Skip to main content

Advertisement

Log in

Systemic Therapy in the Setting of Central Nervous System (CNS) Metastases in Breast Cancer

  • Systemic Therapies (M Liu and T Haddad, Section Editors)
  • Published:
Current Breast Cancer Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Over 25% of patients with metastatic breast cancer will develop brain metastases. Recent advances in systemic therapy, especially molecularly targeted agents, have improved control of extracranial disease, but have had limited effect on intracranial disease. In this review, we discuss the barriers and challenges associated with employing systemic therapy to treat brain metastases. We also provide an overview of current systemic therapy used as standard of care in all subtypes of breast cancer that have metastasized to the brain, as well as describe novel agents that are currently under study in preclinical models or clinical trials.

Recent Findings

While there are few systemic therapies that are standard of care for the treatment of breast cancer brain metastases, there are many novel agents currently in development or under active investigation. Detailed genomic analysis has led to a better understanding of the molecular aberrations that drive metastasis in the different subtypes of breast cancer, leading to rational approaches to the development of targeted molecular therapy.

Summary

The most promising systemic therapeutic modalities for treating breast cancer brain metastases utilize targeted molecular agents or molecular exploitation of the blood-brain barrier in combination with cytotoxic chemotherapy to enhance entry into the CNS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Brufsky AM, Mayer M, Rugo HS, Kaufman PA, Tan-Chiu E, Tripathy D, et al. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res. 2011;17(14):4834–43.

    Article  CAS  PubMed  Google Scholar 

  2. Lin NU, Vanderplas A, Hughes ME, Theriault RL, Edge SB, Wong Y-N, et al. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer. 2012;118(22):5463–72.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer. Cancer. 2008;113(10):2638–45.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Anders CK. Management of brain metastases in breast cancer. Clin Adv Hematol Oncol. 2016;14(9):686–8.

    PubMed  Google Scholar 

  5. Rostami R, Mittal S, Rostami P, Tavassoli F, Jabbari B. Brain metastasis in breast cancer: a comprehensive literature review. J Neuro-Oncol. 2016. p. 407–14.

  6. Rostami R, Mittal S, Rostami P, Tavassoli F, Jabbari B. Brain metastasis in breast cancer: a comprehensive literature review. J Neuro-Oncol. 2016;127(3):407–14.

    Article  CAS  Google Scholar 

  7. Martin AM, Cagney DN, Catalano PJ, Warren LE, Bellon JR, Punglia RS, et al. Brain metastases in newly diagnosed breast cancer: a population-based study. JAMA Oncol. 2017.

  8. Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271–7.

    Article  PubMed  Google Scholar 

  9. Pestalozzi BC. Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol. 2006;17(6):935–44.

    Article  CAS  PubMed  Google Scholar 

  10. Ramakrishna N, Temin S, Chandarlapaty S, Crews JR, Davidson NE, Esteva FJ, et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(19):2100–8.

    Article  PubMed  Google Scholar 

  11. Olson EM, Abdel-Rasoul M, Maly J, Wu CS, Lin NU, Shapiro CL. 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. 2013;24(6):1526–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pestalozzi BC, Holmes E, de Azambuja E, Metzger-Filho O, Hogge L, Scullion M, 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. Elsevier Ltd. 2013;14(3):244–8.

    Article  CAS  Google Scholar 

  13. Park Y, Park M, Ji S, Yi S, Lim D, Nam D, 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. 2009;100:894–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Morikawa A, Peereboom DM, Thorsheim HR, Samala R, Balyan R, Murphy CG, et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro-Oncology. 2015;17(2):289–95.

    Article  CAS  PubMed  Google Scholar 

  15. Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010;16(23):5664–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25(16):2306–12.

    Article  PubMed  Google Scholar 

  17. Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND, et al. Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab. 2013;33(1):13–21.

    Article  CAS  PubMed  Google Scholar 

  18. Bos PD, Zhang XH-F, Nadal C, Shu W, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459(7249):1005–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-weiner A, Jones RT, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 2015;5(11):1164–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fidler IJ. The biology of brain metastasis: challenges for therapy. Cancer J. 2015;21(4):284–93.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang W-C, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527(7576):100–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik CM, et al. Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc Natl Acad Sci U S A. 2014;111(3):984–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res. 2013;19(23):6404–18.

