Skip to main content

Advertisement

Log in

A multicenter, phase II study of epirubicin/cyclophosphamide followed by docetaxel and concurrent trastuzumab as primary systemic therapy for HER-2 positive advanced breast cancer (the HER2NAT study)

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

The outcome in patients with human epidermal growth factor receptor-2 (HER-2)-positive locally advanced breast cancer may be improved by integrating trastuzumab with primary systemic therapy (PST).

Methods

The efficacy and safety of PST comprising EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2, four cycles every 3 weeks) followed by docetaxel (75 mg/m2, four cycles every 3 weeks) and concurrent trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg, 12 cycles every week) was investigated in a multicenter, prospective, phase II study in patients with HER-2-positive stage IIIB/IIIC/IV breast cancer. The primary endpoint was pathologic complete response (pCR) including the tumor intraductal component confirmed by central pathologic review.

Results

In total, 38 patients were enrolled (stage IIIB, 63.2 %; IIIC, 23.7 %; IV, 13.2 %; estrogen receptor- and/or progesterone receptor-positive, 47.4 %). The pCR rate was 16.2 % in the primary tumor (six of 37 patients in the Full Analysis Set) and 56.8 % (21/37) in the ipsilateral axillary lymph nodes. Treatment was given according to protocol in 28 of 37 patients; six of 28 in the Per-Protocol Set achieved pCR (21.4 %). The clinical response rate was 67.6 % (25/37 patients; complete response, 13.5 %; partial response, 54.1 %). No patients developed congestive heart failure; however, three patients had a non-symptomatic decrease of >10 % of left ventricular ejection fraction.

Conclusions

PST including concurrent use of trastuzumab combined with docetaxel is effective and well-tolerated in HER-2-positive advanced breast cancer patients, including those patients requiring mastectomy for local control.

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.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chia S, Swain SM, Byrd DR et al (2008) Locally advanced and inflammatory breast cancer. J Clin Oncol 26:786–790

    Article  PubMed  Google Scholar 

  2. Kaufmann M, Hortobagyi GN, Goldhirsch A et al (2006) Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol 24:1940–1949

    Article  PubMed  Google Scholar 

  3. Bear HD, Anderson S, Smith RE et al (2006) Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 24:2019–2027

    Article  PubMed  CAS  Google Scholar 

  4. Buzdar AU, Valero V, Ibrahim NK et al (2007) Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 13:228–233

    Article  PubMed  CAS  Google Scholar 

  5. Ross JS, Slodkowska EA, Symmans WF et al (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14:320–368

    Article  PubMed  CAS  Google Scholar 

  6. Penault-Llorca F, Abrial C, Mouret-Reynier MA et al (2007) Achieving higher pathological complete response rates in HER-2-positive patients with induction chemotherapy without trastuzumab in operable breast cancer. Oncologist 12:390–396

    Article  PubMed  CAS  Google Scholar 

  7. Cobleigh MA, Vogel CL, Tripathy D et al (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648

    PubMed  CAS  Google Scholar 

  8. Vogel CL, Cobleigh MA, Tripathy D et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726

    Article  PubMed  CAS  Google Scholar 

  9. Baselga J, Carbonell X, Castañeda-Soto NJ et al (2005) Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 23:2162–2171

    Article  PubMed  CAS  Google Scholar 

  10. Inoue K, Nakagami K, Mizutani M et al (2010) Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group. Breast Cancer Res Treat 119:127–136

    Article  PubMed  CAS  Google Scholar 

  11. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  12. Marty M, Cognetti F, Maraninchi D et al (2005) Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 23:4265–4274

    Article  PubMed  CAS  Google Scholar 

  13. Smith I, Procter M, Gelber RD et al (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36

    Article  PubMed  CAS  Google Scholar 

  14. Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684

    Article  PubMed  CAS  Google Scholar 

  15. Ewer SM, Ewer MS (2008) Cardiotoxicity profile of trastuzumab. Drug Saf 31:459–467

    Article  PubMed  CAS  Google Scholar 

  16. Coudert BP, Arnould L, Moreau L et al (2006) Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: results of a multicenter phase II trial. Ann Oncol 17:409–414

