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Pathological complete response rates following different neoadjuvant chemotherapy regimens for operable breast cancer according to ER status, in two parallel, randomized phase II trials with an adaptive study design (ECTO II)

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Abstract

Sequential doxorubicin/paclitaxel (AT) followed by CMF treatment was shown to be an active neoadjuvant chemotherapy regimen in the first European Cooperative Trial in Operable Breast Cancer (ECTO I trial). The aim of the current study (ECTO II) is to assess the complete pathological response (pCR) rate following three different anthracycline and taxane-containing neoadjuvant chemotherapy regimens, with or without capecitabine (X). Patients with operable, invasive breast cancer >2.0 cm in diameter, were randomized to AT→CMF, AT→CMX or AC→TX regimens in two parallel, randomized, open-label, phase II trials (within a single study) in patients with estrogen receptor negative (ER−) and estrogen receptor positive (ER+) diseases, respectively. Exemestane was delivered concomitantly with neoadjuvant chemotherapy in ER+ tumors. Achievement of pCR was more common in ER− than ER+ women (45.3 vs. 10.4%). Capecitabine was only associated with a higher frequency of pCR in ER+ patients receiving AT→CMX. Overall response rates (ORR) ranged from 88 to 97%, and this translated into high rates of breast-conserving surgery (67% of ER− patients and 72% of ER+ patients). All three regimens were well tolerated. Febrile neutropenia and gastrointestinal effects were the most common grade ≥3 adverse events. As expected, the ECTO II study showed higher pCR rates in patients with ER− disease. Substituting capecitabine for fluorouracil (± methotrexate) in anthracycline/taxane-containing regimens appeared to be beneficial only in ER+ tumors. Translational studies investigating interactions between therapeutic agents and tumor biology are warranted to refine patient selection and improve the results of neoadjuvant chemotherapy.

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References

  1. 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  Google Scholar 

  2. Bonadonna G, Valagussa P, Brambilla C et al (1998) Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93–100

    PubMed  CAS  Google Scholar 

  3. Guarneri V, Broglio K, Kau SW et al (2006) Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 24:1037–1044

    Article  PubMed  Google Scholar 

  4. 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 

  5. Bear HD, Anderson S, Brown A et al (2003) The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from national surgical adjuvant breast and bowel project protocol B-27. J Clin Oncol 21:4165–4174

    Article  PubMed  CAS  Google Scholar 

  6. von Minckwitz G, Raab G, Caputo A et al (2005) Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German breast group. J Clin Oncol 23:2676–2685

    Article  Google Scholar 

  7. Gianni L, Baselga J, Eiermann W et al (2005) Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res 11:8715–8721

    Article  PubMed  CAS  Google Scholar 

  8. Goldhirsch A, Ingle JN, Gelber RD et al (2009) Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20:1319–1329

    Article  PubMed  CAS  Google Scholar 

  9. Kaufmann M, von Minckwitz G, Bear HD et al (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  PubMed  CAS  Google Scholar 

  10. 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 

  11. Gianni L, Baselga J, Eiermann W et al (2009) Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European cooperative trial in operable breast cancer. J Clin Oncol 27:2474–2481

    Article  PubMed  CAS  Google Scholar 

  12. O’Shaughnessy JA (2003) The evolving role of capecitabine in breast cancer. Clin Breast Cancer 4(Suppl 1):S20–S25

    Article  PubMed  Google Scholar 

  13. Gradishar WJ, Meza LA, Amin B et al (2004) Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study. J Clin Oncol 22:2321–2327

    Article  PubMed  CAS  Google Scholar 

  14. Batista N, Perez-Manga G, Constenla M et al (2004) Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Br J Cancer 90:1740–1746

    PubMed  CAS  Google Scholar 

  15. Mariani G, Petrelli F, Zambetti M et al (2006) Capecitabine/cyclophosphamide/methotrexate for patients with metastatic breast cancer: a dose-finding, feasibility, and efficacy study. Clin Breast Cancer 7:321–325

    Article  PubMed  CAS  Google Scholar 

  16. Fisher B, Bryant J, Wolmark N et al (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672–2685

    PubMed  CAS  Google Scholar 

  17. Simon R, Wittes RE, Ellenberg SS (1985) Randomized phase II clinical trials. Cancer Treat Rep 69:1375–1381

    PubMed  CAS  Google Scholar 

  18. Wieand HS (2005) Randomized phase II trials: what does randomization gain? J Clin Oncol 23:1794–1795

    Article  PubMed  Google Scholar 

  19. von Minckwitz G, Rezai M, Loibl S et al (2010) Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 28:2015–2023

    Article  Google Scholar 

  20. von Minckwitz G, Kummel S, Vogel P et al (2008) Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst 100:542–551

    Article  Google Scholar 

  21. Ellis MJ, Ma C (2007) Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat 105(Suppl 1):33–43

    Article  PubMed  CAS  Google Scholar 

  22. Eiermann W, Paepke S, Appfelstaedt J et al (2001) Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 12:1527–1532

    Article  PubMed  CAS  Google Scholar 

  23. Smith IE, Dowsett M, Ebbs SR et al (2005) Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23:5108–5116

    Article  PubMed  CAS  Google Scholar 

  24. Dixon JM, Jackson J, Renshaw L et al (2003) Neoadjuvant tamoxifen and aromatase inhibitors: comparisons and clinical outcomes. J Steroid Biochem Mol Biol 86:295–299

    Article  PubMed  CAS  Google Scholar 

  25. Semiglazov VF, Semiglazov VV, Dashyan GA et al (2007) Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 110:244–254

    Article  PubMed  CAS  Google Scholar 

  26. Pico C, Martin M, Jara C et al (2004) Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study. Ann Oncol 15:79–87

    Article  PubMed  CAS  Google Scholar 

  27. 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 

  28. Precht LM, Lowe KA, Atwood M et al (2010) Neoadjuvant chemotherapy of breast cancer: tumor markers as predictors of pathologic response, recurrence, and survival. Breast J 16:362–368

    PubMed  Google Scholar 

  29. Bhargava R, Beriwal S, Dabbs DJ et al (2010) Immunohistochemical surrogate markers of breast cancer molecular classes predicts response to neoadjuvant chemotherapy: a single institutional experience with 359 cases. Cancer 116:1431–1439

    Article  PubMed  CAS  Google Scholar 

  30. Carey LA, Dees EC, Sawyer L et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329–2334

    Article  PubMed  CAS  Google Scholar 

  31. 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 

  32. 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 

  33. Pierga JY, Delaloge S, Espie M et al (2010) 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

    Article  PubMed  CAS  Google Scholar 

  34. 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 

  35. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R et al (2009) Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicine for breast cancer: an open-label, randomised controlled trial. Lancet Oncol 10:1145–1151

    Article  PubMed  CAS  Google Scholar 

  36. ATAC Trialists’ Group (2005) Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62

    Article  Google Scholar 

  37. BIG 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757

    Article  Google Scholar 

  38. Smith IE, Dowsett M, Yap YS et al (2006) Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol 24:2444–2447

    Article  PubMed  CAS  Google Scholar 

  39. Gnant M, Mlineritsch B, Stoeger H, et al. on behalf of the Austrian Breast and colorectal cancer study group, Vienna, Austria (2011) Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol (in press)

Download references

Acknowledgments

The authors are indebted to all the patients who have participated in our clinical trial and to the many associates, in particular medical oncologists, surgeons, radiation therapists, pathologists, research nurses, and data managers for their cooperation during the study. The authors are particularly indebted to the members of the International Advisory Board: Dr. John Bryant, Dr. Gabriel Hortobagyi, Dr. Larry Norton, Dr. Abraham Recht, and Dr. William Wood. The authors would like to thank Dr Claire Barton for assistance in preparing the manuscript, Rossella Vio and Lidia Mariani from the Michelangelo Operations Office, and Sergi Hernandez from SOLTI for coordinating the Spanish sites. The study was supported by unrestricted grants from Bristol-Myers Squibb, Roche and Pfizer.

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Author notes

  1. Milvia Zambetti & Gianni Luca

    Present address: Fondazione Centro San Raffaele del Monte Tabor, Via Olgettina, 60, 20132, Milano, Italy

Authors and Affiliations

  1. Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Milvia Zambetti, Elena De Benedictis & Gianni Luca

  2. Ospedale Universitario Santa Maria della Misericordia, Udine, Italy

    Mauro Mansutti

  3. Hospital General Vall d’Hebron, Barcelona, Spain

    Patricia Gomez

  4. Hospital Clínico Universitario de Valencia, Valencia, Spain

    Ana Lluch

  5. LBI-ACR & ACR-ITR VIEnna, Kaiser Franz Josef-Spital, Vienna, Austria

    Christian Dittrich

  6. Ospedale Policlinico S.Orsola Malpighi, Bologna, Italy

    Claudio Zamagni

  7. Hospital Universitario 12 de Octubre, Madrid, Spain

    Eva Ciruelos

  8. Fondazione Salvatore Maugeri, Pavia, Italy

    Lorenzo Pavesi

  9. NN Petrov Research Institute of Oncology, St. Petersburg, Russian Federation

    Vladimir Semiglazov

  10. Ospedale Civile di Camposampiero, Camposampiero, Italy

    Fernando Gaion

  11. Presidio Ospedaliero di Noale, Noale, Italy

    Mario Bari

  12. Ospedale S. Bortolo, Vicenza, Italy

    Paolo Morandi

  13. Fondazione Michelangelo, Milan, Italy

    Pinuccia Valagussa

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  1. Milvia Zambetti
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Corresponding author

Correspondence to Gianni Luca.

Appendix: List of active ECTO II participating centers

Appendix: List of active ECTO II participating centers

Coordinating Center, Istituto Nazionale Tumori, Milano, Italy:, L. Gianni, M. Zambetti, E. De Benedictis

Ospedale Universitario S. Maria della Misericordia, Udine, Italy: M. Mansutti, G. Gentile

Hospital Vall d’Hebron, Barcelona, Spain: P. Gomez

Hospital Clinico Universitario de Valencia, Valencia, Spain: A. Lluch

Ludwig Boltzmann – Institute for Applied Cancer Research, Kaiser Franz Josef-Spital, Wien, Austria: C. Dittrich

Ospedale Policlinico S. Orsola Malpighi, Bologna, Italy: C. Zamagni

Hospital Universitario 12 de Octubre, Madrid, Spain: E. Ciruelos

Fondazione Salvatore Maugeri, Pavia, Italy: L. Pavesi

N.N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation: V. Semiglazov

Ospedale Civile di Camposampiero, Camposampiero, Italy: F. Gaion

Presidio Ospedaliero di Noale, Noale, Italy: M. Bari

Ospedale S. Bortolo, Vicenza, Italy: P. Morandi

Hospital de San Pau, Barcelona, Spain: B. Ojeda

Ospedale S. Giovanni Battista, Torino, Italy: M. Donadio

Hospital Arnau de Vilanova, Lleida, Spain: A. Llombart

Ospedale Civile di Legnano, Legnano, Italy: S. Fava

Frauenklinik vom Roten Kreuz, Munich, Germany: W. Eiermann

Istituto San Raffaele, Milano, Italy: E. Villa

Presidio Ospedaliero di Saronno, Saronno, Italy: C. Verusio

University Hospital Dr. Peset, Valencia, Spain: S. Olmos

Hospital Clíníco Universitario Lozano Bleza de Zaragoza, Zaragoza, Spain: R. Andrés

Medizinisches Zentrum, Ulm, Germany: C.Wolf

Istituto Valenciano de Oncologia, Valencia, Spain: M. A. Climent

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Zambetti, M., Mansutti, M., Gomez, P. et al. Pathological complete response rates following different neoadjuvant chemotherapy regimens for operable breast cancer according to ER status, in two parallel, randomized phase II trials with an adaptive study design (ECTO II). Breast Cancer Res Treat 132, 843–851 (2012). https://doi.org/10.1007/s10549-011-1660-6

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