    Article  CAS  PubMed  Google Scholar 

  24. Tsimberidou AM, Letourneau K, Wen S, Wheler J, Hong D, Naing A, et al. Phase I clinical trial outcomes in 93 patients with brain metastases: the MD Anderson Cancer Center experience. Clin Cancer Res. 2011;17(12):4110–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015;16(6):e270–8.

    Article  PubMed  Google Scholar 

  26. Qian JM, Mahajan A, Yu JB, Tsiouris AJ, Goldberg SB, Kluger HM, et al. Comparing available criteria for measuring brain metastasis response to immunotherapy. J Neurooncol. 2017.

  27. Muldoon LL, Soussain C, Jahnke K, Johanson C, Siegal T, Smith QR, et al. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol. 2007;25(16):2295–305.

    Article  CAS  PubMed  Google Scholar 

  28. Ekenel M, Hormigo AM, Peak S, DeAngelis LM, Abrey LE. Capecitabine therapy of central nervous system metastases from breast cancer. J Neuro-Oncol. 2007;85(2):223–7.

    Article  CAS  Google Scholar 

  29. Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, 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. 1999;85(7):1599–605.

    Article  CAS  PubMed  Google Scholar 

  30. Koukourakis MI, Koukouraki S, Fezoulidis I, Kelekis N, Kyrias G, Archimandritis S, et al. High intratumoural accumulation of stealth® liposomal doxorubicin (Caelyx®) in glioblastomas and in metastatic brain tumours. Br J Cancer. 2000;83(10):1281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kemper EM, van Zandbergen AE, Cleypool C, Mos HA, Boogerd W, Beijnen JH, et al. Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein. Clin Cancer Res. 2003;9(7):2849–55.

    CAS  PubMed  Google Scholar 

  32. Sarantopoulos J, Gabrail N, Moulder S, Brenner A, Smith C, Bouchard D et al. NG1005: results of a phase I study in patients with advanced solid tumors and brain metastases. J Clin Oncol. 2010;28:Abstract nbr 2556.

  33. Lin N, Schwartzberg L, Kesari S, Yardley D, Verma S, Anders C. A phase 2, multi-center, open label study evaluating the efficacy and safety of GRN1005 alone or in combination with trastuzumab in patients with brain metastases from breast cancer. Cancer Res. 2012;72:Abstract nr P3–12-04. 52.

  34. Thomas FC, Taskar K, Rudraraju V, Goda S, Helen R, Gaasch JA, et al. Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res. 2009;26(11):2486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kumthekar P, Tang S-C, Brenner AJ, Kesari S, Piccioni DE, Anders CK, 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. 2016;34:suppl; abstr 2004.

  36. Hoch U, Staschen C-M, Johnson RK, Eldon MA. Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models. Cancer Chemother Pharmacol. 2014;74(6):1125–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Adkins CE, Nounou MI, Hye T, Mohammad AS, Terrell-Hall T, Mohan NK, et al. NKTR-102 efficacy versus irinotecan in a mouse model of brain metastases of breast cancer. BMC Cancer. 2015;15(1):685.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Perez EA, Awada A, O’Shaughnessy J, Rugo HS, Twelves C, Im S-A, et al. Etirinotecan pegol (NKTR-102) versus treatment of physician’s choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015;16(15):1556–68.

    Article  CAS  PubMed  Google Scholar 

  39. Cortés J, Rugo HS, Awada A, Twelves C, Perez EA, Im S-A, 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. 2017;165(2):329–41.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sachdev JC, Ramanathan RK, Raghunand N, Kim J, Klinz SG, Bayever E, et al. Characterization of metastatic breast cancer lesions with ferumoxytol MRI and treatment response to MM-398, nanoliposomal irinotecan (nal-IRI). Cancer Res. 2015;75(9 Supplement):P5-1-6-P5-01–6.

    Google Scholar 

  41. Lien EA, Wester K, Lønning PE, Solheim E, Ueland PM. Distribution of tamoxifen and metabolites into brain tissue and brain metastases in breast cancer patients. Br J Cancer. 1991;63(4):641–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ito K, Ito T, Okada T, Watanabe T, Gomi K, Kanai T, et al. A case of brain metastases from breast cancer that responded to anastrozole monotherapy. Breast J. 2009;15(4):435–7.

