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Brain metastases

Abstract

An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood–tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve.

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Fig. 1: Cancer cell metastatic dissemination.
Fig. 2: Central nervous system barriers.
Fig. 3: Imaging characteristics of metastatic brain lesions.
Fig. 4: Minimally invasive neurosurgical techniques.
Fig. 5: Evolution of radiation-based treatments of brain metastases.
Fig. 6: Selected potential targets in the blood–tumour microenvironment for future therapies.

References

  1. 1.

    Hall, W. A., Djalilian, H. R., Nussbaum, E. S. & Cho, K. H. Long-term survival with metastatic cancer to the brain. Med. Oncol. 17, 279–286 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Nayak, L., Lee, E. Q. & Wen, P. Y. Epidemiology of brain metastases. Curr. Oncol. Rep. 14, 48–54 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Tabouret, E. et al. Recent trends in epidemiology of brain metastases: an overview. Anticancer Res. 32, 4655–4662 (2012).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Barnholtz-Sloan, J. S. et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J. Clin. Oncol. 22, 2865–2872 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Tsukada, Y., Fouad, A., Pickren, J. W. & Lane, W. W. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 52, 2349–2354 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Posner, J. B. & Chernik, N. L. Intracranial metastases from systemic cancer. Adv. Neurol. 19, 579–592 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Percy, A. K. Neoplasms of the central nervous system: epidemiologic considerations. Neurology 20, 398–399 (1970).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 67, 7–30 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Sperduto, P. W. et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int. J. Radiat. Oncol. Biol. Phys. 77, 655–661 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Berghoff, A. S. et al. Descriptive statistical analysis of a real life cohort of 2419 patients with brain metastases of solid cancers. ESMO Open 1, e000024 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Nieder, C., Spanne, O., Mehta, M. P., Grosu, A. L. & Geinitz, H. Presentation, patterns of care, and survival in patients with brain metastases: what has changed in the last 20 years? Cancer 117, 2505–2512 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Martin, A. M. et al. Brain metastases in newly diagnosed breast cancer: a population-based study. JAMA Oncol. 3, 1069–1077 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Toyokawa, G., Seto, T., Takenoyama, M. & Ichinose, Y. Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary? Cancer Metastasis Rev. 34, 797–805 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Yamanaka, R. Medical management of brain metastases from lung cancer (review). Oncol. Rep. 22, 1269–1276 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Steeg, P. S., Camphausen, K. A. & Smith, Q. R. Brain metastases as preventive and therapeutic targets. Nat. Rev. Cancer 11, 352–363 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Hung, M. H. et al. Effect of age and biological subtype on the risk and timing of brain metastasis in breast cancer patients. PLOS ONE 9, e89389 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Znaor, A., Lortet-Tieulent, J., Laversanne, M., Jemal, A. & Bray, F. International variations and trends in renal cell carcinoma incidence and mortality. Eur. Urol. 67, 519–530 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Torre, L. A., Siegel, R. L., Ward, E. M. & Jemal, A. International variation in lung cancer mortality rates and trends among women. Cancer Epidemiol. Biomarkers Prev. 23, 1025–1036 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Gaspar, L. et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int. J. Radiat. Oncol. Biol. Phys. 37, 745–751 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Nieder, C., Grosu, A. L. & Gaspar, L. E. Stereotactic radiosurgery (SRS) for brain metastases: a systematic review. Radiat. Oncol. 9, 155 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Ekici, K. et al. Survival and prognostic factors in patients with brain metastasis: single center experience. J. BUON 21, 958–963 (2016).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Gaspar, L. E., Scott, C., Murray, K. & Curran, W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 47, 1001–1006 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Sperduto, P. W., Berkey, B., Gaspar, L. E., Mehta, M. & Curran, W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int. J. Radiat. Oncol. Biol. Phys. 70, 510–514 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Sperduto, P. W. et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J. Clin. Oncol. 30, 419–425 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Sperduto, P. W. et al. Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 82, 2111–2117 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Sperduto, P. W. et al. Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA). JAMA Oncol. 3, 827–831 (2016). This article provides an updated prognostic index for patients with lung cancer brain metastases that reflects the importance of molecular markers as well as clinical factors in overall prognosis.

    PubMed Central  Article  Google Scholar 

  27. 27.

    Balasubramanian, S. K. et al. Impact of EGFR and ALK mutaiton on the outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 2005 (2016).

    Article  Google Scholar 

  28. 28.

    Chen, L. F., Patel, J. D. & Lukas, R. V. Advances in brain metastases presented at the American Society of Clinical Oncology 2016 annual meeting: part I. Future Oncol. 12, 2535–2538 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    McTyre, E. R. et al. Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy. Neuro Oncol. 19, 558–566 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Neal, M. T. et al. Predictors of survival, neurologic death, local failure, and distant failure after gamma knife radiosurgery for melanoma brain metastases. World Neurosurg. 82, 1250–1255 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Cabezas, R. et al. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front. Cell Neurosci. 8, 211 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Shi, C. & Pamer, E. G. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762–774 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Johanson, C. E., Stopa, E. G. & McMillan, P. N. The blood-cerebrospinal fluid barrier: structure and functional significance. Methods Mol. Biol. 686, 101–131 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Boire, A. et al. Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis. Cell 168, 1101–1113 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Berghoff, A. S. & Preusser, M. The inflammatory microenvironment in brain metastases: potential treatment target? Chin. Clin. Oncol. 4, 21 (2015).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Heyn, C. et al. In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn. Reson. Med. 56, 1001–1010 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Bos, P. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1010 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Fan, J. et al. Integrin β4 signaling promotes mammary tumor cell adhesion to brain microvascular endothelium by inducing ErbB2-mediated secretion of VEGF. Ann. Biomed. Eng. 39, 2223–2241 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Küsters, B. et al. Vascular endothelial growth factor-A165 induces progression of melanoma brain metastases without induction of sprouting angiogenesis. Cancer Res. 62, 341–345 (2002).

    PubMed  Google Scholar 

  42. 42.

