Skip to main content

Advertisement

SpringerLink
Log in

A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients

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

Abstract

To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m2)–cyclophosphamide (750 mg/m2) for four cycles followed by docetaxel (100 mg/m2) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5–8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier’s classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming’s design used in this trial.

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

Similar content being viewed by others

References

  1. Jones RL, Smith IE (2006) Neoadjuvant treatment for early-stage breast cancer: opportunities to assess tumour response. Lancet Oncol 7:869–874

    Article  CAS  PubMed  Google Scholar 

  2. Untch M, von Minckwitz G (2009) Recent advances in systemic therapy. Advances in neoadjuvant (primary) systemic therapy with cytotoxic agents. Breast Cancer Res 11:203

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kaufmann M, von Minckwitz G, Bear HD, Buzdar A, McGale P, Bonnefoi H, Colleoni M, Denkert C, Eiermann W, Jackesz R, Makris A, Miller W, Pierga JY, Semiglazov V, Schneeweiss A, Souchon R, Stearns V, Untch M, Loibl S (2007) Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Oncol 18:1927–1934

    Article  CAS  PubMed  Google Scholar 

  4. Gralow JR, Burstein HJ, Wood W, Hortobagyi GN, Gianni L, von Minckwitz G, Buzdar AU, Smith IE, Symmans WF, Singh B, Winer EP (2008) Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 26:814–819

    Article  PubMed  Google Scholar 

  5. Mauri D, Pavlidis N, Ioannidis JP (2005) Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97:188–194

    Article  PubMed  Google Scholar 

  6. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N (2008) Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26:778–785

    Article  PubMed  Google Scholar 

  7. Cleator SJ, Makris A, Ashley SE, Lal R, Powles TJ (2005) Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival. Ann Oncol 16:267–272

    Article  CAS  PubMed  Google Scholar 

  8. Pierga JY, Mouret E, Dieras V, Laurence V, Beuzeboc P, Dorval T, Palangie T, Jouve M, Vincent-Salomon A, Scholl S, Extra JM, Asselain B, Pouillart P (2000) Prognostic value of persistent node involvement after neoadjuvant chemotherapy in patients with operable breast cancer. Br J Cancer 83:1480–1487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422

    Article  PubMed  Google Scholar 

  10. Guarneri V, Frassoldati A, Giovannelli S, Borghi F, Conte P (2007) Primary systemic therapy for operable breast cancer: a review of clinical trials and perspectives. Cancer Lett 248:175–185

    Article  CAS  PubMed  Google Scholar 

  11. Hennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, Kau SW, Fornage B, Sahin A, Broglio K, Singletary SE, Valero V (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 

  12. Wang D, Dubois RN (2004) Cyclooxygenase-2: a potential target in breast cancer. Semin Oncol 31:64–73

    Article  CAS  PubMed  Google Scholar 

  13. Wang D, DuBois RN (2004) Cyclooxygenase 2-derived prostaglandin E2 regulates the angiogenic switch. Proc Natl Acad Sci USA 101:415–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dang CT, Shapiro CL, Hudis CA (2002) Potential role of selective COX-2 inhibitors in cancer management. Oncology (Williston Park) 16:30–36

    Google Scholar 

  15. Xu XC (2002) COX-2 inhibitors in cancer treatment and prevention, a recent development. Anticancer Drugs 13:127–137

    Article  CAS  PubMed  Google Scholar 

  16. Lucci A, Krishnamurthy S, Singh B, Bedrosian I, Meric-Bernstam F, Reuben J, Broglio K, Mosalpuria K, Lodhi A, Vincent L, Cristofanilli M (2009) Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow. Breast Cancer Res Treat 117:61–68

    Article  CAS  PubMed  Google Scholar 

  17. Kucab JE, Lee C, Chen CS, Zhu J, Gilks CB, Cheang M, Huntsman D, Yorida E, Emerman J, Pollak M, Dunn SE (2005) Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours. Breast Cancer Res 7:R796–R807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Anton A, Lluch A, Kennedy J, O’Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM (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  CAS  PubMed  Google Scholar 

  19. Mariani G, Fasolo A, De Benedictis E, Gianni L (2009) Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nat Clin Pract Oncol 6:93–104

    Article  CAS  PubMed  Google Scholar 

  20. Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H (2008) Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. Cancer Treat Rev 34:539–557

    Article  CAS  PubMed  Google Scholar 

  21. Burstein HJ, Harris LN, Gelman R, Lester SC, Nunes RA, Kaelin CM, Parker LM, Ellisen LW, Kuter I, Gadd MA, Christian RL, Kennedy PR, Borges VF, Bunnell CA, Younger J, Smith BL, Winer EP (2003) Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. J Clin Oncol 21:46–53

    Article  CAS  PubMed  Google Scholar 

  22. Limentani SA, Brufsky AM, Erban JK, Jahanzeb M, Lewis D (2007) Phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer. J Clin Oncol 25:1232–1238

    Article  CAS  PubMed  Google Scholar 

  23. Lazaridis G, Pentheroudakis G, Pavlidis N (2008) Integrating trastuzumab in the neoadjuvant treatment of primary breast cancer: accumulating evidence of efficacy, synergy and safety. Crit Rev Oncol Hematol 66:31–41

    Article  PubMed  Google Scholar 

  24. Coudert BP, Largillier R, Arnould L, Chollet P, Campone M, Coeffic D, Priou F, Gligorov J, Martin X, Trillet-Lenoir V, Weber B, Bleuse JP, Vasseur B, Serin D, Namer M (2007) Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. J Clin Oncol 25:2678–2684

