Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Management of brain metastases according to molecular subtypes

Nature Reviews Neurology volume 16, pages 557–574 (2020)Cite this article

Subjects

Abstract

The incidence of brain metastases has markedly increased in the past 20 years owing to progress in the treatment of malignant solid tumours, earlier diagnosis by MRI and an ageing population. Although local therapies remain the mainstay of treatment for many patients with brain metastases, a growing number of systemic options are now available and/or are under active investigation. HER2-targeted therapies (lapatinib, neratinib, tucatinib and trastuzumab emtansine), alone or in combination, yield a number of intracranial responses in patients with HER2-positive breast cancer brain metastases. New inhibitors are being investigated in brain metastases from ER-positive or triple-negative breast cancer. Several generations of EGFR and ALK inhibitors have shown activity on brain metastases from EGFR and ALK mutant non-small-cell lung cancer. Immune-checkpoint inhibitors (ICIs) hold promise in patients with non-small-cell lung cancer without druggable mutations and in patients with triple-negative breast cancer. The survival of patients with brain metastases from melanoma has substantially improved after the advent of BRAF inhibitors and ICIs (ipilimumab, nivolumab and pembrolizumab). The combination of targeted agents or ICIs with stereotactic radiosurgery could further improve the response rates and survival but the risk of radiation necrosis should be monitored. Advanced neuroimaging and liquid biopsy will hopefully improve response evaluation.

Key points

  • The blood–brain, blood–tumour and blood–cerebral fluid barriers limit the effective delivery of water-soluble drugs and macromolecules, such as monoclonal antibodies, to the CNS.

  • Brain metastases from EGFR-mutant and ALK-rearranged non-small-cell lung cancer (NSCLC), HER2-positive breast cancer and BRAF-mutant melanoma can be successfully targeted with specific inhibitors.

  • Immune-checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab and atezolizumab) have clearly improved the outcome of patients with brain metastases from melanoma and now show promising efficacy in patients with brain metastases from non-druggable subtypes of NSCLC and triple-negative breast cancer.

  • The combination of targeted agents and immune-checkpoint inhibitors with stereotactic radiosurgery might yield better results over single modalities but the risk of radionecrosis is still debated.

  • New druggable targets are being investigated in brain metastases from NSCLC (ROS1 rearrangement, NTRK fusions, BRAF and KRAS mutations), breast cancer (DNA repair, CDK4/CDK6 and ER signalling pathways) and melanoma (MEK resistance pathway).

  • Advanced neuroimaging modalities and liquid biopsy represent more precise tools than standard MRI to evaluate early response or progression following targeted therapies or immunotherapy, while phase 0 trials will give the opportunity for in vivo testing of new compounds before entering phase II or III clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kromer, C. et al. Estimating the annual frequency of synchronous brain metastasis in the United States 2010-2013: a population-based study. J. Neurooncol. 134, 55–64 (2017).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. National Comprehensive Cancer Network. Central nervous system cancers: extensive brain metastases. v.4.2012. http://www.nccn.org (2019).

  4. Brastianos, P. K. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 5, 1164–1177 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shih, D. J. H. et al. Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat. Genet. 52, 371–377 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kim, M. et al. Barriers to effective drug treatment for brain metastases: a multifactorial problem in the delivery of precision medicine. Pharm. Res. 35, 177 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Sprowls, S. A. et al. Improving CNS delivery to brain metastases by blood-tumor barrier disruption. Trends Cancer 5, 495–505 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Pardridge, W. M. CSF, blood-brain barrier, and brain drug delivery. Expert. Opin. Drug Deliv. 13, 963–975 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Noone A. M. et al. SEER Cancer Statistics Review, 1975-2015. (National Cancer Institute, 2015).

  12. Sørensen, J. B., Hansen, H. H., Hansen, M. & Dombernowsky, P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J. Clin. Oncol. 6, 1474–1480 (1988).

    Article  PubMed  Google Scholar 

  13. 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 (2017).

    Article  PubMed  Google Scholar 

  14. Kris, M. G. et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311, 1998–2006 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Dong, J., Li, B., Lin, D., Zhou, Q. & Huang, D. Advances in targeted therapy and immunotherapy for non-small cell lung cancer based on accurate molecular typing. Front. Pharmacol. 10, 230 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rosell, R. et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361, 958–967 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from ‘Never Smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eichler, A. F. et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 12, 1193–1199 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu, Y. L. et al. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG–0803). Ann. Oncol. 24, 993–999 (2013).