    Izraely, S. et al. The metastatic microenvironment: brain-residing melanoma metastasis and dormant micrometastasis. Int. J. Cancer 131, 1071–1082 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Gorantla, V., Kirkwood, J. M. & Tawbi, H. A. Melanoma brain metastases: an unmet challenge in the era of active therapy. Curr. Oncol. Rep. 15, 483–491 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Eichler, A. F. et al. The biology of brain metastases-translation to new therapies. Nat. Rev. Clin. Oncol. 8, 344–356 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Zhang, S. Y. et al. Src family kinases as novel therapeutic targets to treat breast cancer brain metastases. Cancer Res. 73, 5764–5774 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Lorger, M. & Felding-Habermann, B. Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am. J. Pathol. 176, 2958–2971 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Sevenich, L. et al. Analysis of tumour-and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16, 876–888 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Simonsen, T. G., Gaustad, J. V. & Rofstad, E. K. Intracranial tumor cell migration and the development of multiple brain metastases in malignant melanoma. Transl Oncol. 9, 211–218 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Lockman, P. R. et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin. Cancer Res. 16, 5664–5678 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Nduom, E. K., Yang, C. Z., Merrill, M. J., Zhuang, Z. P. & Lonser, R. R. Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms laboratory investigation. J. Neurosurg. 119, 427–433 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Murrell, D. H. et al. Understanding heterogeneity and permeability of brain metastases in murine models of HER2-positive breast cancer through magnetic resonance imaging: implications for detection and therapy. Transl Oncol. 8, 176–184 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Henry, M. N., Chen, Y. H., McFadden, C. D., Simedrea, F. C. & Foster, P. J. In-vivo longitudinal MRI study: an assessment of melanoma brain metastases in a clinically relevant mouse model. Melanoma Res. 25, 127–137 (2015).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Morikawa, A. et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro-oncology 17, 289–295 (2015).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Lyle, L. et al. Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer. Clin. Cancer Res. 22, 5287–5299 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Yonemori, K. et al. Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breast cancer. Cancer 116, 302–308 (2010).

    PubMed  Article  Google Scholar 

  58. 58.

    Connell, J. J. et al. Selective permeabilization of the blood-brain barrier at sites of metastasis. J. Natl Cancer Inst. 105, 1634–1643 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Avraham, H. K. et al. Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain. J. Pathol. 232, 369–381 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Ma, S. C. et al. Claudin-5 regulates blood-brain barrier permeability by modifying brain microvascular endothelial cell proliferation, migration, and adhesion to prevent lung cancer metastasis. CNS Neurosci. Ther. 23, 947–960 (2017).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Gril, B. et al. Reactive astrocytic S1P3 signaling modulates the blood-tumor barrier in brain metastases. Nat. Commun. 9, 2705 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Fitzgerald, D. et al. Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin. Exp. Metastasis 25, 799–810 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Chen, Q. et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Kim, S. J. et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13, 286–298 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Sartorius, C. A. et al. Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism. Oncogene 35, 2881–2892 (2016). This study demonstrates that oestrogen blockade can decrease the formation of triple-negative breast cancer brain metastases through inhibition of ER-positive astrocytes in the brain microenvironment, providing initial data for prevention as a strategy against brain metastases.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Xu, L., Gao, G., Ren, J., Su, F. & Zhang, W. Estrogen receptor β of host promotes the progression of lung cancer brain metastasis of an orthotopic mouse model. J. Cancer Ther. 3, 352–358 (2012).

    Article  CAS  Google Scholar 

  67. 67.

    Zhang, L. et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Louie, E. et al. Neurotrophin-3 modulates breast cancer cells and the microenvironment to promote the growth of breast cancer brain metastasis. Oncogene 32, 4064–4077 (2013).

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Berghoff, A. S., Lassmann, H., Preusser, M. & Hoftberger, R. Characterization of the inflammatory response to solid cancer metastases in the human brain. Clin. Exp. Metastasis 30, 69–81 (2013).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Bowman, R. L. et al. Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 17, 2445–2459 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Harter, P. N. et al. Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases. Oncotarget 6, 40836–40849 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Zakaria, R. et al. T-cell densities in brain metastases are associated with patient survival times and diffusion tensor MRI changes. Cancer Res. 78, 610–616 (2018).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Mansfield, A. S. et al. Contraction of T cell richness in lung cancer brain metastases. Sci. Rep. 8, 2171 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Duchnowska, R. et al. Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. Breast Cancer Res. 18, 43 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Berghoff, A. S. et al. Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology 66, 289–299 (2015).

    PubMed  Article  Google Scholar 

  76. 76.

    Berghoff, A. S. et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J. Neurooncol. 130, 19–29 (2016).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Teglasi, V. et al. Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis. Neuro-oncology 19, 1058–1067 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Taggart, D. et al. Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Proc. Natl Acad. Sci. USA 115, E1540–E1549 (2018).

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Samson, A. et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci. Transl Med. 10, eaam7577 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Chen, E. I. et al. Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res. 67, 1472–1486 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    Chen, J. et al. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain. Cancer Res. 75, 554–565 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Leenders, W. P. J. et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin. Cancer Res. 10, 6222–6230 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Valiente, M. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Allen, J. E. et al. COX-2 drives metastatic breast cells from brain lesions into the cerebrospinal fluid and systemic circulation. Cancer Res. 74, 2385–2390 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Zhang, C. Y., Zhang, F. H., Tsan, R. & Fidler, I. J. Transforming growth factor-β2 is a molecular determinant for site-specific melanoma metastasis in the brain. Cancer Res. 69, 828–835 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Park, E. S. et al. Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis. Proc. Natl Acad. Sci. USA 108, 17456–17461 (2011). This study demonstrates that the brain microenvironment (‘soil’) can reprogramme metastatic tumour cells (‘seed’) to gain neuronal cell characteristics.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Brastianos, P. K. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 5, 1164–1177 (2015). This study demonstrates distinct evolution patterns within brain metastases compared with their primary tumours.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Saunus, J. M. et al. Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance. J. Pathol. 237, 363–378 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89.

    Wang, L. et al. Astrocytes directly influence tumor cell invasion and metastasis in vivo. PLOS ONE 8, e80933 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90.

    Neman, J. et al. Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc. Natl Acad. Sci. USA 111, 984–989 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91.

