Skip to main content

Advertisement

SpringerLink
Log in

Prognostic factors of HER2-positive breast cancer patients who develop brain metastasis: a multicenter retrospective analysis

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine prognostic factors associated with HER2-positive patients who develop brain metastases. This retrospective study assessed the largest dataset to date of 432 HER2-positive patients who were diagnosed with brain metastases from 24 institutions of the Japan Clinical Oncology Group, Breast Cancer Study Group. The median age of the 432 patients was 54 years (range, 20–86 years). Of the patients, 162 patients (37.5 %) had ER-positive/HER2-positive (ER+HER2+) breast cancer, and 270 (62.5 %) had ER-negative/HER2-positive (ER−HER2+) breast cancer. The median brain metastasis-free survival period from primary breast cancer was 33.5 months in both groups. The median survival after developing brain metastasis was 16.5 and 11.5 months in the ER+HER2+ and ER−HER2+ groups, respectively, (p = 0.117). Patients with >3 brain metastases had significantly shorter overall survival in both ER+HER2+ (p < 0.001) and ER−HER2+ (p = 0.018) groups. Treatment with trastuzumab before developing brain metastases was not associated with survival duration after developing brain metastases (p = 0.571). However, patients treated with both trastuzumab and lapatinib after developing metastasis had significantly longer survival than patients treated with trastuzumab alone, lapatinib alone, or no HER2-targeting agent (p < 0.001). For HER2-positive patients with brain metastases, regardless of the use of trastuzumab before developing brain metastasis, treatment with both trastuzumab and lapatinib might improve survival.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Prat A, Baselga J (2008) The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2. Nat Clin Pract Oncol 5:531–542. doi:10.1038/ncponc1179

    Article  CAS  PubMed  Google Scholar 

  2. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    Article  CAS  PubMed  Google Scholar 

  3. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that over expresses HER2. N Engl J Med 344:783–792. doi:10.1056/NEJM200103153441101

    Article  CAS  PubMed  Google Scholar 

  4. Yin W, Jiang Y, Shen Z, Shao Z, Lu J (2011) Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS One 6:e21030. doi:10.1371/journal.pone.0021030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Niikura N, Hayashi N, Masuda N, Takashima S, Nakamura R, Watanabe K, Kanbayashi C, Ishida M, Hozumi Y, Tsuneizumi M, Kondo N, Naito Y, Honda Y, Matsui A, Fujisawa T, Oshitanai R, Yasojima H, Tokuda Y, Saji S, Iwata H (2014) Treatment outcomes and prognostic factors for patients with brain metastases from breast cancer of each subtype: a multicenter retrospective analysis. Breast Cancer Res Treat 147:103–112. doi:10.1007/s10549-014-3090-8

    Article  PubMed  Google Scholar 

  6. World Health Organization (1983) The World Health Organization. Histological typing of breast tumors. Neoplasma 30:113–123

    Google Scholar 

  7. Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer; a study of 1,409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359–377

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145. doi:10.1200/JCO.2006.09.2775

    Article  CAS  PubMed  Google Scholar 

  9. Hayashi N, Niikura N, Yamauchi H, Nakamura S, Ueno NT (2013) Adding hormonal therapy to chemotherapy and trastuzumab improves prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor 2-positive primary breast cancer. Breast Cancer Res Treat 137:523–531. doi:10.1007/s10549-012-2336-6

    Article  CAS  PubMed  Google Scholar 

  10. Duchnowska R, Biernat W, Szostakiewicz B, Sperinde J, Piette F, Haddad M, Paquet A, Lie Y, Czartoryska-Arlukowicz B, Wysocki P, Jankowski T, Radecka B, Foszczynska-Kloda M, Litwiniuk M, Debska S, Weidler J, Huang W, Buyse M, Bates M, Jassem J (2012) Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy. Oncologist 17:26–35. doi:10.1634/theoncologist.2011-0212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Gabos Z, Sinha R, Hanson J, Chauhan N, Hugh J, Mackey JR, Abdulkarim B (2006) Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol 24:5658–5663. doi:10.1200/JCO.2006.07.0250