    Article  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Iuchi, T. et al. Phase II trial of gefitinib alone without radiation therapy for japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer 82, 282–287 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Yang, J. J. et al. Icotinib versus Whole-Brain Irradiation in Patients with EGFR-Mutant Non-Small-Cell Lung Cancer and Multiple Brain Metastases (BRAIN): A Multicentre, Phase 3, Open-Label, Parallel, Randomised Controlled Trial. Lancet Respir. Med. 5, 707–716 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Zhao, J. et al. Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin. Lung Cancer 14, 188–193 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Deng, Y. et al. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol. Clin. Oncol. 2, 116–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. Yu, H. A. et al. Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann. Oncol. 28, 278–284 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Camidge, D. R., Pao, W. & Sequist, L. V. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat. Rev. Clin. Oncol. 11, 473–481 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Sequist, L. V. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31, 3327–3334 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Wu, Y. L. et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 15, 213–222 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446–454 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Jänne, P. A. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372, 1689–1699 (2015).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Reungwetwattana, T. et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J. Clin. Oncol. 36, 3290–3297 (2018).

    Article  CAS  Google Scholar 

  37. Ramalingam, S. S. et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N. Engl. J. Med. 382, 41–50 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. Wu, Y. L. et al. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J. Clin. Oncol. 36, 2702–2709 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Takeuchi, K. et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin. Cancer Res. 14, 6618–6624 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Wong, D. W. et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115, 1723–1733 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014).

    Article  PubMed  CAS  Google Scholar 

  43. Solomon, B. J. et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J. Clin. Oncol. 34, 2858–2865 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Shaw, A. T. et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 17, 234–242 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, D. W. et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J. Clin. Oncol. 35, 2490–2498 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Nishio, M. et al. Final overall survival and other efficacy and safety results from ASCEND-3: phase II study of ceritinib in ALKi-naive patients with ALK-rearranged NSCLC. J. Thorac. Oncol. 15, 609–617 (2020).

    Article  CAS  PubMed  Google Scholar 

  47. Gadgeel, S. M. et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 15, 1119–1128 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Solomon, B. J. et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 19, 1654–1667 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Russo, A. et al. New targets in lung cancer (Excluding EGFR, ALK, ROS1). Curr. Oncol. Rep. 22, 48 (2020).

    Article  PubMed  Google Scholar 

  51. Planchard, D. et al. Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 17, 984–993 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Drilon, A. et al. Activity of larotrectinib in TRK fusion lung cancer. Ann. Oncol. 30 (Suppl. 2), ii48–ii49 (2019).

    Article  Google Scholar 

  53. Drilon, A. et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials. Lancet Oncol. 21, 261–270 (2020).

    Article  CAS  PubMed  Google Scholar 

  54. Scheel, A. H. et al. PDL-1 expression in non-small cell lung cancer: correlations with genetic alterations. Oncoimmunology 5, e1131379 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Takamori, S. et al. Clinical significance of PDL-1 expression in brain metastases from non-small cell lung cancer. Anticancer Res. 38, 553–557 (2018).

    CAS  PubMed  Google Scholar 

  56. Mansfield, A. S. et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann. Oncol. 27, 1953–1958 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Goldberg, S. B. et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 21, 655–663 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Davis, A. A. & Patel, V. G. The role of PDL-1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer 7, 278–285 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Gadgeel, S. M. et al. Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: exploratory analyses of the phase III OAK study. Lung Cancer 128, 105–112 (2019).

    Article  PubMed  Google Scholar 

  60. Gong, X. et al. Combined radiotherapy and Anti-PDL-1 antibody synergistically enhances antitumor effect in non-small cell lung cancer. J. Thorac. Oncol. 12, 1085–1097 (2017).

    Article  PubMed  Google Scholar 

  61. Singh, C., Qian, J. M., Yu, J. B. & Chiang, V. L. Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases. J. Neurosurg. 132, 512–517 (2019).

