Advertisement

Journal of Neuro-Oncology

, Volume 106, Issue 2, pp 303–313 | Cite as

Clinical outcome of central nervous system metastases from breast cancer: differences in survival depending on systemic treatment

  • Hee-Jun Kim
  • Seock-Ah Im
  • Bhumsuk Keam
  • Yu-Jung Kim
  • Sae-Won Han
  • Tae Min Kim
  • Do-Youn Oh
  • Jee Hyun Kim
  • Se-Hoon Lee
  • Eui Kyu Chie
  • Wonshik Han
  • Dong-Wan Kim
  • Tae-You Kim
  • Dong-Young Noh
  • Dae Seog Heo
  • In Ae Park
  • Yung-Jue Bang
  • Sung Whan Ha
Clinical Study - Patient Study

Abstract

Central nerve system (CNS) metastases are a feared complication of breast cancer and are associated with poor prognosis. The purpose of this study is to investigate the clinical characteristics of CNS metastases and to clarify the prognostic factors after CNS metastases in breast cancer at a single institution over a long time period. We retrospectively reviewed the medical records of breast cancer patients diagnosed at Seoul National University Hospital from 1981 to 2009 and identified the patients who experienced CNS metastases. We collected the data, including demographics, clinico-pathologic characteristics, dates of diagnosis of original breast cancer and subsequent metastases, and date of death, and correlated the findings with the clinical outcome. A total of 400 patients were identified, of whom 17 (4.3%) were diagnosed with CNS metastases and primary breast cancer concurrently and 383 (95.7%) experienced CNS metastases subsequent to the diagnosis of primary breast cancer. Further, 318 patients (79.5%) had only brain parenchymal metastases, 30 (7.5%) had only leptomeningeal metastases, and 52 (13%) had both. After the diagnosis of CNS metastasis, 170 patients (42.5%) received systemic chemotherapy (CTx) and 143 (35.8%) received CTx after whole brain radiation therapy (WBRT). The patients with good performance status (PS), initial CNS metastasis as recurrence, absence of extracranial metastases, non-visceral extracranial metastases, longer interval from the date of primary breast cancer to the date of CNS metastasis, and CTx after WBRT and gamma-knife surgery (GKS), had better outcomes in univariate analyses. In multivariate analysis, good PS, systemic CTx after WBRT, GKS, and longer interval to CNS metastasis, were independent prognostic factors for overall survival after CNS metastases. Our results suggest that appropriate palliative systemic therapy after WBRT or GKS, and adequate palliative treatment via combined modalities are helpful for breast cancer patients, even after the detection of CNS metastases.

Keywords

CNS metastases Prognostic factor Advanced breast cancer 

Notes

Acknowledgments

This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A040151) and by basic science research program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0022299).

