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.

Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies

Abstract

Breast cancer is one of the most prevalent malignancies in women worldwide. Early-stage breast cancer is considered a curable disease; however, once distant metastasis occurs, the 5-year overall survival rate of patients becomes significantly reduced. There are four distinct metastatic patterns in breast cancer: bone, lung, liver and brain. Among these, breast cancer brain metastasis (BCBM) is the leading cause of death; it is highly associated with impaired quality of life and poor prognosis due to the limited permeability of the blood–brain barrier and consequent lack of effective treatments. Although the sequence of events in BCBM is universally accepted, the underlying mechanisms have not yet been fully elucidated. In this review, we outline progress surrounding the molecular mechanisms involved in BCBM as well as experimental methods and research models to better understand the process. We further discuss the challenges in the management of brain metastases, as well as providing an overview of current therapies and highlighting innovative research towards developing novel efficacious targeted therapies.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Breast cancer cell metastatic dissemination to brain.
Fig. 2: Survival, migration and adhesion of CTCs in breast cancer brain metastasis.
Fig. 3: Interactions between cancer cells and resident cells.
Fig. 4: Targeted therapy of BCBM treatment.

References

  1. 1.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).

    Article  Google Scholar 

  2. 2.

    Liang, Y., Zhang, H., Song, X. & Yang, Q. Metastatic heterogeneity of breast cancer: molecular mechanism and potential therapeutic targets. Semin. Cancer Biol. 60, 14–27 (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  3. 3.

    Kanchan, R. K., Siddiqui, J. A., Mahapatra, S., Batra, S. K. & Nasser, M. W. microRNAs orchestrate pathophysiology of breast cancer brain metastasis: advances in therapy. Mol. Cancer 19, 29 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. 4.

    Ren, D., Cheng, H., Wang, X., Vishnoi, M., Teh, B. S., Rostomily, R. et al. Emerging treatment strategies for breast cancer brain metastasis: from translational therapeutics to real-world experience. Ther. Adv. Med. Oncol. 12, 1758835920936151 (2020).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Wang, S., Liang, K., Hu, Q., Li, P., Song, J., Yang, Y. et al. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. J. Clin. Invest. 127, 4498–515. (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Custodio-Santos, T., Videira, M. & Brito, M. A. Brain metastasization of breast cancer. Biochim. Biophys. Acta Rev. Cancer 1868, 132–47. (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  7. 7.

    Wilhelm, I., Molnár, J., Fazakas, C., Haskó, J. & Krizbai, I. Role of the blood-brain barrier in the formation of brain metastases. Int. J. Mol. Sci. 14, 1383–1411 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Sonoshita, M., Aoki, M., Fuwa, H., Aoki, K., Hosogi, H., Sakai, Y. et al. Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19, 125–137 (2011).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  9. 9.

    Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).

  10. 10.

    Leblanc, R. & Peyruchaud, O. Metastasis: new functional implications of platelets and megakaryocytes. Blood 128, 24–31 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  11. 11.

    Papadaki, M., Koutsopoulos, A., Tsoulfas, P., Lagoudaki, E., Aggouraki, D., Monastirioti, A. et al. Clinical relevance of immune checkpoints on circulating tumor cells in breast cancer. Cancers. 12, 376 (2020).

    PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Chan I. S., Knutsdottir, H., Ramakrishnan, G., Padmanaban, V., Warrier, M., Ramirez, J. C. et al. Cancer cells educate natural killer cells to a metastasis-promoting cell state. J. Cell Biol. 219, 9 (2020).

    Article  CAS  Google Scholar 

  13. 13.

    Douma, S., Van Laar, T., Zevenhoven, J., Meuwissen, R., Van Garderen, E. & Peeper, D. S. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430, 1034–1039 (2004).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  14. 14.