    Article  PubMed  Google Scholar 

  62. Chen, L. et al. Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 100, 916–925 (2018).

    Article  PubMed  Google Scholar 

  63. Kotecha, R. et al. The impact of sequencing PD-1/PDL-1 inhibitors and stereotactic radiosurgery for patients with brain metastasis. Neuro Oncol. 21, 1060–1068 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Lin, N. U. et al. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer 118, 5463–5472 (2012).

    Article  PubMed  Google Scholar 

  65. Olson, E. M. et al. Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann. Oncol. 24, 1526–1533 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pestalozzi, B. C. et al. CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01). Lancet Oncol. 14, 244–248 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Dawood, S. et al. Incidence of and survival following brain metastases among women with inflammatory breast cancer. Ann. Oncol. 21, 2348–2355 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Warren, L. E. et al. Inflammatory breast cancer and development of brain metastases: risk factors and outcomes. Breast Cancer Res. Treat. 151, 225–232 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Lin, N. U. et al. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 113, 2638–2645 (2008).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  71. 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).

    Article  PubMed  Google Scholar 

  72. Olson, E. M. et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast 22, 525–531 (2013).

    Article  PubMed  Google Scholar 

  73. von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019).

    Article  Google Scholar 

  74. Bendell, J. C. et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97, 2972–2977 (2003).

    Article  PubMed  Google Scholar 

  75. 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).

    Article  PubMed  Google Scholar 

  76. Cagney, D. N. et al. Breast cancer subtype and intracranial recurrence patterns after brain-directed radiation for brain metastases. Breast Cancer Res. Treat. 176, 171–179 (2019).

    Article  PubMed  Google Scholar 

  77. Gori, S. et al. The HERBA study: a retrospective multi-institutional Italian study on patients with brain metastases from HER2-positive breast cancer. Clin. Breast Cancer 19, e501–e510 (2019).

    Article  PubMed  Google Scholar 

  78. Palmieri, D. et al. Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res. 67, 4190–4198 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Taskar, K. S. et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm. Res. 29, 770–781 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. 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).

    Article  CAS  PubMed  Google Scholar 

  81. 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).

    Article  CAS  PubMed  Google Scholar 

  82. Sutherland, S. et al. Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases–the UK experience. Br. J. Cancer 102, 995–1002 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lin, N. U. et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J. Neurooncol. 105, 613–620 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Metro, G. et al. Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann. Oncol. 22, 625–630 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  Google Scholar 

  86. Freedman, R. A. et al. Pre- and postoperative neratinib for HER2-positive breast cancer brain metastases: translational breast cancer research consortium 022. Clin. Breast Cancer 20, 145–151.e2 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Freedman, R. A. et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J. Clin. Oncol. 37, 1081–1089 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Metzger-Filho, O. et al. Phase I dose-escalation trial of ONT-380 in combination with trastuzumab in participants with brain metastases from HER2+ breast cancer. J. Clin. Oncol. 32 (Suppl. 15), https://doi.org/10.1200/jco.2014.32.15_suppl.tps660 (2014).

  90. Murthy, R. et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 19, 880–888 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Murthy, R. K. et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N. Engl. J. Med. 382, 597–609 (2020).

    Article  CAS  PubMed  Google Scholar 

  92. Dijkers, E. C. et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin. Pharmacol. Ther. 87, 586–592 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lin, N. U. et al. Planned interim analysis of PATRICIA: an open-label, single-arm, phase II study of pertuzumab (P) with high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression post radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC). J. Clin. Oncol. 35 (Suppl. 15), 2074 (2017).

    Article  Google Scholar 

  95. Bartsch, R. et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin. Exp. Metastasis 32, 729–737 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Jacot, W. et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res. Treat. 157, 307–318 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  PubMed  Google Scholar 

  98. Fabi, A. et al. T-DM1 and brain metastases: clinical outcome in HER2-positive metastatic breast cancer. Breast 41, 137–143 (2018).

    Article  PubMed  Google Scholar 

  99. Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).

    Article  CAS  PubMed  Google Scholar 

  100. Lin, N. U., Bellon, J. R. & Winer, E. P. CNS metastases in breast cancer. J. Clin. Oncol. 22, 3608–3617 (2004).

    Article  PubMed  Google Scholar 

  101. Raub, T. J. et al. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab. Dispos. 43, 1360–1371 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Anders, C. K. et al. A phase 2 study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC). J. Clin. Oncol. 37, 1017 (2019).

