Current approaches to the treatment of metastatic brain tumours

Abstract

Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.

Figure 1

The key molecular alterations in the primary cancers that most commonly metastasize to the brain. Important therapies that are currently available or are in clinical development and can cross the BBB are also shown. In lung cancer, expression of cadherin-2, KIFC1, and CXCR4 proteins and ADAM9 mRNA predicts metastasis, and phosphorylated IGF1R is associated with a poor prognosis. Furthermore expression of transcription factors such as LEF1, HOXB9 and BPTF is associated with a higher likelihood of brain metastases. Co-operative signalling involving EGFR and HGFR correlates with transition from an epithelial phenotype to a mesenchymal and invasive phenotype, and therapeutic agents targeting EGFR, as well as ALK, are important in the treatment of lung cancer brain metastases. In breast cancer, expression of IGF1R, α_vβ₃ integrin and Notch1 pathways increases the likelihood of metastasis. The presence of HBEGF, Ki-67 and ST6GalNAc5 increases tumour cell penetration of the BBB and hexokinase 2 and FOXC1 predict brain metastases and poorer survival. In melanomas, hyperactivation of the Akt cascade, expression of MMP-9 and RhoC and mutations in BRAF and N-Ras predict invasion and brain metastasis. The presence of VEGFA and STAT3 is associated with angiogenesis and proliferation, respectively. Immune-targeted therapies, particular blockade of CTLA-4-dependent inhibitory co-stimulatory signalling in T cells, can overcome immune tolerance of melanoma cells. Abbreviations: ADAM9, disintegrin and metalloproteinase domain-containing protein 9; BBB, blood–brain barrier; CTLA-4, cytotoxic T-lymphocyte antigen 4; CXCR4, CXC-motif chemokine receptor 4; FOXC1, forkhead box protein C1; HDAC, histone deacetylase; LEF1, lymphoid enhancer-binding factor 1; MMP-9, matrix metalloproteinase 9; PARP, poly-[ADP-ribose] polymerase; PGF, placenta growth factor; ST6GalNAc5, α-N-acetylgalactosaminide α-2,6-sialyltransferase 5; STAT3, signal transducer and activator of transcription 3.