    Hoshino, A., Costa-Silva, B., Shen, T. L., Rodrigues, G., Hashimoto, A., Tesic Mark, M. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Klotz, R., Thomas, A., Teng, T., Han, S. M., Iriondo, O., Li, L. et al. Circulating tumor cells exhibit metastatic tropism and reveal brain metastasis drivers. Cancer Discov. 10, 86–103 (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  16. 16.

    Chung, B., Esmaeili, A., Gopalakrishna-Pillai, S., Murad, J., Andersen, E., Kumar Reddy, N. et al. Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12. npj Breast Cancer 3, 6 (2017).

  17. 17.

    Kienast, Y., von Baumgarten, L., Fuhrmann, M., Klinkert, W. E., Goldbrunner, R., Herms, J. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  18. 18.

    Kang, S. A., Hasan, N., Mann, A. P., Zheng, W., Zhao, L., Morris, L. et al. Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis. Mol. Ther. 23, 1044–1054 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Geng, Y., Yeh, K., Takatani, T. & king, M. R. Three to tango: MUC1 as a ligand for both E-selectin and ICAM-1 in the breast cancer metastatic cascade. Front. Oncol. 2, 76 (2012).

  20. 20.

    Soto, M. S., Serres, S., Anthony, D. C. & Sibson, N. R. Functional role of endothelial adhesion molecules in the early stages of brain metastasis. Neuro Oncol. 16, 540–551 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  21. 21.

    Daneman, R. & Prat, A. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    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 

  23. 23.

    Winger, R. C., Koblinski, J. E., Kanda, T., Ransohoff, R. M. & Muller, W. A. Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood-brain barrier. J. Immunol. (Baltimore, Md: 1950) 193, 2427–2437 (2014).

    Article  CAS  Google Scholar 

  24. 24.

    Lyle, L., Lockman, P., Adkins, C., Mohammad, A., Sechrest, E., Hua, E. 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).

  25. 25.

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

  26. 26.

    Pedrosa, R., Mustafa, D. A., Soffietti, R. & Kros, J. M. Breast cancer brain metastasis: molecular mechanisms and directions for treatment. Neuro Oncol. 20, 1439–49. (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Yang, Y., Estrada, E. Y., Thompson, J. F., Liu, W. & Rosenberg, G. A. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J. Cereb. Blood Flow Metab. 27, 697–709 (2007).

  28. 28.

    Avraham, H. K., Jiang, S., Fu, Y., Nakshatri, H., Ovadia, H. & Avraham, S. Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain. J. Pathol. 232, 369–381 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  29. 29.

    Rodriguez, P., Jiang, S., Fu, Y. & Avraham, S. The proinflammatory peptide substance P promotes blood-brain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions. Int. J. Cancer 134, 1034–1044 (2014).

  30. 30.

    Sevenich, L., Bowman, R. L., Mason, S. D., Quail, D. F., Rapaport, F., Elie, B. T. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Zhou, W., Fong, M. Y., Min, Y., Somlo, G., Liu, L., Palomares, M. R. et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Lu, Y., Chen, L. & Li, L. Exosomes derived from brain metastatic breast cancer cells destroy the blood-brain barrier by carrying lncRNA GS1-600G8.5. BioMed Research International 2020,1-10 (2020).

  33. 33.

    Lee, B. C., Lee, T. H., Avraham, S. & Avraham, H. K. Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol. Cancer Res. 2, 327–338 (2004).

    PubMed  CAS  PubMed Central  Google Scholar 

  34. 34.

    Bos, P. D., Zhang, X. H., Nadal, C., Shu, W., Gomis, R. R., Nguyen, D. X. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Conrad, C., Gotte, M., Schlomann, U., Roessler, M., Pagenstecher, A., Anderson, P. et al. ADAM8 expression in breast cancer derived brain metastases: functional implications on MMP-9 expression and transendothelial migration in breast cancer cells. Int. J. Cancer 142, 779–791 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  36. 36.

    Mustafa, D., Pedrosa, R., Smid, M., van der Weiden, M., de Weerd, V., Nigg, A. et al. T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression. Acta Neuropathol. 135, 581–599 (2018).

