JCO Early Release, published online ahead of print Nov 9 2009
Journal of Clinical Oncology, 10.1200/JCO.2008.19.6261
Received August 22, 2008
Accepted August 3, 2009
Y-Box–Binding Protein YB-1 Identifies High-Risk Patients With Primary Breast Cancer Benefiting From Rapidly Cycled Tandem High-Dose Adjuvant Chemotherapy
Oleg Gluz, Karin Mengele, Manfred Schmitt, Ronald Kates, Raihana Diallo-Danebrock, Frauke Neff, Hans-Dieter Royer, Niels Eckstein, Svjetlana Mohrmann, Evelyn Ting, Marion Kiechle, Christopher Poremba, Ulrike Nitz, and Nadia Harbeck*
From the Departments of Obstetrics and Gynecology and Pathology, Technische Universitaet Muenchen, Munich; West German Study Group, Heinrich-Heine-University Duesseldorf/Breast Center Niederrhein, Moenchengladbach; Department of Pathology, Heinrich-Heine-University Duesseldorf, Duesseldorf; Research Group for Neurological Therapeutics, Philipps University Marburg, Marburg; and Center of Advanced European Studies and Research, Bonn, Germany.
* To whom correspondence should be addressed. E-mail: nadia.harbeck{at}uk-koeln.de
Purpose: To investigate the potential of Y-box–binding protein YB-1, a multifunctional protein linked to tumor aggressiveness and multidrug resistance, to identify patients with breast cancer likely to benefit from dose-intensified chemotherapy regimens.
Patients and Methods: YB-1 was immunohistochemically determined in 211 primary tumors from the prospective, randomized West German Study Group WSG-AM-01 trial in high-risk (
10 involved lymph-nodes) breast cancer (HRBC). Predictive impact of YB-1 was assessed by multivariate survival analysis, including time-varying factor-therapy interactions.
Results: At median follow-up of 61.7 months, patients receiving rapidly cycled tandem high-dose therapy (HD; two cycles [2x] epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 14 days, followed by 2x epirubicin 90 mg/m2, cyclophosphamide 3,000 mg/m2, and thiotepa 400 mg/m2 every 21 days) had better disease-free survival (DFS; hazard ratio [HR] = 0.62; 95% CI, 0.44 to 0.89) and overall survival (OS; HR = 0.59; 95% CI, 0.4 to 0.89) than those receiving conventional dose-dense chemotherapy (DD; 4x epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2, followed by 3x cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 every 14 days). High YB-1 was associated with aggressive tumor phenotype (negative steroid hormone receptor status, positive human epidermal growth factor receptor 2 and p53 status, high MIB-1, unfavorable tumor grade) and poor OS (median 78 v 97 months; P = .01). In patients with high YB-1, HD yielded a 63-month median DFS (P = .001) and a 46-month median OS advantage (P = .002) versus DD. In multivariate models, patients with high B-1 receiving HD (v DD) had one third the hazard rate after 20 months for DFS and one sixth after 40 months for OS.
Conclusion: In a randomized prospective cancer therapy trial, for the first time, a strong predictive impact of YB-1 on survival has been demonstrated: enhanced benefit from HD (v DD) therapy occurs in HRBC with high YB-1. Future trials could therefore address optimal chemotherapeutic strategies,taking YB-1 into account.
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