    Article  CAS  PubMed  Google Scholar 

  12. Olson EM, Abdel-Rasoul M, Maly J, Wu CS, Lin NU, Shapiro CL (2013) 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. doi:10.1093/annonc/mdt036

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Pestalozzi BC, Holmes E, de Azambuja E, Metzger-Filho O, Hogge L, Scullion M, Lang I, Wardley A, Lichinitser M, Sanchez RI, Muller V, Dodwell D, Gelber RD, Piccart-Gebhart MJ, Cameron D (2013) 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. doi:10.1016/S1470-2045(13)70017-2

    Article  CAS  PubMed  Google Scholar 

  14. Tomasello G, Bedard PL, de Azambuja E, Lossignol D, Devriendt D, Piccart-Gebhart MJ (2010) Brain metastases in HER2-positive breast cancer: the evolving role of lapatinib. Crit Rev Oncol Hematol 75:110–121. doi:10.1016/j.critrevonc.2009.11.003

    Article  PubMed  Google Scholar 

  15. Mehta AI, Brufsky AM, Sampson JH (2013) Therapeutic approaches for HER2-positive brain metastases: circumventing the blood–brain barrier. Cancer Treat Rev 39:261–269. doi:10.1016/j.ctrv.2012.05.006

    Article  CAS  PubMed  Google Scholar 

  16. Musolino A, Ciccolallo L, Panebianco M, Fontana E, Zanoni D, Bozzetti C, Michiara M, Silini EM, Ardizzoni A (2011) Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study. Cancer 117:1837–1846. doi:10.1002/cncr.25771

    Article  PubMed  Google Scholar 

  17. Tamura K, Kurihara H, Yonemori K, Tsuda H, Suzuki J, Kono Y, Honda N, Kodaira M, Yamamoto H, Yunokawa M, Shimizu C, Hasegawa K, Kanayama Y, Nozaki S, Kinoshita T, Wada Y, Tazawa S, Takahashi K, Watanabe Y, Fujiwara Y (2013) 64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer. J Nucl Med 54:1869–1875. doi:10.2967/jnumed.112.118612

    Article  CAS  PubMed  Google Scholar 

  18. Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE (2010) Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist 15:924–934. doi:10.1634/theoncologist.2009-0181

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743. doi:10.1056/NEJMoa064320

    Article  CAS  PubMed  Google Scholar 

  20. DiStefano A, Yap YY, Hortobagyi GN, Blumenschein GR (1979) The natural history of breast cancer patients with brain metastases. Cancer 44:1913–1918

    Article  CAS  PubMed  Google Scholar 

  21. Iwata H, Narabayashi M, Ito Y, Saji S, Fujiwara Y, Usami S, Katsura K, Sasaki Y (2013) A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients. Int J Clin Oncol 18:621–628. doi:10.1007/s10147-012-0444-2

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. Metro G, Foglietta J, Russillo M, Stocchi L, Vidiri A, Giannarelli D, Crino L, Papaldo P, Mottolese M, Cognetti F, Fabi A, Gori S (2011) Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann Oncol 22:625–630. doi:10.1093/annonc/mdq434

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Bachelot T, Romieu G, Campone M, Dieras V, Cropet C, Dalenc F, Jimenez M, Le Rhun E, Pierga JY, Goncalves A, Leheurteur M, Domont J, Gutierrez M, Cure H, Ferrero JM, Labbe-Devilliers C (2013) 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. doi:10.1016/S1470-2045(12)70432-1

    Article  CAS  PubMed  Google Scholar 

  26. Pivot X, Semiglazov V, Żurawski BE (2012) CEREBEL (EGF111438): an open label randomized phase III study comparing the incidence of CNS metastases in patients (pts) with HER2+ metastatic breast cancer (MBC), treated with Lapatinib plus Capecitabine (LC) versus Trastuzumab plus Capecitabine (TC). ESMO 2012 Annual Meeting LBA11

  27. Yap YS, Cornelio GH, Devi BC, Khorprasert C, Kim SB, Kim TY, Lee SC, Park YH, Sohn JH, Sutandyo N, Wong DW, Kobayashi M, Landis SH, Yeoh EM, Moon H, Ro J (2012) Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival. Br J Cancer 107:1075–1082. doi:10.1038/bjc.2012.346