    Article  PubMed  Google Scholar 

  43. Goyal S, Puri T, Julka PK, Rath GK. Excellent response to letrozole in brain metastases from breast cancer. Acta Neurochir. 2008;150(6):613-4-5.

    Article  Google Scholar 

  44. Venur VA, Leone JP. Targeted therapies for brain metastases from breast cancer. Int J Mol Sci. 2016;17(9).

  45. Sahebjam S, Le Rhun E, Kulanthaivel P, Turner P, Klise S, Wang H, et al. Assessment of concentrations of abemaciclib and its major active metabolites in plasma, CSF, and brain tumor tissue in patients with brain metastases secondary to hormone receptor positive (HR+) breast cancer. Proceedings of the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting. 2016.

  46. Parrish KE, Pokorny J, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF. Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model. J Pharmacol Exp Ther. 2015;355(2):264–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Michaud K, Solomon DA, Oermann E, Kim J-S, Zhong W-Z, Prados MD, et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 2010;70(8):3228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tolaney S, Lin N, Thornton D, Klise S, Costigan T, Turner P, et al. Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer. J Clin Oncol. 2017;35(15_suppl):1019-1019.

    Google Scholar 

  49. Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, 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. 2008;26(12):1993–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler H-J, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15(4):1452–9.

    Article  CAS  PubMed  Google Scholar 

  51. Bachelot T, Romieu G, Campone M, Diéras 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 Elsevier Ltd. 2013;14(1):64–71.

    Article  CAS  Google Scholar 

  52. Bartsch R, Berghoff AS, Vogl U, Rudas M, Bergen E, Dubsky P, et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis. 2015;32(7):729–37.

    Article  CAS  PubMed  Google Scholar 

  53. Keith KC, Lee Y, Ewend MG, Zagar TM, Anders CK. Activity of trastuzumab-emtansine (TDM1) in HER2-positive breast cancer brain metastases: a case series. Cancer Treat Commun. 2016;7:43–6.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Jacot W, Pons E, Frenel J-S, Guiu S, Levy C, Heudel PE, et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res Treat. 2016;157(2):307–18.

    Article  CAS  PubMed  Google Scholar 

  55. Krop IE, Lin NU, Blackwell K, Guardino E, Huober J, Lu M, et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol. 2015;26(1):113–9.

    Article  CAS  PubMed  Google Scholar 

  56. Freedman R, Gelman R, Melisko M, Anders C, Moy B, Blackwell K, et al. TBCRC 022: phase II trial of neratinib + capecitabine for patients with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J Clin Oncol. 2017;35(15_suppl):1005-1005.

    Google Scholar 

  57. Awada A, Colomer R, Inoue K, Bondarenko I, Badwe RA, Demetriou G, et al. Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer. JAMA Oncol. 2016;2(12):1557.

    Article  PubMed  Google Scholar 

  58. 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 tr. Lancet Oncol. 2015;16(16):1700–10.

    Article  PubMed  Google Scholar 

  59. Dinkel V. ARRY-380, a potent, small-molecule inhibitor of ErbB2, increases survival in intracranial ErbB2 xenograft models in mice. Presented at the American Association of Cancer Research 103rd Annual Meeting. 2012. p. Cancer Res 72 (abstr 852).

  60. Murthy R, Hamilton E, Borges V, Moulder S, Aucoin N, Welch S, et al. ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets). Cancer Res. 2016;76(4 Supplement):P4-14-19-P4-14–9.

    Article  Google Scholar 

  61. Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S, et al. HERMIONE: a randomized phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer. 2016;16:352.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Karginova O, Siegel MB, Van Swearingen AED, Deal AM, Adamo B, Sambade MJ, 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. 2015;14(4):920–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rodler ET, Kurland BF, Griffin M, Gralow JR, Porter P, Yeh RF, et al. Phase I study of Veliparib (ABT-888) combined with cisplatin and vinorelbine in advanced triple-negative breast cancer and/or BRCA mutation-associated breast cancer. Clin Cancer Res. 2016;22(12):2855–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Somlo G, Frankel P, Arun B, Ma CX, Garcia A, Cigler T, et al. Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer. Clin Cancer Res. 2017.

  65. Mehta MP, Wang D, Wang F, Kleinberg L, Brade A, Robins HI, et al. Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neuro-Oncol. 2015 Apr;122(2):409–17.