  37. 37.

    Choi, Y., Lee, J., Gao, M., Kim, B., Kang, S., Kim, S. et al. Cancer-associated fibroblast promote transmigration through endothelial brain cells in three-dimensional in vitro models. Int. J. Cancer 135, 2024–2033 (2014).

  38. 38.

    Krizbai, I. A., Gasparics, A., Nagyoszi, P., Fazakas, C., Molnar, J., Wilhelm, I. et al. Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation. PLoS ONE 10, e0119655 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Sosa, M., Avivar-Valderas, A., Bragado, P. & Wen, H. ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clin. Cancer Res. 17, 5850–5857 (2011).

  40. 40.

    Narkhede, A., Crenshaw, J., Crossman, D. & Shevde, L. An in vitro hyaluronic acid hydrogel based platform to model dormancy in brain metastatic breast cancer cells. Acta Biomater. 107, 65–77 (2020).

  41. 41.

    Sosa, M. & Bragado, P. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).

  42. 42.

    Valiente, M., Obenauf, A. C., Jin, X., Chen, Q., Zhang, X. H., Lee, D. J. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Carbonell, W. S., Ansorge, O., Sibson, N. & Muschel, R. The vascular basement membrane as “soil” in brain metastasis. PLoS ONE 4, e5857 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Cordero, A., Kanojia, D., Miska, J., Panek, W. K., Xiao, A., Han, Y. et al. FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis. Oncogene 38, 6445–60. (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Santana-Codina, N., Muixí, L., Foj, R., Sanz-Pamplona, R., Badia-Villanueva, M., Abramowicz, A. et al. GRP94 promotes brain metastasis by engaging pro-survival autophagy. Neuro Oncol. 22, 652–64. (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  46. 46.

    Chen, J., Lee, H. J., Wu, X., Huo, L., Kim, S. J., Xu, L. et al. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain. Cancer Res. 75, 554–565 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  47. 47.

    Blazquez, R., Rietkotter, E., Wenske, B., Wlochowitz, D., Sparrer, D., Vollmer, E. et al. LEF1 supports metastatic brain colonization by regulating glutathione metabolism and increasing ROS resistance in breast cancer. Int. J. Cancer. 146, 3170–3183 (2019).

  48. 48.

    Neman, J., Termini, J., Wilczynski, S., Vaidehi, N., Choy, C., Kowolik, C. M. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Zeng, Q., Michael, I. P., Zhang, P., Saghafinia, S., Knott, G., Jiao, W. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–31. (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R. & Zlokovic, B. V. Blood-brain barrier: from physiology to disease and back. Physiol. Rev. 99, 21–78 (2019).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  51. 51.

    Kaverina, N., Borovjagin, A. V., Kadagidze, Z., Baryshnikov, A., Baryshnikova, M., Malin, D. et al. Astrocytes promote progression of breast cancer metastases to the brain via a KISS1-mediated autophagy. Autophagy 13, 1905–23. (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Chen, Q., Boire, A., Jin, X., Valiente, M., Er, E. E., Lopez-Soto, A. et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Kim, S. W., Choi, H. J., Lee, H. J., He, J., Wu, Q., Langley, R. R. et al. Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells. Neuro Oncol. 16, 1585–1598 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    Kim, S. J., Kim, J. S., Park, E. S., Lee, J. S., Lin, Q., Langley, R. R. et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13, 286–298 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Zhang, L., Zhang, S., Yao, J., Lowery, F. J., Zhang, Q., Huang, W. C. et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Zou, Y., Watters, A., Cheng, N., Perry, C. E., Xu, K., Alicea, G. M. et al. Polyunsaturated fatty acids from astrocytes activate PPARgamma signaling in cancer cells to promote brain metastasis. Cancer Discov. 9, 1720–35. (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Shumakovich, M. A., Mencio, C. P., Siglin, J. S., Moriarty, R. A., Geller, H. M., Stroka, K. M. Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells. FASEB J. 31, 5049–5067 (2017).