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Swain SM, Baselga J, Miles D, Im YH, Quah C, Lee LF, Cortes J (2014) Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA. Ann Oncol. doi:10.1093/annonc/mdu133

    PubMed Central  PubMed  Google Scholar 

  29. Wildiers H, Kim SB, Gonzalez-Martin A (2013) T-DM1 for HER2-positive metastatic breast cancer (MBC): primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician’s choice. In: European Cancer Congress 2013

  30. Krop IE, Lin NU, Blackwell K, Guardino E, Huober J, Lu M, Miles D, Samant M, Welslau M, Dieras V (2014) 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. doi:10.1093/annonc/mdu486

    PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank the following people for providing us with the data of patients with brain metastases: Yasuyuki Sato, Nagoya Medical Center; Yoshimasa Kosaka, Kitasato University School of Medicine; Tsutomu Iwasa, Kinki University School of Medicine; Hiroyasu Yamashiro, Kure Medical Center/Chugoku Cancer Center; Tadahiko Shien; Okayama University Hospital; Kazuya Miyoshi, NHO Fukuyama Medical Center; Anan Keisei, Kitakyushu Municipal Medical Center, Department of Surgery; Hitoshi Arioka, Yokohama Rosai Hospital; and Maeda Shigeto, National Nagasaki Medical Center. This study was supported by the National Cancer Center Research and Development Fund (23-A-17) and the Health and Labour Sciences Research Expenses for Commision Fund for Applied Research for Innovative Treatment of Cancer (H26-applied-general-046).

Conflict of interest

Naoki Niikura belongs to the Endowed Chair Department of Chugai Co. Ltd. Hiroji Iwata has received a honorarium from Chugai Co. Ltd and GlaxoSmithKline. Other authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Breast Surgical Oncology, St. Luke’s International Hospital, Tokyo, Japan

    Naoki Hayashi & Hideko Yamauchi

  2. Departments of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

    Naoki Niikura & Risa Oshitanai

  3. Department of Target Therapy Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Naoki Niikura & Shigehira Saji

  4. Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Norikazu Masuda & Hiroyuki Yasojima

  5. Department of Breast Oncology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan

    Seiki Takashima

  6. Department of Breast Surgery, Chiba Cancer Center Hospital, Chiba, Japan

    Rikiya Nakamura

  7. Department of Breast Surgery, Hokkaido Cancer Center, Sapporo, Japan

    Ken-ichi Watanabe

  8. Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan

    Chizuko Kanbayashi

  9. Department of Breast Oncology, National Kyushu Cancer Center, Fukuoka, Japan

    Mayumi Ishida

  10. Department of Breast Oncology, Jichi Medical University, Tochigi, Japan

    Yasuo Hozumi

  11. Department of Breast Surgery, Shizuoka General Hospital, Shizuoka, Japan

    Michiko Tsuneizumi

  12. Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan

    Naoto Kondo & Hiroji Iwata

  13. Department of Experimental Therapeutics, National Cancer Center Exploratory Oncology Research and Clinical Trial Center, Tokyo, Japan

    Yoichi Naito

  14. Department of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan

    Yoichi Naito

  15. Division of Breast Surgery, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan

    Yayoi Honda

  16. Department of Surgery National Hospital Organization, Tokyo Medical Center, Tokyo, Japan

    Akira Matsui

  17. Department of Breast Oncology, Gunma Prefectural Cancer Center, Gunma, Japan

    Tomomi Fujisawa

Authors
  1. Naoki Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoki Niikura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norikazu Masuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seiki Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rikiya Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ken-ichi Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chizuko Kanbayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mayumi Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasuo Hozumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michiko Tsuneizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Naoto Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoichi Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yayoi Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Akira Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tomomi Fujisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Risa Oshitanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hiroyuki Yasojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hideko Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Shigehira Saji
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Hiroji Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naoki Niikura.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hayashi, N., Niikura, N., Masuda, N. et al. Prognostic factors of HER2-positive breast cancer patients who develop brain metastasis: a multicenter retrospective analysis. Breast Cancer Res Treat 149, 277–284 (2015). https://doi.org/10.1007/s10549-014-3237-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-3237-7

Keywords

Search

Navigation