Y-box-binding protein YB-1 identifies high-risk patients with primary breast cancer benefiting from rapidly cycled tandem high-dose adjuvant chemotherapy.
OBJECTIVE
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.


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 (> or = 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/m(2) and cyclophosphamide 600 mg/m(2) every 14 days, followed by 2x epirubicin 90 mg/m(2), cyclophosphamide 3,000 mg/m(2), and thiotepa 400 mg/m(2) 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/m(2) and cyclophosphamide 600 mg/m(2), followed by 3x cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) 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.


CONCLUSIONS
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.
Gluz
Oleg
O
Breast Center, University of Cologne, Kerpener Strasse 34, 50931 Cologne, Germany.
Mengele
Karin
K
Schmitt
Manfred
M
Kates
Ronald
R
Diallo-Danebrock
Raihana
R
Neff
Frauke
F
Royer
Hans-Dieter
HD
Eckstein
Niels
N
Mohrmann
Svjetlana
S
Ting
Evelyn
E
Kiechle
Marion
M
Poremba
Christopher
C
Nitz
Ulrike
U
Harbeck
Nadia
N
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015999:Multivariate Analysis; D009687:Nuclear Proteins / Q000378:metabolism*; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome; D051840:Y-Box-Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human