    Article  Google Scholar 

  103. Patel, H. K. & Bihani, T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol. Ther. 186, 1–24 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Ni, J. et al. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat. Med. 22, 723–726 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kodack, D. P. et al. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation. Sci. Transl Med. 9, 391 (2017).

    Article  Google Scholar 

  106. Ippen, F. M. et al. Targeting the PI3K/Akt/mTOR-pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro Oncol. 21, 1401–1411 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Song, Y. et al. Patterns of recurrence and metastasis in BRCA1/BRCA2-associated breast cancers. Cancer 126, 271–280 (2020).

    Article  CAS  PubMed  Google Scholar 

  108. Puri, A., Reddy, T. P., Patel, T. A. & Chang, J. C. Metastatic triple-negative breast cancer: established and emerging treatments. Breast J. https://doi.org/10.1111/tbj.13946 (2020).

  109. Litton, J. K. et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J. Clin. Oncol. 38, 388–394 (2020).

    Article  CAS  PubMed  Google Scholar 

  110. Karginova, O. et al. Efficacy of carboplatin alone and in combination with ABT888 in intracranial murine models of BRCA-mutated and BRCA-wild-type triple-negative breast cancer. Mol. Cancer Ther. 14, 920–930 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Voutouri, C. et al. Experimental and computational analyses reveal dynamics of tumor vessel cooption and optimal treatment strategies. Proc. Natl Acad. Sci. USA 116, 2662–2671 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lin, N. U. et al. Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). J. Clin. Oncol. 31 (Suppl. 15), 513 (2013).

    Article  Google Scholar 

  114. Lu, Y. S. et al. Bevacizumab preconditioning followed by etoposide and cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole-brain radiotherapy. Clin. Cancer Res. 21, 1851–1858 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Wagner, A. D., Thomssen, C., Haerting, J. & Unverzagt, S. Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer. Cochrane Database Syst. Rev. 7, CD008941 (2012).

    Google Scholar 

  116. Schmid, P. et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 21, 44–59 (2020).

    Article  CAS  PubMed  Google Scholar 

  117. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Ogiya, R. et al. Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer. Oncotarget 8, 103671–103681 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Yomo, S., Hayashi, M. & Cho, N. Impacts of HER2-overexpression and molecular targeting therapy on the efficacy of stereotactic radiosurgery for brain metastases from breast cancer. J. Neurooncol. 112, 199–207 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Kim, J. M. et al. Stereotactic radiosurgery with concurrent HER2-directed therapy is associated with improved objective response for breast cancer brain metastasis. Neuro Oncol. 21, 659–668 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Parsai, S. et al. Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases. J. Neurosurg. 132, 503–511 (2019).

    Article  PubMed  Google Scholar 

  122. Lin, N. U. et al. A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases. Breast Cancer Res. Treat. 142, 405–414 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Stumpf, P. K. et al. Combination of trastuzumab emtansine and stereotactic radiosurgery results in high rates of clinically significant radionecrosis and dysregulation of aquaporin-4. Clin. Cancer Res. 25, 3946–3953 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Geraud, A., Xu, H. P., Beuzeboc, P. & Kirova, Y. M. Preliminary experience of the concurrent use of radiosurgery and T-DM1 for brain metastases in HER2-positive metastatic breast cancer. J. Neurooncol. 131, 69–72 (2017).

    Article  CAS  PubMed  Google Scholar 

  125. Rosner, D., Nemoto, T. & Lane, W. W. Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer 58, 832–839 (1986).

    Article  CAS  PubMed  Google Scholar 

  126. Franciosi, V. et al. 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 85, 1599–1605 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. Caraglia, M. et al. Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours. Cancer Chemother. Pharmacol. 57, 34–39 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Rivera, E. et al. Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 107, 1348–1354 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Linot, B. et al. Use of liposomal doxorubicin-cyclophosphamide combination in breast cancer patients with brain metastases: a monocentric retrospective study. J. Neurooncol. 117, 253–259 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Anders, C. et al. TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases. Breast Cancer Res. Treat. 146, 557–566 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Melisko, M. E. et al. Phase II study of irinotecan and temozolomide in breast cancer patients with progressing central nervous system disease. Breast Cancer Res. Treat. 177, 401–408 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Shah, N. et al. Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol. Res. 132, 47–68 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cortés, J. et al. Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res. Treat. 165, 329–341 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Anders, C. et al. Phase 1 expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC): findings from the cohort with active brain metastasis (BM). Neuro-oncol. Adv. 1 (Suppl. 1), https://doi.org/10.1093/noajnl/vdz014.039 (2019).