References

  1. 1.
    Chang EL, Lo S (2003) Diagnosis and management of central nervous system metastases from breast cancer. Oncologist 8:398–410PubMedCrossRefGoogle Scholar
  2. 2.
    Lassman AB, DeAngelis LM (2003) Brain metastases. Neurol Clin 21:1–23 viiPubMedCrossRefGoogle Scholar
  3. 3.
    Altundag K, Bondy ML, Mirza NQ, Kau SW, Broglio K, Hortobagyi GN, Rivera E (2007) Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis. Cancer 110:2640–2647. doi: 10.1002/cncr.23088 PubMedCrossRefGoogle Scholar
  4. 4.
    Nussbaum ES, Djalilian HR, Cho KH, Hall WA (1996) Brain metastases, histology, multiplicity, surgery, and survival. Cancer 78:1781–1788. doi: 10.1002/(SICI)1097-0142(19961015)78:8<1781:AID-CNCR19>3.0.CO;2-U PubMedCrossRefGoogle Scholar
  5. 5.
    Kim HJ, Hong S, Kim S, Kim JH, Kim IH, Park CI, Ha SH, Wu HG, Kang WS (2002) Treatment outcome of brain metastasis after the cranial radiotherapy followed by fractionated stereotactic radiotherapy and its prognostic factors. Cancer Res Treat 34(4):284–288Google Scholar
  6. 6.
    Boogerd W, Vos VW, Hart AA, Baris G (1993) Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol 15:165–174PubMedCrossRefGoogle Scholar
  7. 7.
    Harputluoglu H, Dizdar O, Aksoy S, Kilickap S, Dede DS, Ozisik Y, Guler N, Barista I, Gullu I, Hayran M, Selek U, Cengiz M, Zorlu F, Tekuzman G, Altundag K (2008) Characteristics of breast cancer patients with central nervous system metastases: a single-center experience. J Natl Med Assoc 100:521–526PubMedGoogle Scholar
  8. 8.
    Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, Bunnell C, Rue M, Gelman R, Winer E (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972–2977. doi: 10.1002/cncr.11436 PubMedCrossRefGoogle Scholar
  9. 9.
    Kleihues P, Sobin LH (2000) World Health Organization classification of tumors. Cancer 88:2887. doi: 10.1002/1097-0142(20000615)88:12<2887:AID-CNCR32>3.0.CO;2-F PubMedCrossRefGoogle Scholar
  10. 10.
    Tsukada Y, Fouad A, Pickren JW, Lane WW (1983) Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 52:2349–2354PubMedCrossRefGoogle Scholar
  11. 11.
    Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R (1997) Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–751PubMedCrossRefGoogle Scholar
  12. 12.
    Evans AJ, James JJ, Cornford EJ, Chan SY, Burrell HC, Pinder SE, Gutteridge E, Robertson JF, Hornbuckle J, Cheung KL (2004) Brain metastases from breast cancer: identification of a high-risk group. Clin Oncol (R Coll Radiol) 16:345–349CrossRefGoogle Scholar
  13. 13.
    Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, Yoder BJ, Crowe JP, Choueiri TK, Dawson AE, Budd GT, Tubbs RR, Casey G, Weil RJ (2006) Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 30:1097–1104. doi: 10.1097/01.pas.0000213306.05811.b9 PubMedGoogle Scholar
  14. 14.
    Miller KD, Weathers T, Haney LG, Timmerman R, Dickler M, Shen J, Sledge GW Jr (2003) Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol 14:1072–1077PubMedCrossRefGoogle Scholar
  15. 15.
    Tham YL, Sexton K, Kramer R, Hilsenbeck S, Elledge R (2006) Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer 107:696–704. doi: 10.1002/cncr.22041 PubMedCrossRefGoogle Scholar
  16. 16.
    Souglakos J, Vamvakas L, Apostolaki S, Perraki M, Saridaki Z, Kazakou I, Pallis A, Kouroussis C, Androulakis N, Kalbakis K, Millaki G, Mavroudis D, Georgoulias V (2006) Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status. Breast Cancer Res 8:R36. doi: 10.1186/bcr1516 PubMedCrossRefGoogle Scholar
  17. 17.
    Bae SH, Choi DH, Huh SJ, Lim DH, Park W, Nam H, Yang JH, Nam SJ, Lee JE, Im YH, Ahn JS, Park YH (2011) Incidence of brain metastasis and related subtypes in patients with breast cancer receiving adjuvant radiation therapy after surgery. J Breast Cancer 14(S):S57–S63Google Scholar
  18. 18.
    Soffietti R, Ruda R, Trevisan E (2008) Brain metastases: current management and new developments. Curr Opin Oncol 20:676–684. doi: 10.1097/CCO.0b013e32831186fe PubMedCrossRefGoogle Scholar
  19. 19.
    Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roche H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum JL, Rubin SD, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer EP (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459. doi: 10.1158/1078-0432.CCR-08-1080 PubMedCrossRefGoogle Scholar
  20. 20.
    Sutherland S, Ashley S, Miles D, Chan S, Wardley A, Davidson N, Bhatti R, Shehata M, Nouras H, Camburn T, Johnston SR (2010) 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. doi: 10.1038/sj.bjc.6605586 PubMedCrossRefGoogle Scholar
  21. 21.
    Han HS, Kim JS, Park JH, Jeon YK, Lee KW, Oh DY, Kim JH, Park SY, Im SA, Kim TY, Park IA, Bang YJ (2009) Weekly paclitaxel and trastuzumab as a first-line therapy in patients with HER2-overexpressing metastatic breast cancer: magnitude of HER2/neu amplification as a predictive factor for efficacy. J Korean Med Sci 24:910–917. doi: 10.3346/jkms.2009.24.5.910 PubMedCrossRefGoogle Scholar
  22. 22.
    Keam B, Im SA, Kim HJ, Oh DY, Kim JH, Lee SH, Chie EK, Han W, Kim DW, Cho N, Moon WK, Kim TY, Park IA, Noh DY, Heo DS, Ha SW, Bang YJ (2009) Clinical significance of axillary nodal ratio in stage II/III breast cancer treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 116:153–160. doi: 10.1007/s10549-008-0160-9 PubMedCrossRefGoogle Scholar
  23. 23.