  58. 58.

    Sartorius, C. A., Hanna, C. T., Gril, B., Cruz, H., Serkova, N. J., Huber, K. M. 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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  59. 59.

    Dudvarski Stankovic, N., Teodorczyk, M., Ploen, R., Zipp, F. & Schmidt, M. H. H. Microglia-blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol. 131, 347–363 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Louie, E., Chen, X. F., Coomes, A., Ji, K., Tsirka, S. & Chen, E. I. Neurotrophin-3 modulates breast cancer cells and the microenvironment to promote the growth of breast cancer brain metastasis. Oncogene 32, 4064–4077 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  61. 61.

    Pukrop, T., Dehghani, F., Chuang, H. N., Lohaus, R., Bayanga, K., Heermann, S. et al. Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way. Glia 58, 1477–1489 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Xing, F., Liu, Y., Wu, S. Y., Wu, K., Sharma, S., Mo, Y. Y. et al. Loss of XIST in breast cancer activates MSN-c-Met and reprograms microglia via exosomal miRNA to promote brain metastasis. Cancer Res. 78, 4316–30. (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Nagpal, A., Redvers, R. P., Ling, X., Ayton, S., Fuentes, M., Tavancheh, E. et al. Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2(+ve) breast cancer metastasis. Breast Cancer Res. 21, 94 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Contreras-Zarate, M. J., Ormond, D. R., Gillen, A. E., Hanna, C., Day, N. L., Serkova, N. J. et al. Development of novel patient-derived xenografts from breast cancer brain metastases. Front. Oncology 7, 252 (2017).

    Article  Google Scholar 

  65. 65.

    Kim, S. H., Redvers, R. P., Chi, L. H., Ling, X., Lucke, A. J., Reid, R. C., et al. Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis. Dis. Models Mech. 11, DMM034850 (2018).

  66. 66.

    Price, J., Fabra, A., Zhang, R., Radinsky, R. & Pathak, S. Characterization of variants of a human breast-cancer cell-line isolated from metastases in different organs of nude-mice. Int. J. Oncol. 5, 459–467 (1994).

    PubMed  CAS  PubMed Central  Google Scholar 

  67. 67.

    Martinez-Aranda, A., Hernandez, V., Picon, C., Modolell, I. & Sierra, A. Development of a preclinical therapeutic model of human brain metastasis with chemoradiotherapy. Int. J. Mol. Sci. 14, 8306–8327 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Malin, D., Strekalova, E., Petrovic, V., Deal, A., Al Ahmad, A., Adamo, B. et al. αB-crystallin: a novel regulator of breast cancer metastasis to the brain. Clinical cancer research: an official journal of the American Association for. Cancer Res. 20, 56–67 (2014).

    CAS  Google Scholar 

  69. 69.

    Diossy, M., Reiniger, L., Sztupinszki, Z., Krzystanek, M., Timms, K. M., Neff, C. et al. Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors. Ann. Oncol. 29, 1948–54. (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Delaney, L. J., Ciraku, L., Oeffinger, B. E., Wessner, C. E., Liu, J. B., Li, J. et al. Breast cancer brain metastasis response to radiation after microbubble oxygen delivery in a murine model. J. Ultrasound Med. 38, 3221–3228 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Oshi, M., Okano, M., Maiti, A., Rashid, O. M., Saito, K., Kono, K. et al. Novel breast cancer brain metastasis patient-derived orthotopic xenograft model for preclinical studies. Cancers (Basel) 12, 444 (2020).

  73. 73.

    Zhang, X., Claerhout, S., Prat, A., Dobrolecki, L. E., Petrovic, I., Lai, Q. et al. A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res. 73, 4885–4897 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Ryken, T. C., McDermott, M., Robinson, P. D., Ammirati, M., Andrews, D. W., Asher, A. L. et al. The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J. Neuro Oncol. 96, 103–114 (2010).