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

    Article  Google Scholar 

  137. James, J., Tang, K. & Wei, T. Tesetaxel, a novel, oral taxane, crosses intact blood-brain barrier (BBB) at therapeutically relevant concentrations [abstract 3078]. Cancer Res. 79 (Suppl. 13), https://doi.org/10.1158/1538-7445.AM2019-3078 (2019).

  138. Seidman, A. D. et al. Activity of tesetaxel, an oral taxane, given as a single-agent in patients (Pts) with HER2-, hormone receptor+ (HR+) locally advanced or metastatic breast cancer (MBC) in a phase 2 study. J. Clin. Oncol. https://doi.org/10.1200/JCO.2018.36.15_suppl.1042 (2018).

  139. Zakrzewski, J. et al. Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival. Cancer 117, 1711–1720 (2011).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  141. Bucheit, A. D. et al. Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer 119, 3821–3829 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Hanniford, D. et al. A miRNA-based signature detected in primary melanoma tissue predicts development of brain metastasis. Clin. Cancer Res. 21, 4903–4912 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Fischer, G. M. et al. Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases. Cancer Discov. 9, 628–645 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Davies, M. A. et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117, 1687–1696 (2011).

    Article  PubMed  Google Scholar 

  145. Sperduto, P. W. et al. Estimating survival in melanoma patients with brain metastases: an update of the graded prognostic assessment for melanoma using molecular markers (Melanoma-molGPA). Int. J. Radiat. Oncol. Biol. Phys. 99, 812–816 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sloot, S. et al. Improved survival of patients with melanoma brain metastases in the era of targeted BRAF and immune checkpoint therapies. Cancer 124, 297–305 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Iorgulescu, J. B. et al. Improved risk-adjusted survival for melanoma brain metastases in the era of checkpoint blockade immunotherapies: results from a national cohort. Cancer Immunol. Res. 6, 1039–1045 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Schvartsman, G. et al. Incidence, patterns of progression and outcomes of preexisting and newly discovered brain metastases during treatment with anti-PD-1 in patients with metastatic melanoma. Cancer 125, 4193–4202 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Colombino, M. et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J. Clin. Oncol. 30, 2522–2529 (2012).

    Article  PubMed  Google Scholar 

  150. Chapman, P. B. et al. BRIM-3 study group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 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).

    Article  CAS  PubMed  Google Scholar 

  152. 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).

    Article  CAS  PubMed  Google Scholar 

  153. 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).

    Article  CAS  PubMed  Google Scholar 

  154. Mittapalli, R. K., Vaidhyanathan, S., Dudek, A. Z. & Elmquist, W. F. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J. Pharmacol. Exp. Ther. 344, 655–664 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Davies, M. A. et al. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 18, 863–873 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Vaidhyanathan, S., Mittapalli, R. K., Sarkaria, J. N. & Elmquist, W. F. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab. Dispos. 42, 1292–1300 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Drago, J. Z. et al. Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study. Melanoma Res. 29, 65–69 (2019).

    Article  CAS  PubMed  Google Scholar 

  158. Babiker, H. M. et al. E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases. Invest. N. Drugs 37, 636–645 (2019).

    Article  CAS  Google Scholar 

  159. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Gopal, Y. N. et al. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Cancer Res. 74, 7037–7047 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tolcher, A. W. et al. A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors. Ann. Oncol. 26, 58–64 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Haueis, S. A. et al. Does the distribution pattern of brain metastases during BRAF inhibitor therapy reflect phenotype switching? Melanoma Res. 27, 231–237 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  165. 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).

    Article  PubMed  Google Scholar 

  166. Kluger, H. M. et al. Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial. J. Clin. Oncol. 37, 52–60 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Tawbi, H. A. et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N. Engl. J. Med. 379, 722–730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Tawbi, H. A. et al. Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). J. Clin. Oncol. 37 (Suppl. 15), 9501 (2019).