    Article  PubMed  CAS  Google Scholar 

  17. Untch M, Rezai M, Loibl S et al (2010) Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28:2024–2031

    Article  PubMed  CAS  Google Scholar 

  18. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Herceptin Adjuvant (HERA) Trial Study Team et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    Article  PubMed  CAS  Google Scholar 

  19. Kurosumi M, Akashi-Tanaka S, Akiyama F, Committee for Production of Histopathological Criteria for Assessment of Therapeutic Response of Japanese Breast Cancer Society et al (2008) Histopathological criteria for assessment of therapeutic response in breast cancer (2007 version). Breast Cancer 15:5–7

    Article  PubMed  Google Scholar 

  20. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  21. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed Nov 2010

  22. Buzdar AU, Ibrahim NK, Francis D et al (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676–3685

    Article  PubMed  CAS  Google Scholar 

  23. Dixon WJ, Massey FJ (1983) Introduction to statistical analysis, 4th edn. McGraw-Hill, New York

    Google Scholar 

  24. Gianni L, Eiermann W, Semiglazov V et al (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375:377–384

    Article  PubMed  CAS  Google Scholar 

  25. Untch M, Fasching PA, Konecny GE et al (2011) Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 29:3351–3357

    Article  PubMed  CAS  Google Scholar 

  26. von Minckwitz G, Untch M, Nüesch E et al (2011) Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials. Breast Cancer Res Treat 125:145–156

    Article  Google Scholar 

  27. Hortobagyi GN (2002) Can we cure limited metastatic breast cancer? J Clin Oncol 20:620–623

    PubMed  Google Scholar 

  28. Ruiterkamp J, Ernst MF (2011) The role of surgery in metastatic breast cancer. Eur J Cancer 47:S6–22

    Article  PubMed  Google Scholar 

  29. Hennessy BT, Hortobagyi GN, Rouzier R et al (2005) Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 23:9304–9311

    Article  PubMed  Google Scholar 

  30. Chen JH, Feig B, Agrawal G et al (2008) MRI evaluation of pathologically complete response and residual tumors in breast cancer after neoadjuvant chemotherapy. Cancer 112:17–26

    Article  PubMed  Google Scholar 

  31. Perez EA, Suman VJ, Davidson NE et al (2008) Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 26:1231–1238

    Article  PubMed  CAS  Google Scholar 

  32. Ewer MS, Lippman SM (2005) Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 23:2900–2902

    Article  PubMed  CAS  Google Scholar 

  33. Hurley J, Doliny P, Reis I et al (2006) Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J Clin Oncol 24:1831–1838

    Article  PubMed  CAS  Google Scholar 

  34. Sikov WM, Dizon DS, Strenger R et al (2009) Frequent pathologic complete responses in aggressive stages II to III breast cancers with every-4-week carboplatin and weekly paclitaxel with or without trastuzumab: a Brown University Oncology Group Study. J Clin Oncol 27:4693–4700

    Article  PubMed  CAS  Google Scholar 

  35. Guiu S, Liegard M, Favier L et al (2011) Long-term follow-up of HER2-overexpressing stage II or III breast cancer treated by anthracycline-free neoadjuvant chemotherapy. Ann Oncol 22:321–328

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the Translational Research Informatics Center (Director Masanori Fukushima, MD, PhD), Takako Jyono, Yasuyo Kusunoki, and Kotone Matsuyama for their excellent technical support. Trastuzumab to be used preoperatively in combination with chemotherapy was supplied by Chugai Pharmaceutical Co., Ltd. HER2NAT was sponsored by Chugai Pharmaceutical. Chugai Pharmaceutical also funded medical writing support provided by Tim Kelly.

Conflict of interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenjiro Aogi.

About this article

Cite this article

Aogi, K., Saeki, T., Nakamura, S. et al. A multicenter, phase II study of epirubicin/cyclophosphamide followed by docetaxel and concurrent trastuzumab as primary systemic therapy for HER-2 positive advanced breast cancer (the HER2NAT study). Int J Clin Oncol 18, 598–606 (2013). https://doi.org/10.1007/s10147-012-0437-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-012-0437-1

Keywords

Navigation