    Hayes, D. N. et al. Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts. J. Clin. Oncol. 24, 5079–5090 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Ansari, J., Palmer, D. H., Rea, D. W. & Hussain, S. A. Role of tyrosine kinase inhibitors in lung cancer. Anticancer Agents Med. Chem. 9, 569–575 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Venur, V. A. & Ahluwalia, M. S. Targeted therapy in brain metastases: ready for primetime? Am. Soc. Clin. Oncol. Educ. Book 35, e123–130 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Peters, S. et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Zhao, N. et al. Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer 86, 255–261 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Nguyen, D. X. et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138, 51–62 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Ilhan-Mutlu, A. et al. Expression profiling of angiogenesis-related genes in brain metastases of lung cancer and melanoma. Tumour Biol. 37, 1173–1182 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Kennecke, H. et al. Metastatic behavior of breast cancer subtypes. J. Clin. Oncol. 28, 3271–3277 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Nik-Zainal, S. & Morganella, S. Mutational signatures in breast cancer: the problem at the DNA level. Clin. Cancer Res. 23, 2617–2629 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Salhia, B. et al. Integrated genomic and epigenomic analysis of breast cancer brain metastasis. PLOS ONE 9, e85448 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Harrell, J. C. et al. Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res. Treat 132, 523–535 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. 104.

    Jin, H. et al. Methylation status of T-lymphoma invasion and metastasis 1 promoter and its overexpression in colorectal cancer. Hum. Pathol. 42, 541–551 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Duchnowska, R. et al. Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients. J. Neurooncol. 122, 205–216 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Adamo, B. et al. Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases. Breast Cancer Res. 13, R125 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Kodack, D. P. et al. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation. Sci. Transl Med. 9, eaal4682 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Phillips, G. D. et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin. Cancer Res. 20, 456–468 (2014).

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Askoxylakis, V. et al. Preclinical efficacy of ado-trastuzumab emtansine in the brain microenvironment. J. Natl Cancer Inst. 108, djv313 (2016).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Hodis, E. et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Chen, G. et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin. Cancer Res. 20, 5537–5546 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Jakob, J. A. et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118, 4014–4023 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Long, G. V. et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 1087–1095 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Bucheit, A. D. et al. Complete loss of PTEN protein expression correlates with shorter time to brain metastasis and survival in stage IIIB/C melanoma patients with BRAFV600 mutations. Clin. Cancer Res. 20, 5527–5536 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Jilaveanu, L. B. et al. PLEKHA5 as a biomarker and potential mediator of melanoma brain metastasis. Clin. Cancer Res. 21, 2138–2147 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Niessner, H. et al. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Med. 2, 76–85 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Hamilton, R. et al. Pathologic and gene expression features of metastatic melanomas to the brain. Cancer 119, 2737–2746 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Kluger, H. M. et al. Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin. Cancer Res. 21, 3052–3060 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Cairns, P. Renal cell carcinoma. Cancer Biomark 9, 461–473 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  120. 120.

    Takahashi, M. et al. Gene expression profiling of clear cell renal cell carcinoma: gene identification and prognostic classification. Proc. Natl Acad. Sci. USA 98, 9754–9759 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Han, C. H. & Brastianos, P. K. Genetic characterization of brain metastases in the era of targeted therapy. Front. Oncol. 7, 230 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Yaeger, R. et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer 121, 1195–1203 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

    Soffietti, R., Ducati, A. & Rudà, R. Brain metastases. Handb. Clin. Neurol. 105, 747–755 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Usinskiene, J. et al. Optimal differentiation of high- and low-grade glioma and metastasis: a meta-analysis of perfusion, diffusion, and spectroscopy metrics. Neuroradiology 58, 339–350 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  126. 126.

    Sze, G., Milano, E., Johnson, C. & Heier, L. Detection of brain metastases: comparison of contrast-enhanced MR with unenhanced MR and enhanced CT. AJNR Am. J. Neuroradiol. 11, 785–791 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Schellinger, P. D., Meinck, H. M. & Thron, A. Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J. Neurooncol. 44, 275–281 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Sze, G. et al. Comparison of single- and triple-dose contrast material in the MR screening of brain metastases. AJNR Am. J. Neuroradiol. 19, 821–828 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Mills, S. J., Thompson, G. & Jackson, A. Advanced magnetic resonance imaging biomarkers of cerebral metastases. Cancer Imag. 12, 245–252 (2012).

    CAS  Article  Google Scholar 

  130. 130.

    Yeh, R. H. et al. Distinct MR imaging features of triple-negative breast cancer with brain metastasis. J. Neuroimag. 25, 474–481 (2015).

    Article  Google Scholar 

  131. 131.

    Desprechins, B. et al. Use of diffusion-weighted MR imaging in differential diagnosis between intracerebral necrotic tumors and cerebral abscesses. AJNR Am. J. Neuroradiol. 20, 1252–1257 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Sternberg, E. J., Lipton, M. L. & Burns, J. Utility of diffusion tensor imaging in evaluation of the peritumoral region in patients with primary and metastatic brain tumors. AJNR Am. J. Neuroradiol. 35, 439–444 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Bulakbasi, N. et al. Assessment of diagnostic accuracy of perfusion MR imaging in primary and metastatic solitary malignant brain tumors. AJNR Am. J. Neuroradiol. 26, 2187–2199 (2005).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Law, M. et al. High-grade gliomas and solitary metastases: differentiation by using perfusion and proton spectroscopic MR imaging. Radiology 222, 715–721 (2002).

    PubMed  Article  Google Scholar 

  135. 135.

    Sparacia, G., Gadde, J. A., Iaia, A., Sparacia, B. & Midiri, M. Usefulness of quantitative peritumoural perfusion and proton spectroscopic magnetic resonance imaging evaluation in differentiating brain gliomas from solitary brain metastases. Neuroradiol. J. 29, 160–167 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Toh, C. H. et al. Differentiation of brain abscesses from glioblastomas and metastatic brain tumors: comparisons of diagnostic performance of dynamic susceptibility contrast-enhanced perfusion MR imaging before and after mathematic contrast leakage correction. PLOS ONE 9, e109172 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    Shim, W. H., Kim, H. S., Choi, C. G. & Kim, S. J. Comparison of apparent diffusion coefficient and intravoxel incoherent motion for differentiating among glioblastoma, metastasis, and lymphoma focusing on diffusion-related parameter. PLOS ONE 10, e0134761 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. 138.

    Chiang, I. C. et al. Distinction between high-grade gliomas and solitary metastases using peritumoral 3-T magnetic resonance spectroscopy, diffusion, and perfusion imagings. Neuroradiology 46, 619–627 (2004).

    PubMed  Article  Google Scholar 

  139. 139.

    Server, A. et al. Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors. Acta Radiol. 51, 316–325 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Kosaka, N. et al. 18F-FDG PET of common enhancing malignant brain tumors. AJR Am. J. Roentgenol. 190, W365–W369 (2008).