    Article  Google Scholar 

  169. Long, G. V. et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 19, 672–681 (2018).

    Article  CAS  PubMed  Google Scholar 

  170. Long, G. V. et al. Long-term outcomes from the randomized phase II study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets): anti-PD1 brain collaboration (ABC). Ann. Oncol. 30, v533–v563 (2019).

    Article  Google Scholar 

  171. Cooper, Z. A. et al. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol. Res. 2, 643–654 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  176. Yi, M. et al. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol. Cancer 18, 60–64 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Manon, R. et al. Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: an Eastern Cooperative Oncology Group study (E 6397). J. Clin. Oncol. 23, 8870–8876 (2005).

    Article  PubMed  Google Scholar 

  178. Sambade, M. J. et al. Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother. Oncol. 98, 394–399 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Narayana, A. et al. Vemurafenib and radiation therapy in melanoma brain metastases. J. Neurooncol. 113, 411–416 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. Wolf, A. et al. Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. J. Neurooncol. 127, 607–615 (2016).

    Article  CAS  PubMed  Google Scholar 

  181. Xu, Z. et al. BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases. J. Neurosurg. 126, 726–734 (2017).

    Article  CAS  PubMed  Google Scholar 

  182. Kotecha, R. et al. Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome. J. Neurosurg. 29, 50–59 (2018).

    Article  Google Scholar 

  183. Mastorakos, P. et al. BRAF V600 mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases: a multicenter retrospective study. Neurosurgery 84, 868–880 (2019).

    Article  PubMed  Google Scholar 

  184. Lukas, R. V. Commentary: BRAF V600 mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases: a multicenter retrospective study. Neurosurgery 84, 881–882 (2019).

    Article  PubMed  Google Scholar 

  185. Anker, C. J. et al. Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the eastern cooperative oncology group (ECOG). Int. J. Radiat. Oncol. Biol. Phys. 95, 632–646 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Patel, K. R. et al. BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis. Melanoma Res. 26, 387–394 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Ly, D. et al. Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment. J. Neurosurg. 123, 395–401 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. Walle, T. et al. Radiation effects on antitumor immune responses: current perspectives and challenges. Ther. Adv. Med. Oncol. 10, 1758834017742575 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Pfannenstiel, L. W. et al. Combination PD-1 blockade and irradiation of brain metastasis induces an effective abscopal effect in melanoma. Oncoimmunology 8, e1507669 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Knisely, J. P. et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J. Neurosurg. 117, 227–233 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Silk, A. W., Bassetti, M. F., West, B. T., Tsien, C. I. & Lao, C. D. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med. 2, 899–906 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Kiess, A. P. et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int. J. Radiat. Oncol. Biol. Phys. 92, 368–375 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Sumimoto, H. et al. Effective inhibition of cell growth and invasion of melanoma by combined suppression of BRAF (V599E) and Skp2 with lentiviral RNAi. Int. J. Cancer 118, 472–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  195. Colaco, R. J., Martin, P., Kluger, H. M., Yu, J. B. & Chiang, V. L. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J. Neurosurg. 125, 17–23 (2016).

    Article  CAS  PubMed  Google Scholar 

  196. Patel, K. R. et al. Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases. Am. J. Clin. Oncol. 40, 444–450 (2017).

    Article  CAS  PubMed  Google Scholar 

  197. Cohen-Inbar, O., Shih, H. H., Xu, Z., Schlesinger, D. & Sheehan, J. P. The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab. J. Neurosurg. 127, 1007–1014 (2017).

    Article  PubMed  Google Scholar 

  198. Pin, Y. et al. Brain metastasis formation and irradiation by stereotactic radiation therapycombined with immunotherapy: a systematic review. Crit. Rev. Oncol. Hematol. 149, 102923 (2020).

    Article  PubMed  Google Scholar 

  199. Forst, D. A. & Wen, P. Y. Neurological complications of targeted therapies in cancer neurology in clinical practice (eds D. Schiff, I. Arrillaga, P. Y. Wen) 311–334 (Springer, 2018).

  200. Tran, T. T. et al. Complications associated with immunotherapy for brain metastases. Curr. Opin. Neurol. 32, 907–916 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Galldiks, N. et al. Imaging challenges of immunotherapy and targeted therapy in patients with brain metastases: response, progression, and pseudoprogression. Neuro Oncol. 22, 17–30 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  202. Hendriks, L. E. L. et al. Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors. J. Thorac. Oncol. 14, 1244–1254 (2019).