    Article  CAS  Google Scholar 

  75. 75.

    Jaeckle, K. A., Dixon, J. G., Anderson, S. K., Moreno-Aspitia, A., Colon-Otero, G., Hebenstreit, K. et al. Intra-CSF topotecan in treatment of breast cancer patients with leptomeningeal metastases. Cancer Med. 9, 7935–7942 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Le Rhun, E., Wallet, J., Mailliez, A., Le Deley, M., Rodrigues, I., Boulanger, T. et al. Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer. Neuro Oncol. 22, 524–538. (2020).

  77. 77.

    Sperduto, P. W., Mesko, S., Li, J., Cagney, D., Aizer, A., Lin, N. U. et al. Estrogen, progesterone and HER2 receptor discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival. Neuro Oncol. 22, 1359–1367 (2020).

  78. 78.

    Schrijver, W., Suijkerbuijk, K. P. M., van Gils, C. H., van der Wall, E., Moelans, C. B. & van Diest, P. J. Receptor conversion in distant breast cancer metastases: a systematic review and meta-analysis. J. Natl Cancer Inst. 110, 568–80. (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    De Mattos-Arruda, L., Ng, C. K. Y., Piscuoglio, S., Gonzalez-Cao, M., Lim, R. S., De Filippo, M. R. et al. Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases. Oncotarget 9, 20617–30. (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Brastianos, P., Carter, S., Santagata, S., Cahill, D., Taylor-Weiner, A., Jones, R. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 5, 1164–1177 (2015).

  81. 81.

    Dong, X. Current strategies for brain drug delivery. Theranostics 8, 1481–93. (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Robey, R. W., Pluchino, K. M., Hall, M. D., Fojo, A. T., Bates, S. E. & Gottesman, M. M. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer 18, 452–64. (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    de Lange, E. Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. Adv. Drug Delivery Rev. 56, 1793–1809 (2004).

    Article  CAS  Google Scholar 

  84. 84.

    Ghersi-Egea, J. & Strazielle, N. Brain drug delivery, drug metabolism, and multidrug resistance at the choroid plexus. Microscopy Res. Tech. 52, 83–88 (2001).

    Article  CAS  Google Scholar 

  85. 85.

    Arvanitis, C. D., Ferraro, G. B. & Jain, R. K. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat. Rev. Cancer 20, 26–41 (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  86. 86.

    Park, Y. H., Park, M. J. Ji, S. H., Yi, S. Y. Lim, D. H. Nam, D. H. et al. Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients. Br. J. Cancer. 100, 894–900 (2009).

  87. 87.

    Swain, S. M., Baselga, J., Kim, S. B., Ro, J., Semiglazov, V., Campone, M. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl. J. Med. 372, 724–734 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Dieras, V., Miles, D., Verma, S., Pegram, M., Welslau, M., Baselga, J. et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 18, 732–42. (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Montemurro, F., Delaloge, S., Barrios, C. H., Wuerstlein, R., Anton, A., Brain, E., et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. Ann. Oncol.31, 1350–1358 (2020).

  90. 90.

    Radic-Sarikas, B., Halasz, M., Huber, K. V. M., Winter, G. E., Tsafou, K. P., Papamarkou, T. et al. Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter. Sci. Rep. 7, 3091 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Bachelot, T., Romieu, G., Campone, M., Dieras, V., Cropet, C., Dalenc, F. 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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  92. 92.

    Freedman, R. A., Gelman, R. S., Anders, C. K., Melisko, M. E., Parsons, H. A., Cropp, A. M. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Murthy, R. K., Loi, S, Okines, A, Paplomata, E., Hamilton, E., Hurvitz, S. A. et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N. Engl. J. Med. 382, 597–609 (2020).

  94. 94.

    Ma, F., Li, Q., Chen, S., Zhu, W., Fan, Y., Wang, J. et al. Phase I study and biomarker analysis of pyrotinib, a novel irreversible Pan-ErbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J. Clin. Oncol. 35, 3105–3112 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  95. 95.