    PubMed  Article  Google Scholar 

  141. 141.

    Hutterer, M. et al. [18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. Neuro-oncology 15, 341–351 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Calabria, F. F., Barbarisi, M., Gangemi, V., Grillea, G. & Cascini, G. L. Molecular imaging of brain tumors with radiolabeled choline PET. Neurosurg. Rev. 41, 67–76 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Soffietti, R. et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro-oncology 19, 162–174 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Berghoff, A. S. et al. Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues. Acta Neuropathol. 128, 879–891 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. 145.

    Shen, Q. et al. Breast cancer with brain metastases: clinicopathologic features, survival, and paired biomarker analysis. Oncologist 20, 466–473 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Monzon, F. A. & Koen, T. J. Diagnosis of metastatic neoplasms: molecular approaches for identification of tissue of origin. Arch. Pathol. Lab Med. 134, 216–224 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Pentsova, E. I. et al. Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J. Clin. Oncol. 34, 2404–2415 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Grossman, S. A. & Krabak, M. J. Leptomeningeal carcinomatosis. Cancer Treat. Rev. 25, 103–119 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  149. 149.

    Chamberlain, M. et al. Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials. Neuro-oncology 16, 1176–1185 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Chamberlain, M. et al. Leptomeningeal metastases: a RANO proposal for response criteria. Neuro-oncology 19, 484–492 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  151. 151.

    Niwinska, A., Tacikowska, M. & Murawska, M. The effect of early detection of occult brain metastases in HER2-positive breast cancer patients on survival and cause of death. Int. J. Radiat. Oncol. Biol. Phys. 77, 1134–1139 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  152. 152.

    Zhu, H. et al. Risk factors for brain metastases in completely resected small cell lung cancer: a retrospective study to identify patients most likely to benefit from prophylactic cranial irradiation. Radiat. Oncol. 9, 216 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Koiso, T. et al. A case-matched study of stereotactic radiosurgery for patients with brain metastases: comparing treatment results for those with versus without neurological symptoms. J. Neurooncol. 130, 581–590 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Wolf, A. et al. Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery. J. Neurosurg. 128, 23–31 (2017).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Le Pechoux, C. et al. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann. Oncol. 22, 1154–1163 (2011).

    PubMed  Article  Google Scholar 

  156. 156.

    Boggs, D. H. et al. Strategies to prevent brain metastasis in high-risk non-small-cell lung cancer: lessons learned from a randomized study of maintenance temozolomide versus observation. Clin. Lung Cancer 15, 433–440 (2014).

    PubMed  Article  Google Scholar 

  157. 157.

    Li, N. et al. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann. Oncol. 26, 504–509 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  158. 158.

    National Comprehensive Cancer Network. NCCN guidelines. NCCN https://www.nccn.org/professionals/physician_gls/default.aspx (2018).

  159. 159.

    Ramakrishna, N. et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: ASCO Clinical Practice Guideline Update. J. Clin. Oncol. 36, 2804–2807 (2018).

    PubMed  Article  Google Scholar 

  160. 160.

    Taylor, M. B., Bromham, N. R. & Arnold, S. E. Carcinoma of unknown primary: key radiological issues from the recent National Institute for Health and Clinical Excellence guidelines. Br. J. Radiol. 85, 661–671 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Klee, B., Law, I., Hojgaard, L. & Kosteljanetz, M. Detection of unknown primary tumours in patients with cerebral metastases using whole-body 18F-flouorodeoxyglucose positron emission tomography. Eur. J. Neurol. 9, 657–662 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  162. 162.

    Almuhaideb, A., Papathanasiou, N. & Bomanji, J. 18F-FDG PET/CT imaging in oncology. Ann. Saudi Med. 31, 3–13 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Siravegna, G. et al. Genotyping tumour DNA in cerebrospinal fluid and plasma of a HER2-positive breast cancer patient with brain metastases. ESMO Open 2, e000253 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Rudà, R., Borgognone, M., Benech, F., Vasario, E. & Soffietti, R. Brain metastases from unknown primary tumour: a prospective study. J. Neurol. 248, 394–398 (2001).

    PubMed  Article  PubMed Central  Google Scholar 

  165. 165.

    Nguyen, L. N., Maor, M. H. & Oswald, M. J. Brain metastases as the only manifestation of an undetected primary tumor. Cancer 83, 2181–2184 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  166. 166.

    Lagerwaard, F. J. et al. Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int. J. Radiat. Oncol. Biol. Phys. 43, 795–803 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  167. 167.

    Subbiah, I. M. et al. Validation and development of a modified breast graded prognostic assessment as a tool for survival in patients with breast cancer and brain metastases. J. Clin. Oncol. 33, 2239–2245 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Barnholtz-Sloan, J. S. et al. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro-oncology 14, 910–918 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Lorenzoni, J. et al. Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems. Int. J. Radiat. Oncol. Biol. Phys. 60, 218–224 (2004).

    PubMed  Article  Google Scholar 

  170. 170.

    Weltman, E. et al. Radiosurgery for brain metastases: a score index for predicting prognosis. Int. J. Radiat. Oncol. Biol. Phys. 46, 1155–1161 (2000).

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Ryken, T. C. et al. The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J. Neurooncol. 96, 103–114 (2010).

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Kong, X. et al. A meta-analysis: do prophylactic antiepileptic drugs in patients with brain tumors decrease the incidence of seizures? Clin. Neurol. Neurosurg. 134, 98–103 (2015).

    PubMed  Article  Google Scholar 

  173. 173.

    Fortin, D. The blood-brain barrier: its influence in the treatment of brain tumors metastases. Curr. Cancer Drug Targets 12, 247–259 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  174. 174.

    Askoxylakis, V., Arvanitis, C. D., Wong, C. S. F., Ferraro, G. B. & Jain, R. K. Emerging strategies for delivering antiangiogenic therapies to primary and metastatic brain tumors. Adv. Drug Deliv. Rev. 119, 159–174 (2017).

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    Kodack, D. P. et al. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc. Natl Acad. Sci. USA 109, E3119–E3127 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  176. 176.

    Falchook, G. S. et al. A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer. Invest. New Drugs 33, 177–186 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177.

    Barlesi, F. et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann. Oncol. 22, 2466–2470 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  178. 178.

    Robinet, G. et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) protocol 95-1. Ann. Oncol. 12, 59–67 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  179. 179.

    Cortes, J. et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology 64, 28–35 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  180. 180.