    Article  CAS  Google Scholar 

  66. Liu X, Shi Y, Maag DX, Palma JP, Patterson MJ, Ellis PA, et al. Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res. 2012;18(2):510–23.

    Article  CAS  PubMed  Google Scholar 

  67. Anders C, Deal AM, Abramson V, Liu MC, Storniolo AM, Carpenter JT, 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. 2014;146(3):557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. O’Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, et al. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014;32(34):3840–7.

    Article  PubMed  Google Scholar 

  69. Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Adamo B, Deal AM, Burrows E, Geradts J, Hamilton E, Blackwell KL, et al. Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases. Breast Cancer Res. 2011;13(6):R125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yardley DA, Noguchi S, Pritchard KI, Burris HA, Baselga J, Gnant M, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.

    Article  CAS  PubMed  Google Scholar 

  74. Anders C, Deal A, Van Swearingen A, Siegel M, Hayes D, Jo H, et al. LCCC 1025: phase II study of everolimus, trastuzumab, and vinorelbine for HER2+ breast cancer brain metastases. J Clin Oncol. 2017;35(15_suppl):1011-1011.

    Google Scholar 

  75. Nanni P, Nicoletti G, Palladini A, Croci S, Murgo A, Ianzano ML, et al. Multiorgan metastasis of human HER-2+ breast cancer in Rag2−/−;Il2rg−/− mice and treatment with PI3K inhibitor. PLoS One. 2012;7(6):e39626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30(3):282–90.

    Article  CAS  PubMed  Google Scholar 

  77. Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, 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. 2016;22(7):723–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kodack DP, Askoxylakis V, Ferraro GB, Sheng Q, Badeaux M, Goel S, et al. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation. Sci Transl Med. 2017;9(391):eaal4682.

    Article  PubMed  Google Scholar 

  79. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol Off J Eur Soc Med Oncol. 2014;25(8):1544–50.

    Article  CAS  Google Scholar 

  80. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32(27):2959–66.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Mao Y, Qu Q, Zhang Y, Liu J, Chen X, Shen K. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS One. 2014;9(12):e115103.

    Article  PubMed  PubMed Central  Google Scholar 

  82. García-Teijido P, Cabal ML, Fernández IP, Pérez YF. Tumor-infiltrating lymphocytes in triple negative breast cancer: the future of immune targeting. Clin Med Insights Oncol. 2016;10(Suppl 1):31–9.

    PubMed  PubMed Central  Google Scholar 

  83. Prince G, Deal A, McKee M, Trembath D, Keith K, Ramirez J, et al. Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases. J Clin Oncol. 2017;5(15_suppl):2072-2072.

    Google Scholar 

  84. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    Article  CAS  PubMed  Google Scholar 

  85. Duchnowska R, Pęksa R, Radecka B, Mandat T, Trojanowski T, Jarosz B, et al. Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. Breast Cancer Res. 2016;18(1):43.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Costa R, Carneiro BA, Wainwright DA, Santa-Maria CA, Kumthekar P, Chae YK, et al. Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives. Ann Oncol. 2016;27(1):44–56.

    Google Scholar 

  87. Narloch J, Luedke C, Broadwater G, Priedigkeit N, Hall A, Hyslop T, et al. Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries. J Clin Oncol. 2017;35(15_suppl):2049-2049.

    Google Scholar 

  88. Nanda R, Chow LQM, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460–7.

    Article  CAS  PubMed  Google Scholar 

  89. Costa R, Gill N, Rademaker AW, Carneiro BA, Chae YK, Kumthekar P, et al. Systematic analysis of early phase clinical studies for patients with breast cancer: inclusion of patients with brain metastasis. Cancer Treat Rev. 2017;55:10–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carey K. Anders.

Ethics declarations

Conflict of Interest

Carey K. Anders has received grants from Novartis, Sanofi, toBBB, GERON, Angiochem, Merrimack, PUMA, Lily, Merck, Oncothyreon, Cascadian, Nektar, and Tesaro.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Systemic Therapies

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chao, Y.L., Anders, C.K. Systemic Therapy in the Setting of Central Nervous System (CNS) Metastases in Breast Cancer. Curr Breast Cancer Rep 9, 217–226 (2017). https://doi.org/10.1007/s12609-017-0253-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12609-017-0253-8

Keywords

Navigation