    Lebeau A, Deimling D, Kaltz C, Sendelhofert A, Iff A, Luthardt B, Untch M, Lohrs U (2001) Her-2/neu analysis in archival tissue samples of human breast cancer: comparison of immunohistochemistry and fluorescence in situ hybridization. J Clin Oncol 19:354–363PubMedGoogle Scholar
  24. 24.
    Tsao MN, Lloyd N, Wong R, Chow E, Rakovitch E, Laperriere N (2006) Whole brain radiotherapy for the treatment of multiple brain metastases. Cochrane Database Syst Rev 3: CD003869 doi: 10.1002/14651858.CD003869.pub2
  25. 25.
    Rades D, Lohynska R, Veninga T, Stalpers LJ, Schild SE (2007) Evaluation of 2 whole-brain radiotherapy schedules and prognostic factors for brain metastases in breast cancer patients. Cancer 110:2587–2592. doi: 10.1002/cncr.23082 PubMedCrossRefGoogle Scholar
  26. 26.
    Bleyer WA (1977) Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev 4:87–101PubMedCrossRefGoogle Scholar
  27. 27.
    D’Agostino RB Jr (1998) Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 17:2265–2281. doi: 10.1002/(SICI)1097-0258(19981015)17:19<2265:AID-SIM918>3.0.CO;2-B PubMedCrossRefGoogle Scholar
  28. 28.
    Lunceford JK, Davidian M (2004) Stratification and weighting via the propensity score in estimation of causal treatment effects: a comparative study. Stat Med 23:2937–2960. doi: 10.1002/sim.1903 PubMedCrossRefGoogle Scholar
  29. 29.
    Boogerd W, Dalesio O, Bais EM, van der Sande JJ (1992) Response of brain metastases from breast cancer to systemic chemotherapy. Cancer 69:972–980PubMedCrossRefGoogle Scholar
  30. 30.
    Niwinska A, Murawska M, Pogoda K (2010) Breast cancer subtypes and response to systemic treatment after whole-brain radiotherapy in patients with brain metastases. Cancer doi: 10.1002/cncr.25391
  31. 31.
    Bartsch R, Rottenfusser A, Wenzel C, Dieckmann K, Pluschnig U, Altorjai G, Rudas M, Mader RM, Poetter R, Zielinski CC, Steger GG (2007) Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer. J Neurooncol 85:311–317. doi: 10.1007/s11060-007-9420-5 PubMedCrossRefGoogle Scholar
  32. 32.
    Rosner D, Nemoto T, Lane WW (1986) Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer 58:832–839PubMedCrossRefGoogle Scholar
  33. 33.
    DiStefano A, Yong Yap Y, Hortobagyi GN, Blumenschein GR (1979) The natural history of breast cancer patients with brain metastases. Cancer 44:1913–1918PubMedCrossRefGoogle Scholar
  34. 34.
    Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr (2004) Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363:1665–1672. doi: 10.1016/S0140-6736(04)16250-8 PubMedCrossRefGoogle Scholar
  35. 35.
    Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G (2006) Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:2483–2491. doi: 10.1001/jama.295.21.2483 PubMedCrossRefGoogle Scholar
  36. 36.
    Sneed PK, Suh JH, Goetsch SJ, Sanghavi SN, Chappell R, Buatti JM, Regine WF, Weltman E, King VJ, Breneman JC, Sperduto PW, Mehta MP (2002) A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:519–526PubMedCrossRefGoogle Scholar
  37. 37.
    Stewart DJ, Mikhael NZ, Nair RC, Kacew S, Montpetit V, Nanji A, Maroun JA, Howard K (1988) Platinum concentrations in human autopsy tumor samples. Am J Clin Oncol 11:152–158PubMedCrossRefGoogle Scholar
  38. 38.
    van Vulpen M, Kal HB, Taphoorn MJ, El-Sharouni SY (2002) Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review). Oncol Rep 9:683–688PubMedGoogle Scholar
  39. 39.
    Hikino H, Yamada T, Johbara K, Obayashi N, Ozaki N (2006) Potential role of chemo-radiation with oral capecitabine in a breast cancer patient with central nervous system relapse. Breast 15:97–99. doi: 10.1016/j.breast.2005.03.006 PubMedCrossRefGoogle Scholar
  40. 40.
    Rogers LR, Remer SE, Tejwani S (2004) Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy. Neuro Oncol 6:63–64. doi: 10.1215/S1152851703000334 PubMedCrossRefGoogle Scholar
  41. 41.
    Mata JF, Garcia-Manteiga JM, Lostao MP, Fernandez-Veledo S, Guillen-Gomez E, Larrayoz IM, Lloberas J, Casado FJ, Pastor-Anglada M (2001) Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol Pharmacol 59:1542–1548PubMedGoogle Scholar
  42. 42.
    Lower EE, Drosick DR, Blau R, Brennan L, Danneman W, Hawley DK (2003) Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival. Clin Breast Cancer 4:114–119PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Hee-Jun Kim
    • 1
  • Seock-Ah Im
    • 1
    • 2
  • Bhumsuk Keam
    • 1
  • Yu-Jung Kim
    • 6
  • Sae-Won Han
    • 1
    • 2
  • Tae Min Kim
    • 1
    • 2
  • Do-Youn Oh
    • 1
    • 2
  • Jee Hyun Kim
    • 1
    • 2
    • 6
  • Se-Hoon Lee
    • 1
    • 2
  • Eui Kyu Chie
    • 3
  • Wonshik Han
    • 4
  • Dong-Wan Kim
    • 1
    • 2
  • Tae-You Kim
    • 1
    • 2
  • Dong-Young Noh
    • 4
  • Dae Seog Heo
    • 1
    • 2
  • In Ae Park
    • 5
  • Yung-Jue Bang
    • 1
    • 2
  • Sung Whan Ha
    • 3
  1. 1.Department of Internal MedicineSeoul National University College of MedicineSeoulKorea
  2. 2.Cancer Research InstituteSeoul National University College of MedicineSeoulKorea
  3. 3.Department of Radiation OncologySeoul National University College of MedicineSeoulKorea
  4. 4.Department of SurgerySeoul National University College of MedicineSeoulKorea
  5. 5.Department of PathologySeoul National University College of MedicineSeoulKorea
  6. 6.Department of Internal MedicineSeoul National University Bundang HospitalSeongnamKorea

Personalised recommendations