    Xuhong, J. C., Qi, X. W., Zhang, Y. & Jiang, J. Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer. Am. J. Cancer Res. 9, 2103–19. (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  96. 96.

    Blair, H. A. Pyrotinib: First global approval. Drugs 78, 1751–1755 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Gril, B., Wei, D., Zimmer, A. S., Robinson, C., Khan, I., Difilippantonio, S. et al. A HER2 antibody drug conjugate controls growth of breast cancer brain metastases in hematogenous xenograft models, with heterogeneous blood-tumor barrier penetration unlinked to a passive marker. Neuro Oncol. 22, 1625–1636 (2020).

  98. 98.

    Cortés, J., Dieras, V., Ro, J., Barriere, J., Bachelot, T., Hurvitz, S. et al. Afatinib alone or afatinib plus vinorelbine versus investigator’s choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. Lancet Oncol. 16, 1700–1710 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  99. 99.

    Han, H. S., Dieras, V., Robson, M., Palacova, M., Marcom, P. K., Jager, A. et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study. Ann. Oncol. 29, 154–161 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  100. 100.

    Loibl, S., O’Shaughnessy, J., Untch, M., Sikov, W. M., Rugo, H. S., McKee, M. D. et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 19, 497–509 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  101. 101.

    Werner, T. L., Sachdev, J., Swisher, E. M., Gutierrez, M., Kittaneh, M., Stein, M. N. et al. Safety and pharmacokinetics of veliparib extended-release in patients with advanced solid tumors: a phase I study. Cancer Med. 7, 2360–2369 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Li, Y., Wei, X., Zhang, S. & Zhang, J. Prognosis of invasive breast cancer after adjuvant therapy evaluated with VEGF microvessel density and microvascular imaging. Tumour Biol. 36, 8755–8760 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  103. 103.

    Hey, S. P., Gyawali, B., D’Andrea, E., Kanagaraj, M., Franklin, J. M. & Kesselheim, A. S. A systematic review and meta-analysis of bevacizumab in first-line metastatic breast cancer: lessons for the research and regulatory enterprises. J. Natl Cancer Inst. 112, 335–342 (2019).

  104. 104.

    Mackey, J. R., Ramos-Vazquez, M., Lipatov, O., McCarthy, N., Krasnozhon, D., Semiglazov, V. et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J. Clin. Oncol. 33, 141–148 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  105. 105.

    Bostrom, J., Yu, S. F., Kan, D., Appleton, B. A., Lee, C. V., Billeci, K. et al. Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science (New York, NY) 323, 1610–1614 (2009).

    Article  CAS  Google Scholar 

  106. 106.

    Hu, S., Fu, W., Xu, W., Yang, Y., Cruz, M., Berezov, S. D. et al. Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk. Cancer Res. 75, 159–170 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  107. 107.

    Ippen, F. M., Alvarez-Breckenridge, C. A., Kuter, B. M., Fink, A. L., Bihun, I. V., Lastrapes, M. et al. The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases. Clin. Cancer Res. 25, 3374–83. (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

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

  109. 109.

    Ippen, F. M., Grosch, J. K., Subramanian, M., Kuter, B. M., Liederer, B. M., Plise, E. G. et al. Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro-oncology 21, 1401–11. (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Pernas, S., Tolaney, S. M., Winer, E. P. & Goel, S. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther. Adv. Med. Oncol. 10, 1758835918786451 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. 111.

    Chong, Q. Y., Kok, Z. H., Bui, N. L., Xiang, X., Li-Ann, Wong A., Peng Yong, W. et al. A unique Cdk4/6 inhibitor: current and future therapeutic strategies of abemaciclib. Pharmacol. Res. 156, 104686 (2020).

  112. 112.

    Patnaik, A., Rosen, L. S., Tolaney, S. M., Tolcher, A. W., Goldman, J. W., Gandhi, L. et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 6, 740–753 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  113. 113.

    Tolaney, S. M., Sahebjam, S., Le Rhun, E., Bachelot, T., Kabos, P., Awada, A. et al. A phase 2 study of abemaciclib in patients with brain metastases secondary to hormone receptor positive breast cancer. Clin. Cancer Res. 26, 5310–5319 (2020).

  114. 114.

    Mills, M., Figura, N., Arrington, J., Yu, H., Etame, A., Vogelbaum, M. et al. Management of brain metastases in breast cancer: a review of current practices and emerging treatments. Breast Cancer Res. Treat. 180, 279–300 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  115. 115.

    Chen, X., Han, J., Chu, J., Zhang, L., Zhang, J., Chen, C. et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 7, 27764–27777 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Priceman, S., Tilakawardane, D., Jeang, B., Aguilar, B., Murad, J., Park, A. et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2 breast cancer metastasis to the brain. Clin. Cancer Res. 24, 95–105 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  117. 117.

    Brastianos, P. K., Lee, E. Q., Cohen, J. V., Tolaney, S. M., Lin, N. U., Wang, N. et al. Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. Nat. Med. 26, 1280–1284 (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  118. 118.

    Zhang, L. & Zhao, D. Applications of nanoparticles for brain cancer imaging and therapy. J. Biomed. Nanotechnol. 10, 1713–1731 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  119. 119.

    He, C., Cai, P., Li, J., Zhang, T., Lin, L., Abbasi, A. Z. et al. Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer. J. Control. Release 246, 98–109 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  120. 120.

    Zhang, S., Deng, G., Liu, F., Peng, B., Bao, Y., Du, F. et al. Autocatalytic delivery of brain tumor-targeting, size-shrinkable nanoparticles for treatment of breast cancer brain metastases. Adv. Funct. Mater. 30, 1910651 (2020).

  121. 121.

    Han, L., Kong, D. K., Zheng, M. Q., Murikinati, S., Ma, C., Yuan, P. et al. Increased nanoparticle delivery to brain tumors by autocatalytic priming for improved treatment and imaging. ACS Nano 10, 4209–4218 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Sierra, A., Price, J. E., Garcia-Ramirez, M., Mendez, O., Lopez, L., Fabra, A. Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab Invest. 77, 357–68 (1997).

  123. 123.

    De Meulenaere, V., Neyt, S., Vandeghinste, B., Mollet, P., De Wever, O., Decrock, E. et al. Species-dependent extracranial manifestations of a brain seeking breast cancer cell line. PLoS One. 13, e0208340 (2018).

Download references

Acknowledgements

We wish to acknowledge the support of all our research group members.

Author information

Affiliations

Authors

Contributions

Y.J.W. and F.Z.Y. are co-first authors who wrote drafts of the manuscript and generated the figures and tables together. Y.R.L. revised and polished the manuscripts. Y.R.L. and Q.F.Y. provided overall supervision and guidance. All authors read and approved the final version of manuscript.

Corresponding author

Correspondence to Qifeng Yang.

Ethics declarations

Ethical approval and consent to participate

Not Applicable.

Consent to publish

Not Applicable.

Data availability

Not Applicable.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by National Key Research and Development Program (No. 2020YFA0712400), Special Foundation for Taishan Scholars (No. ts20190971), National Natural Science Foundation of China (No. 81874119; No. 82072912), Special Support Plan for National High Level Talents (Ten Thousand Talents Program W01020103), National Key Research and Development Program (No. 2018YFC0114705), Foundation from Clinical Research Center of Shandong University (No.2020SDUCRCA015), Qilu Hospital Clinical New Technology Developing Foundation (No. 2018–7; No. 2019–3).

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Ye, F., Liang, Y. et al. Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies. Br J Cancer 125, 1056–1067 (2021). https://doi.org/10.1038/s41416-021-01424-8

Download citation

Search

Quick links