    Article  CAS  PubMed  Google Scholar 

  25. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN (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  CAS  PubMed  Google Scholar 

  26. Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN (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  CAS  PubMed  Google Scholar 

  27. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J (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  CAS  PubMed  Google Scholar 

  28. Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kuhn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, von Minckwitz G (2010) Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28:2024–2031

    Article  CAS  PubMed  Google Scholar 

  29. Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P (1993) Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 16:223–228

    Article  CAS  PubMed  Google Scholar 

  30. Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N (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  CAS  PubMed  Google Scholar 

  31. Falandry C, Debled M, Bachelot T, Delozier T, Cretin J, Romestaing P, Mille D, You B, Mauriac L, Pujade-Lauraine E, Freyer G (2008) Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: a double-blind phase III GINECO study. Breast Cancer Res Treat

  32. Dirix LY, Ignacio J, Nag S, Bapsy P, Gomez H, Raghunadharao D, Paridaens R, Jones S, Falcon S, Carpentieri M, Abbattista A, Lobelle JP (2008) Treatment of advanced hormone-sensitive breast cancer in postmenopausal women with exemestane alone or in combination with celecoxib. J Clin Oncol 26:1253–1259

    Article  CAS  PubMed  Google Scholar 

  33. Falandry C, Canney PA, Freyer G, Dirix LY (2009) Role of combination therapy with aromatase and cyclooxygenase-2 inhibitors in patients with metastatic breast cancer. Ann Oncol 20:615–620

    Article  CAS  PubMed  Google Scholar 

  34. Fabi A, Metro G, Papaldo P, Mottolese M, Melucci E, Carlini P, Sperduti I, Russillo M, Gelibter A, Ferretti G, Tomao S, Milella M, Cognetti F (2008) Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation. Cancer Chemother Pharmacol 62:717–725

    Article  CAS  PubMed  Google Scholar 

  35. Boughey JC, Gonzalez RJ, Bonner E, Kuerer HM (2007) Current treatment and clinical trial developments for ductal carcinoma in situ of the breast. Oncologist 12:1276–1287

    Article  CAS  PubMed  Google Scholar 

  36. Peintinger F, Buzdar AU, Kuerer HM, Mejia JA, Hatzis C, Gonzalez-Angulo AM, Pusztai L, Esteva FJ, Dawood SS, Green MC, Hortobagyi GN, Symmans WF (2008) Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. Ann Oncol 19:2020–2025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Colleoni M, Viale G, Zahrieh D, Pruneri G, Gentilini O, Veronesi P, Gelber RD, Curigliano G, Torrisi R, Luini A, Intra M, Galimberti V, Renne G, Nole F, Peruzzotti G, Goldhirsch A (2004) Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res 10:6622–6628

    Article  CAS  PubMed  Google Scholar 

  38. Ring AE, Smith IE, Ashley S, Fulford LG, Lakhani SR (2005) Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer 92:906–912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275–1281

    Article  PubMed  Google Scholar 

  40. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685

    Article  CAS  PubMed  Google Scholar 

  41. Bertheau P, Turpin E, Rickman DS, Espie M, de Reynies A, Feugeas JP, Plassa LF, Soliman H, Varna M, de Roquancourt A, Lehmann-Che J, Beuzard Y, Marty M, Misset JL, Janin A, de The H (2007) Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicin-cyclophosphamide regimen. PLoS Med 4:e90

    Article  PubMed  PubMed Central  Google Scholar 

  42. Frasci G, D’Aiuto G, Comella P, D’Aiuto M, Di Bonito M, Ruffolo P, Iodice G, Petrillo A, Lastoria S, Oliviero P, Capasso I, Montella M, Siani C, Santangelo M, Vizioli L, Comella G (2010) Preoperative weekly cisplatin, epirubicin, and paclitaxel (PET) improves prognosis in locally advanced breast cancer patients: an update of the Southern Italy Cooperative Oncology Group (SICOG) randomised trial 9908. Ann Oncol 21:707–716

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr Olivier Tembo for study monitoring and Jocelyne Goubet for data management. This study was supported by a grant of the French Programme Hospitalier de Recherche Clinique ISRCTN10059974, PHRC: AOM 02 11 and by unrestricted grants from Pfizer Inc. France, Roche Pharmaceutical, and Sanofi-Aventis.

Author information

Authors and Affiliations

  1. Institut Curie, 26 rue d’Ulm, 75005, Paris, France

    Jean-Yves Pierga, Brigitte Sigal-Zafrani & Alexia Savignoni

  2. Institut Gustave Roussy, Villejuif, France

    Suzette Delaloge, Marie-Christine Mathieu & Marc Spielmann

  3. Saint Louis University Hospital, Paris, France

    Marc Espié, Philippe Bertheau & Michel Marty

  4. Centre René Huguenin, Saint Cloud, France

    Etienne Brain & Jean Marc Guinebretière

  5. Université Paris Descartes, Paris, France

    Jean-Yves Pierga

Authors
  1. Jean-Yves Pierga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suzette Delaloge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Espié
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Etienne Brain
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brigitte Sigal-Zafrani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marie-Christine Mathieu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philippe Bertheau
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean Marc Guinebretière
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marc Spielmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexia Savignoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michel Marty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-Yves Pierga.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pierga, JY., Delaloge, S., Espié, M. et al. A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients. Breast Cancer Res Treat 122, 429–437 (2010). https://doi.org/10.1007/s10549-010-0939-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-0939-3

Keywords

Search

Navigation