    Article  CAS  PubMed  Google Scholar 

  203. Rahman, R. et al. The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity. J. Neurooncol. 138, 299–306 (2018).

    Article  PubMed  Google Scholar 

  204. Okada, H. et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 16, 534–542 (2015).

    Article  Google Scholar 

  205. Champiat, S. et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat. Rev. Clin. Oncol. 15, 748–762 (2018).

    Article  CAS  PubMed  Google Scholar 

  206. Ferrara, R. et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PDL-1 inhibitors or with single-agent chemotherapy. JAMA Oncol. 4, 1543–1552 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Kanai, O., Fujita, K., Okamura, M., Nakatani, K. & Mio, T. Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases. Ann. Oncol. 27, 1354–1356 (2016).

    Article  CAS  PubMed  Google Scholar 

  208. Chuang, M. T., Liu, Y. S., Tsai, Y. S., Chen, Y. C. & Wang, C. K. Differentiating radiation-induced necrosis from recurrent brain tumor using MR perfusion and spectroscopy: a meta-analysis. PLoS ONE 11, e0141438 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Galldiks, N. et al. PET imaging in patients with brain metastasis-report of the RANO/PET group. Neuro Oncol. 21, 585–595 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Abdulla, D. S. Y. et al. Monitoring treatment response to erlotinib in EGFR-mutated non-small-cell lung cancer brain metastases using serial O-(2-[18F]fluoroethyl)-L-tyrosine PET. Clin. Lung Cancer 20, e148–e151 (2019).

    Article  CAS  PubMed  Google Scholar 

  211. Kebir, S. et al. Dynamic O-(2-[18F]fluoroethyl)-L-tyrosine PET imaging for the detection of checkpoint inhibitor-related pseudoprogression in melanoma brain metastases. Neuro Oncol. 18, 1462–1464 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Lohmann, P. et al. Radiation injury vs. recurrent brain metastasis: combining textural feature radiomics analysis and standard parameters may increase 18F-FET PET accuracy without dynamic scans. Eur. Radiol. 27, 2916–2927 (2017).

    Article  PubMed  Google Scholar 

  213. Lohmann, P. et al. Combined FET PET/MRI radiomics differentiates radiation injury from recurrent brain metastasis. Neuroimage Clin. 20, 537–542 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  215. 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).

    Article  PubMed  Google Scholar 

  216. Vogelbaum, M. A. et al. Phase 0 and window of opportunity clinical trial design in neuro-oncology: a RANO review. Neuro Oncol. https://doi.org/10.1093/neuonc/noaa149 (2020).

  217. Boire, A. et al. Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications. Neuro Oncol. 21, 571–584 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Priego, N. et al. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat. Med. 24, 1024–1035 (2018).

    Article  CAS  PubMed  Google Scholar 

  219. Izraely, S. et al. The metastatic microenvironment: Melanoma-microglia cross-talk promotes the malignant phenotype of melanoma cells. Int. J. Cancer 144, 802–817 (2019).

    Article  CAS  PubMed  Google Scholar 

  220. Zeng, Q. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–531 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Soffietti, R., Pellerino, A. & Rudà, R. Strategies to prevent brain metastasis. Curr. Opin. Oncol. 31, 493–500 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy

    Riccardo Soffietti & Roberta Rudà

  2. Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Center Institute, Cleveland Clinic, Cleveland, Ohio, USA

    Manmeet Ahluwalia

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Nancy Lin

Authors
  1. Riccardo Soffietti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manmeet Ahluwalia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nancy Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberta Rudà
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.S. researched data for the article, made a substantial contribution to the discussion of content, and wrote and reviewed/edited the manuscript before submission. M.A., N.U.L. and R.R. researched data for the article, made a substantial contribution to the discussion of content and wrote the manuscript.

Corresponding author

Correspondence to Riccardo Soffietti.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

ClinicalTrials.gov: https://clinicaltrials.gov

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soffietti, R., Ahluwalia, M., Lin, N. et al. Management of brain metastases according to molecular subtypes. Nat Rev Neurol 16, 557–574 (2020). https://doi.org/10.1038/s41582-020-0391-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-020-0391-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer