Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression.

BACKGROUND Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only. PATIENTS AND METHODS A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. RESULTS Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥ 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). CONCLUSION EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. CLINICAL TRIAL NUMBER ClinicalTrials.gov, NCT02115204.

[1]  S. Paik,et al.  Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  C. Perou,et al.  Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  R. Gelber,et al.  Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[4]  I. Henderson,et al.  Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials: Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (Clinical Trial Service Unit (CTSU), Oxford, UK) Lancet 379:432-444, 2012§ , 2013 .

[5]  J. Hainsworth,et al.  Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. , 2013, The Lancet. Oncology.

[6]  L. Neumayer,et al.  Abstract S3-5: Myelodysplatic syndrome and/or acute myelogenous leukemia (MDS and/or AML) after a breast cancer diagnosis: the National Comprehensive Cancer Network (NCCN) experience. , 2012 .

[7]  R. Peto,et al.  Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. , 2012, Lancet.

[8]  D. Cutter,et al.  Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials , 2012, The Lancet.

[9]  E. Rutgers,et al.  The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase. , 2011, European journal of cancer.

[10]  Pierre-Marie Martin,et al.  Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review , 2011, Breast Cancer Research and Treatment.

[11]  M. Buyse,et al.  Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  M. Kiechle,et al.  Phase III study of sequential treatment with epirubicin/cyclophosphamide followed by docetaxel compared to FEC120 in the adjuvant treatment of breast cancer patients: The German ADEBAR study. , 2010 .

[13]  E. Perez,et al.  Cyclophosphamide, epirubicin, and Fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by Paclitaxel versus Doxorubicin and cyclophosphamide followed by Paclitaxel in node-positive or high-risk node-negative breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  E. Álava,et al.  Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer , 2010, Breast Cancer Research and Treatment.

[15]  F. Penault-Llorca,et al.  Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  I. Ellis,et al.  Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial , 2009, The Lancet.

[17]  C. Perou,et al.  Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Xueri Li,et al.  Sequential Adjuvant Epirubicin-Based and Docetaxel Chemotherapy for Node-Positive Breast Cancer Patients:The FNCLCC PACS 01 Trial , 2009 .

[19]  O. Dizdar,et al.  Weekly paclitaxel in the adjuvant treatment of breast cancer. , 2008, The New England journal of medicine.

[20]  J. Thigpen.  Phase III Randomized Trial of Docetaxel-Carboplatin Versus Paclitaxel-Carboplatin as First-Line Chemotherapy for Ovarian Carcinoma , 2006 .

[21]  Barbara L. Smith,et al.  Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Richard L Schilsky,et al.  Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.