    Dinglin, X. X. et al. Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial. J. Neurooncol. 112, 461–466 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    Antonadou, D. et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J. Clin. Oncol. 20, 3644–3650 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  182. 182.

    Verger, E. et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 61, 185–191 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  183. 183.

    Sperduto, P. W. et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int. J. Radiat. Oncol. Biol. Phys. 85, 1312–1318 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Chua, D. et al. Whole-brain radiation therapy plus concomitant temozolomide for the treatment of brain metastases from non-small-cell lung cancer: a randomized, open-label phase II study. Clin. Lung Cancer 11, 176–181 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  185. 185.

    Robins, H. I., O’Neill, A., Mehta, M. & Grossman, S. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT & SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320: in regard to Sperduto et al. Int. J. Radiat. Oncol. Biol. Phys. 86, 809–810 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Lekic, M. et al. Outcome of small cell lung cancer (SCLC) patients with brain metastases in a routine clinical setting. Radiol. Oncol. 46, 54–59 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  187. 187.

    Isakoff, S. J. Triple-negative breast cancer: role of specific chemotherapy agents. Cancer J. 16, 53–61 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Christodoulou, C. et al. Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) phase II study. J. Neurooncol. 71, 61–65 (2005).

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Trudeau, M. E. et al. Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada - Clinical Trials Group (NCIC-CTG). Ann. Oncol. 17, 952–956 (2006).

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Ekenel, M., Hormigo, A. M., Peak, S., Deangelis, L. M. & Abrey, L. E. Capecitabine therapy of central nervous system metastases from breast cancer. J. Neurooncol. 85, 223–227 (2007).

    CAS  PubMed  Article  Google Scholar 

  191. 191.

    Nieder, C. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma. A prospective study. Cancer 86, 900–903 (1999).

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    Silvani, A. et al. Systemic sagopilone (ZK-EPO) treatment of patients with recurrent malignant gliomas. J. Neurooncol. 95, 61–64 (2009).

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Kumthekar, P. et al. ANG1005, a novel brain-penetrant taxane derivative, for the treatment of recurrent brain metastases and leptomeningeal carcinomatosis from breast cancer [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 2004 (2016).

    Article  Google Scholar 

  194. 194.

    Tang, S. C. et al. ANG1005, a novel peptide-paclitaxel conjugate crosses the BBB and shows activity in patients with recurrent CNS metastasis from breast cancer, results from a phase II clinical study [abstract]. Ann. Oncol. 27 (Suppl. 6), 324O (2016).

    Google Scholar 

  195. 195.

    Eichler, A. F. et al. Survival in patients with brain metastases from breast cancer: the importance of HER-2 status. Cancer 112, 2359–2367 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  196. 196.

    Stewart, D. J. & Dahrouge, S. Response of brain metastases from breast cancer to megestrol acetate: a case report. J. Neurooncol. 24, 299–301 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  197. 197.

    Salvati, M., Cervoni, L., Innocenzi, G. & Bardella, L. Prolonged stabilization of multiple and single brain metastases from breast cancer with tamoxifen. Report of three cases. Tumori 79, 359–362 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Mornex, F. et al. A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melanoma Res. 13, 97–103 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  199. 199.

    Agarwala, S. S. et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J. Clin. Oncol. 22, 2101–2107 (2004).

    CAS  PubMed  Article  Google Scholar 

  200. 200.

    Larkin, J. M. et al. A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. Br. J. Cancer 96, 44–48 (2007).

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Welsh, J. W. et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J. Clin. Oncol. 31, 895–902 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Ceresoli, G. L. et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann. Oncol. 15, 1042–1047 (2004).

    CAS  PubMed  Article  Google Scholar 

  203. 203.

    Grommes, C. et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 13, 1364–1369 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  204. 204.

    How, J., Mann, J., Laczniak, A. N. & Baggstrom, M. Q. Pulsatile erlotinib in EGFR-positive non-small-cell lung cancer patients with leptomeningeal and brain metastases: review of the literature. Clin. Lung Cancer 18, 354–363 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).

    PubMed  Article  Google Scholar 

  206. 206.

    Ahn, M. et al. Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in patients with TKI-naïve, EGFRm NSCLC with CNS metastases [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 2006 (2017).

    Article  Google Scholar 

  207. 207.

    Wang, H. et al. The ability of avitinib to penetrate the blood brain barrier and its control of intra-/extra- cranial disease in patients of non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation[abstract]. J. Clin. Oncol. 35 (Suppl. 15), e20613 (2017).

    Article  Google Scholar 

  208. 208.

    Li, D. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702–4711 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    Economopoulou, P. & Mountzios, G. Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy. Transl Lung Cancer Res. 5, 588–598 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Soria, J. C. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389, 917–929 (2017).

    CAS  Article  Google Scholar 

  211. 211.

    Gadgeel, S. et al. Alectinib versus crizotinib in treatment-naïve anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann. Oncol. 29, 2214–2222 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Camidge, D. R. et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 379, 2027–2039 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  213. 213.

    Shaw, A. T. et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 18, 1590–1599 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  214. 214.

    Petrelli, F. et al. Efficacy of ALK inhibitors on NSCLC brain metastases: a systematic review and pooled analysis of 21 studies. PLOS ONE 13, e0201425 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  215. 215.

    Venur, V. A. & Leone, J. P. Targeted therapies for brain metastases from breast cancer. Int. J. Mol. Sci. 17, 1543 (2016).

    PubMed Central  Article  CAS  Google Scholar 

  216. 216.

    Lin, N. U., Amiri-Kordestani, L., Palmieri, D., Liewehr, D. J. & Steeg, P. S. CNS metastases in breast cancer: old challenge, new frontiers. Clin. Cancer Res. 19, 6404–6418 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  217. 217.

    Kabraji, S. et al. Drug resistance in HER2-positive breast cancer brain metastases: blame the barrier or the brain? Clin. Cancer Res. 24, 1795–1804 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  218. 218.

    Askoxylakis, V., Kodack, D. P., Ferraro, G. B. & Jain, R. K. Antibody-based therapies for the treatment of brain metastases from HER2-positive breast cancer: time to rethink the importance of the BBB? Breast Cancer Res. Treat. 165, 467–468 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  219. 219.

    Lewis Phillips, G. D. et al. Trastuzumab uptake and its relation to efficacy in an animal model of HER2-positive breast cancer brain metastasis. Breast Cancer Res. Treat. 164, 581–591 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  220. 220.

    Lin, N. U. et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin. Cancer Res. 15, 1452–1459 (2009).

    CAS  PubMed  Article  Google Scholar 

  221. 221.

    Lin, N. U. et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 26, 1993–1999 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  222. 222.

    Bachelot, T. et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 14, 64–71 (2013).

    CAS  PubMed  Article  Google Scholar 

  223. 223.

    Freedman, R. A. et al. Translational breast cancer research consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J. Clin. Oncol. 34, 945–952 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Freedman, R. et al. TBCRC 022: phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM) [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 1005 (2017).

    Article  Google Scholar 

  225. 225.

    Borges, V. F. et al. Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 513 (2016).

    Article  Google Scholar 

  226. 226.

    Lin, N. U. et al. Determination of the maximum tolerated dose (MTD) of the CNS penetrant tyrosine kinase inhibitor (TKI) tesevatinib administered in combination with trastuzumab in HER2+ patients with metastatic breast cancer (BC) [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 514 (2016).

    Article  Google Scholar 

  227. 227.

    McArthur, G. A. et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann. Oncol. 28, 634–641 (2017).

    CAS  PubMed  Article  Google Scholar 

  228. 228.

    Davies, M. A. et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 18, 863–873 (2017). This phase II clinical trial demonstrates intracranial response rates >50% using targeted molecular therapies on the BRAF and MAPK pathways combined.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  229. 229.

    Shonka, N., Venur, V. A. & Ahluwalia, M. S. Targeted treatment of brain metastases. Curr. Neurol. Neurosci. Rep. 17, 37 (2017).

    PubMed  Article  CAS  Google Scholar 

  230. 230.

    Obenauf, A. C. et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 520, 368–372 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. 231.

    Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27, 574–588 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  232. 232.

    Boogerd, W., Dalesio, O., Bais, E. M. & van der Sande, J. J. Response of brain metastases from breast cancer to systemic chemotherapy. Cancer 69, 972–980 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  233. 233.

    Valpione, S. et al. Rechallenge with BRAF-directed treatment in metastatic melanoma: a multi-institutional retrospective study. Eur. J. Cancer 91, 116–124 (2018). This study demonstrates that rechallenge BRAF-targeted molecular therapies after initial failure can have significant response rates (>40%) in patients with melanoma brain metastases.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  234. 234.

    Berghoff, A. S., Venur, V. A., Preusser, M. & Ahluwalia, M. S. Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am. Soc. Clin. Oncol. Educ. Book 35, e116–e122 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  235. 235.

    Margolin, K. et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet. Oncol. 13, 459–465 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  236. 236.

    Goldberg, S. B. et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet. Oncol. 17, 976–983 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. 237.

    Gadgeel, S. et al. OAK, a randomized Ph III study of atezolizumab vs docetaxel in patients with advanced NSCLC: results from subgroup analyses [abstract PL04a.02]. J. Thorac Oncol. 12 (Suppl.), S9–S10 (2017).

    Article  Google Scholar 

  238. 238.

    Tawbi, H. et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study CheckMate 204 [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 9507 (2017).

    Article  Google Scholar 

  239. 239.

    Long, G. et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): the Anti-PD1 Brain Collaboration (ABC) [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 9508 (2017).

    Article  Google Scholar 

  240. 240.

    Tawbi, H. A. et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N. Engl. J. Med. 379, 722–730 (2018). This phase II trial demonstrates that combined nivolumab and ipilimumab have a 56% intracranial response rate (comparable to the extracranial response) and result in an overall survival of 81.5% at 1 year and ~70% at 2 years in patients with melanoma brain metastases.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  241. 241.

    Anderson, E. S. et al. Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. J. Immunother. Cancer 5, 76 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  242. 242.

    Nardin, C. et al. Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases. Melanoma Res. 28, 111–119 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  243. 243.

    Quail, D. F. & Joyce, J. A. The microenvironmental landscape of brain tumors. Cancer Cell 31, 326–341 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  244. 244.

    Cohen, J. V. et al. Melanoma brain metastasis pseudoprogression after pembrolizumab treatment. Cancer Immunol. Res. 4, 179–182 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  245. 245.

    Patchell, R. A. et al. A randomized trial of surgery in the treatment of single metastases to the brain. N. Engl. J. Med. 322, 494–500 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  246. 246.

    Vecht, C. J. et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann. Neurol. 33, 583–590 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  247. 247.

    Paek, S. H., Audu, P. B., Sperling, M. R., Cho, J. & Andrews, D. W. Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery 56, 1021–1034 (2005).

    PubMed  PubMed Central  Google Scholar 

  248. 248.

    Stark, A. M., Tscheslog, H., Buhl, R., Held-Feindt, J. & Mehdorn, H. M. Surgical treatment for brain metastases: prognostic factors and survival in 177 patients. Neurosurg. Rev. 28, 115–119 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  249. 249.

    Bindal, R. K., Sawaya, R., Leavens, M. E. & Lee, J. J. Surgical treatment of multiple brain metastases. J. Neurosurg. 79, 210–216 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  250. 250.

    Wron´ski, M., Arbit, E., McCormick, B. & Wrónski, M. Surgical treatment of 70 patients with brain metastases from breast carcinoma. Cancer 80, 1746–1754 (1997).

    Article  Google Scholar 

  251. 251.

    Hatiboglu, M. A., Wildrick, D. M. & Sawaya, R. The role of surgical resection in patients with brain metastases. Ecancermedicalscience 7, 308 (2013).

    PubMed  PubMed Central  Google Scholar 

  252. 252.

    Iwadate, Y., Namba, H. & Yamaura, A. Significance of surgical resection for the treatment of multiple brain metastases. Anticancer Res. 20, 573–577 (2000). This article provides evidence that surgical resection of tumours >2 cm have improved outcomes after adjuvant radiotherapy including overall survival, even in the presence of multiple brain metastases.

    CAS  PubMed  PubMed Central  Google Scholar 

  253. 253.

    Mahajan, A. et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 18, 1040–1048 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  254. 254.

    Ali, M. A. et al. Stereotactic laser ablation as treatment for brain metastases that recur after stereotactic radiosurgery: a multiinstitutional experience. Neurosurg. Focus 41, E11 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  255. 255.

    Ahluwalia, M. et al. Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis. J. Neurosurg. https://doi.org/10.3171/2017.11.JNS171273 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  256. 256.

    Rennert, R. C. et al. Patterns of clinical use of stereotactic laser ablation: analysis of a multicenter prospective registry. World Neurosurg. 116, e566–e570 (2018).

    PubMed  Article  Google Scholar 

  257. 257.

    Beechar, V. B. et al. Volumetric response of progressing post-SRS lesions treated with laser interstitial thermal therapy. J. Neurooncol 137, 57–65 (2018).

    PubMed  Article  Google Scholar 

  258. 258.

    Kann, B. H., Park, H. S., Johnson, S. B., Chiang, V. L. & Yu, J. B. Radiosurgery for brain metastases: changing practice patterns and disparities in the United States. J. Natl Compr. Canc. Netw. 15, 1494–1502 (2017).

    PubMed  Article  Google Scholar 

  259. 259.

    Patchell, R. A. et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280, 1485–1489 (1998).

    CAS  PubMed  Article  Google Scholar 

  260. 260.

    Brown, P. D. et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA 316, 401–409 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  261. 261.

    Hardee, M. E. & Formenti, S. C. Combining stereotactic radiosurgery and systemic therapy for brain metastases: a potential role for temozolomide. Front. Oncol. 2, 99 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  262. 262.

    Andrews, D. W. et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363, 1665–1672 (2004).

    PubMed  Article  Google Scholar 

  263. 263.

    Sperduto, P. W. et al. Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int. J. Radiat. Oncol. Biol. Phys. 90, 526–531 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  264. 264.

    Aoyama, H. et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295, 2483–2491 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  265. 265.

    Kocher, M. et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J. Clin. Oncol. 29, 134–141 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  266. 266.

    Chang, E. L. et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 10, 1037–1044 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  267. 267.

    American Society for Radiation Oncology. 2014 choosing wisely list. ASTRO https://www.astro.org/Patient-Care-and-Research/Patient-Education/2014-Choosing-Wisely-List (2015).

  268. 268.

    Kim, H., Rajagopalan, M. S., Beriwal, S. & Smith, K. J. Cost-effectiveness analysis of stereotactic radiosurgery alone versus stereotactic radiosurgery with upfront whole brain radiation therapy for brain metastases. Clin. Oncol. (R. Coll. Radiol) 29, e157–e164 (2017).

    CAS  Article  Google Scholar 

  269. 269.

    Sahgal, A. et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int. J. Radiat. Oncol. Biol. Phys. 91, 710–717 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  270. 270.

    Aoyama, H., Tago, M., Shirato, H. & Japanese Radiation Oncology Study Group 99-1 (JROSG 99-1) Investigators. Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases: secondary analysis of the JROSG 99-1 randomized clinical trial. JAMA. Oncol. 1, 457–464 (2015).

    Google Scholar 

  271. 271.

    Liu, Y. et al. Salvage whole brain radiotherapy or stereotactic radiosurgery after initial stereotactic radiosurgery for 1-4 brain metastases. J. Neurooncol. 124, 429–437 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  272. 272.

    Zeng, K. L. et al. Patient preference for stereotactic radiosurgery plus or minus whole brain radiotherapy for the treatment of brain metastases. Ann. Palliat. Med. 6, S155–S160 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  273. 273.

    Mulvenna, P. et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 388, 2004–2014 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  274. 274.

    Slotman, B. et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N. Engl. J. Med. 357, 664–672 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  275. 275.

    Aupérin, A. et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N. Engl. J. Med. 341, 476–484 (1999).

    PubMed  Article  PubMed Central  Google Scholar 

  276. 276.

    Takahashi, T. et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 18, 663–671 (2017).

    PubMed  Article  Google Scholar 

  277. 277.

    Yamamoto, M. et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 15, 387–395 (2014). This prospective observational study of nearly 1,200 patients demonstrated that SRS without WBRT may be a suitable alternative for patients with up to ten brain metastases.

    PubMed  Article  PubMed Central  Google Scholar 

  278. 278.

    Johnson, M. D. et al. Surgical resection of brain metastases and the risk of leptomeningeal recurrence in patients treated with stereotactic radiosurgery. Int. J. Radiat. Oncol. Biol. Phys. 94, 537–543 (2016).

    PubMed  Article  Google Scholar 

  279. 279.

    Thomas, E. M. et al. Comparison of plan quality and delivery time between volumetric arc therapy (RapidArc) and gamma knife radiosurgery for multiple cranial metastases. Neurosurgery 75, 409–417 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  280. 280.

    Rajakesari, S. et al. Local control after fractionated stereotactic radiation therapy for brain metastases. J. Neurooncol. 120, 339–346 (2014).

    CAS  PubMed  Article  Google Scholar 

  281. 281.

    Muacevic, A., Kufeld, M., Wowra, B., Kreth, F. W. & Tonn, J. C. Feasibility, safety, and outcome of frameless image-guided robotic radiosurgery for brain metastases. J. Neurooncol. 97, 267–274 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  282. 282.

    Brown, P. D. et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 18, (1049–1060 (2017). This randomized controlled trial demonstrates less frequent declines in cognitive function with postoperative SRS versus WBRT in patients with brain metastases, with no difference in overall survival.

    Google Scholar 

  283. 283.

    Soliman, H. et al. Consensus contouring guidelines for postoperative completely resected cavity stereotactic radiosurgery for brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 100, 436–442 (2018).

    PubMed  Article  Google Scholar 

  284. 284.

    Gondi, V. et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J. Clin. Oncol. 32, 3810–3816 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  285. 285.

    Brown, P. D. et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-oncology 15, 1429–1437 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  286. 286.

    Bezjak, A. et al. Symptom response after palliative radiotherapy for patients with brain metastases. Eur. J. Cancer 38, 487–496 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  287. 287.

    Doyle, M. et al. Quality of life in patients with brain metastases treated with a palliative course of whole-brain radiotherapy. J. Palliat. Med. 10, 367–374 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  288. 288.

    Gerrard, G. E. et al. Investigating the palliative efficacy of whole-brain radiotherapy for patients with multiple-brain metastases and poor prognostic features. Clin. Oncol. (R. Coll. Radiol) 15, 422–428 (2003).

    CAS  Article  Google Scholar 

  289. 289.

    Steinmann, D. et al. Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases. BMC Cancer 12, 283 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  290. 290.

    Wong, J. et al. Symptoms and quality of life in cancer patients with brain metastases following palliative radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 75, 1125–1131 (2009).

    PubMed  Article  Google Scholar 

  291. 291.

    Chow, E., Davis, L., Holden, L., Tsao, M. & Danjoux, C. Prospective assessment of patient-rated symptoms following whole brain radiotherapy for brain metastases. J. Pain Symptom Manage. 30, 18–23 (2005).

    PubMed  Article  Google Scholar 

  292. 292.

    Fernandez, G., Pocinho, R., Travancinha, C., Netto, E. & Roldão, M. Quality of life and radiotherapy in brain metastasis patients. Rep. Pract. Oncol. Radiother. 17, 281–287 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  293. 293.

    Pulenzas, N. et al. Fatigue scores in patients with brain metastases receiving whole brain radiotherapy. Support Care Cancer 22, 1757–1763 (2014).

    PubMed  Article  Google Scholar 

  294. 294.

    Caissie, A. et al. Quality of life in patients with brain metastases using the EORTC QLQ-BN20+2 and QLQ-C15-PAL. Int. J. Radiat. Oncol. Biol. Phys. 83, 1238–1245 (2012).

    PubMed  Article  Google Scholar 

  295. 295.

    Li, B. et al. Comparison of three treatment options for single brain metastasis from lung cancer. Int. J. Cancer 90, 37–45 (2000).

    CAS  PubMed  Article  Google Scholar 

  296. 296.

    DiBiase, S. J., Chin, L. S. & Ma, L. Influence of gamma knife radiosurgery on the quality of life in patients with brain metastases. Am. J. Clin. Oncol. 25, 131–134 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  297. 297.

    Lowe, S. S. et al. Associations between objectively measured physical activity and quality of life in cancer patients with brain metastases. J. Pain Symptom Manage. 48, 322–332 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  298. 298.

    Fernandes, A. W., Wu, B. & Turner, R. M. Brain metastases in non-small cell lung cancer patients on epidermal growth factor receptor tyrosine kinase inhibitors: symptom and economic burden. J. Med. Econ. 20, 1136–1147 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  299. 299.

    Burudpakdee, C. et al. Economic impact of preventing brain metastases with alectinib in ALK-positive non-small cell lung cancer. Lung Cancer 119, 103–111 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  300. 300.

    El-Habashy, S. E. et al. Novel treatment strategies for brain tumors and metastases. Pharm. Pat. Anal. 3, 279–296 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  301. 301.

    Crino, L. et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J. Clin. Oncol. 34, 2866–2873 (2016).

    CAS  PubMed  Article  Google Scholar 

  302. 302.

    Bonoiu, A. et al. MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier. Brain Res. 1282, 142–155 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  303. 303.

    Pinaud, F., King, D., Moore, H. P. & Weiss, S. Bioactivation and cell targeting of semiconductor CdSe/ZnS nanocrystals with phytochelatin-related peptides. J. Am. Chem. Soc. 126, 6115–6123 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  304. 304.

    Kodack, D. P., Askoxylakis, V., Ferraro, G. B., Fukumura, D. & Jain, R. K. Emerging strategies for treating brain metastases from breast cancer. Cancer Cell 27, 163–175 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  305. 305.

    Siravegna, G., Marsoni, S., Siena, S. & Bardelli, A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 14, 531–548 (2017).

    CAS  Article  Google Scholar 

  306. 306.

    Sahgal, A. et al. Stereotactic radiosurgery alone for multiple brain metastases? A review of clinical and technical issues. Neuro-oncology 19 (Suppl. 2), ii2–ii15 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  307. 307.

    Lin, N. U. et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 16, e270–e278 (2015).

    PubMed  Article  Google Scholar 

  308. 308.

    Camidge, D. R. et al. Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group. Lancet Oncol. 19, e20–e32 (2018).

    PubMed  Article  Google Scholar 

  309. 309.

    Alexander, B. M. et al. Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group. Lancet Oncol. 19, e33–e42 (2018).

    PubMed  Article  Google Scholar 

  310. 310.

    Dummer, R. et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur. J. Cancer 50, 611–621 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  311. 311.

    Gadgeel, S. M. et al. Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive non–small-cell lung cancer. J. Clin. Oncol. 34, 4079–4085 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  312. 312.

    Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  313. 313.

    Di Giacomo, A. M. et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann. Oncol. 26, 798–803 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  314. 314.

    Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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Reviewer information

Nature Reviews Disease Primers thanks M. Davies, G. Rao, J. Saunus, and other anonymous reviewer(s), for their contribution to the peer review of this work.

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Contributions

Introduction (A.S.A., R.C.R. and S.D.C.); Epidemiology (L.N.); Mechanisms/pathophysiology (C.A. and P.S.S.); Diagnosis, screening and prevention (R.S.); Management (M.S.A., A.S.A., R.C.R., S.D.C., G.R.H. and N.D.A.); Quality of life (S.P.); Outlook (S.P.); Overview of the Primer (A.S.A, R.C.R. and S.D.C.). A.S.A. and R.C.R. contributed equally to the manuscript.

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Correspondence to Achal Singh Achrol or Robert C. Rennert or Steven D. Chang.

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C.A. has received funding support from Novartis, Merrimack, PUMA, Lilly, Merck, Cascadian/Seattle Genetics, Nektar, Tesaro and G1-Therapuetics; she has held uncompensated advisory roles with Novartis, Merrimack, Lilly, Genentech, Nektar and Cascadian/Seattle Genetics; she has held compensated advisory roles with PUMA, Merck and Eisai; and she has received royalties from UpToDate, Jones and Bartlett. M.S.A. has stock options in MimiVax and Doctible and has received grants and/or personal fees from Monteris Medical, AbbVie, BMS, AstraZeneca, Datar Genetics, CBT Pharmaceuticals, Kadmon Pharmaceuticals, Elsevier, NovoCure, Novartis, Incyte, Pharmacyclics, Tracon Pharmaceuticals, Prime Oncology, Flatiron, Merck, Bayer, Varian Medical Systems, VBI Vaccines and Caris Lifesciences. S.P. receives honoraria or consultation fees from AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda; she has given talks in an organized public event for AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, Pfizer and Takeda; and she is a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, MedImmune and Pfizer. P.S.S. receives research funding from MedImmune. The remaining authors declare no competing interests.

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Achrol, A.S., Rennert, R.C., Anders, C. et al. Brain metastases. Nat Rev Dis Primers 5, 5 (2019). https://doi.org/10.1038/s41572-018-0055-y

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