–6%). Ironically, as Cancer cells metastasizing to brain are often molecularly and cancer therapies improve and patients live longer with their phylogenetically distinct from their primary tumor source (5), primary tumors, the incidence of brain metastases is increasing possessing added capacities for penetrating the BBB and coloniz- and now approaches 200,000 per year in the United States (3). ing the brain microenvironment. Mechanistic considerations are Patients harboring brain metastases often present with neuro- outlined below. logic symptoms such as headache, cognitive impairment, sei- fi zures, and focal de cits, all precipitating declines in quality of Extravasation and traversing the BBB life and survival (1). Effective therapies are limited by poor The BBB is composed of endothelial cells, pericytes, base- understanding of metastasis tropism, growth, and survival in the ment membrane proteins, and astrocytes. To cross the BBB, brain microenvironment. Furthermore, many systemic therapies metastatic cells employ diverse processes, including proteolysis – fail to penetrate the blood brain barrier (BBB) and therefore do of tight junction proteins by cathepsins and matrix metallo- not accumulate at therapeutic doses (4). A new focus on brain- proteinases (Fig. 1; ref. 6). Alternatively, metastatic cells elab- fi speci c considerations and therapies is warranted. orate inflammatory cytokines, chemokines, and soluble factors In this review, we outline the molecular mechanisms favoring to disrupt intercellular junctions. These include TGFb,IL1b, brain metastasis and the peculiarities of the brain immune VEGF, and basic fibroblastgrowthfactor(Fig.1;ref.7).Finally, environment that allow metastases to persist and immunothera- some metastatic cells disrupt the BBB by inducing endothelial cell death (8). Following BBB disruption, metastatic cells primarily employ 1Department of Neurosurgery, Duke University Medical Center, Durham, North paracellular migration to enter the brain parenchyma (9). Carolina. 2Duke Center for Brain and Spinal Metastases, Duke University Medical Studies using a cranial window mouse model coupled with Center, Durham, North Carolina. 3Department of Pharmacology and Cancer multiphoton laser scanning microscopy have permitted visu- 4 Biology, Duke University School of Medicine, Durham, North Carolina. Depart- alization of the process (10). Essential steps include the fol- ment of Radiation Oncology, Duke University Medical Center, Durham, North lowing: (i) size-restricted arrest of tumor cells at vascular Carolina. 5Duke Cancer Institute, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina. branch points; (ii) active extravasation by the tumor cell from the abluminal vessel surface into the perivascular space; (iii) Corresponding Author: John H. Sampson, Duke University Medical Center, positional maintenance of the tumor cell within the perivas- DUMC Box 3271, Durham, NC 27710. Phone: 919-684-1043; Fax: 919-684- 9045; E-mail: [email protected] cular space; and (iv) angiogenic growth (lung cancer cells and renalcellcarcinoma)orvascular cooption (breast cancer cells Clin Cancer Res 2019;25:6570–80 and melanoma; refs. 10, 11). doi: 10.1158/1078-0432.CCR-18-1624 Mouse models of brain metastasis have identified several Ó2019 American Association for Cancer Research. molecules required for tumor cell extravasation, including 6570 Clin Cancer Res; 25(22) November 15, 2019 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst June 18, 2019; DOI: 10.1158/1078-0432.CCR-18-1624 The Evolving Modern Management of Brain Metastasis 1. Tumor cell arrest at vascular branch 3. Positional maintenance in points perivascular space prior to proliferation L1CAM Serpin D1 Serpin B2 Neuroserpin 2. Active extravasation into the perivascular space Cathepsins b-FGF 4b. Promotion of L1CAM COX-2 4a. Vascular cooption angiogenesis MMPs HB-EGF (breast and melanoma) (NSCLC, RCC) TGFβ ST6GALNAC5 IL-1β SDF-1α L1CAM ANGPT2 ADAM8 IL8 VEGF VEGF PLAT VEGF CXCL1 c-MET © 2019 American Association for Cancer Research Figure 1. Several steps are required for the initiation and maintenance of brain metastasis of lung cancer, breast cancer, melanoma, and renal cell cancer. Molecules involved at each step are indicated. L1-Cell Adhesion Molecule (L1CAM), a protein implicated in mal cell–derived factor 1a (SDF-1a; also known as CXCL12) axon guidance. Elevated expression of L1CAM by arrested tumor and its receptor CXCR4 promotes migration of breast cancer cells within the abluminal space of the brain microvasculature cells across the BBB. Treatment with AMD3100, a small- promotes tumor cell adhesion to endothelial cells and facilitates molecule antagonist of SDF-1a, inhibited lung cancer brain vascular cooption (Fig. 1; Table 1; ref. 12). Through vascular metastasis by protecting the BBB (18). cooption, cancer cells interact with the preexisting vasculature, Despite these insights, many questions remain. The majority of permitting access to angiogenic factors, nutrients, and oxygen. the mechanistic studies described above have focused on breast Studies using mouse models suggest that the cancer cells remain- carcinoma and non–small cell lung cancer (NSCLC) as little is ing near the perivascular space after extravasation predominantly known regarding the mechanisms employed by other commonly give rise to proliferating metastases (10). metastasizing tumor types, including melanoma, renal cell car- ADAM9, a member of the disintegrin and metalloprotease cinoma, and small-cell lung cancer. Future research may reveal family, regulates lung cancer brain metastasis by targeting new targets for preventing extravasation of metastatic cells into vascular remodeling at the BBB through regulation of VEGFA, the brain parenchyma. Moreover, future studies are needed to ANGPT2,andPLAT expression (13). Increased ADAM8 expres- develop drugs that can effectively cross the BBB, which remains a sion in triple-negative breast cancer (TNBC) stimulates angio- therapeutic delivery barrier despite the partial opening observed genesis through the release of VEGF and increases transen- by the intracranial accumulation of small molecules such as dothelial migration by activating b1-integrin (14). Activation gadolinium and other contrast agents. Drug delivery to brain of the c-MET receptor tyrosine kinase in brain metastatic metastases may be prevented, in part, by the abnormal and breast cancer cells promotes perivascular adhesion and neoan- heterogenous blood vessels surrounding the metastases and giogenesis, in part, through increased expression of IL8 and increased tumor interstitial hypertension leading to decreased CXCL1 (15). Cyclooxygenase-2 (COX-2), HB-EGF ligand, and perfusion thereby impairing drug accumulation at the metastatic ST6 N-Acetylgalactosaminide Alpha 2,6 Sialyltransferase 5 sites (19). (ST6GALNAC5) promote breast cancer cell migration across the BBB (Fig. 1; Table 1; ref. 16). Factors secreted by activated Role of astrocytes brain microvascular endothelial cells such as angiopoietin-2 Colonization and outgrowth of cancer cells requires adaptation (Ang-2) disrupt tight junctions and increase BBB permeability to the brain microenvironment. Such adaptation is mediated by to breast cancer cells in mouse models (17). Thus, inhibition of dynamic intercellular interactions between metastatic cells and Ang-2 can enhance BBB function and impair progression of neighboring astrocytes, which normally function to prevent neu- brain metastases. Similarly, signaling by the chemokine stro- ronal damage. Reactive astrocytes destroy metastatic cells by www.aacrjournals.org