Lack of TIMP-1 tumour cell immunoreactivity predicts effect of adjuvant anthracycline-based chemotherapy in patients (n=647) with primary breast cancer. A Danish Breast Cancer Cooperative Group Study

Purpose: A number of prospective studies have shown that adjuvant CEF significantly improves disease-free and overall survival as compared to CMF in breast cancer patients. Our aim was to determine whether the benefit of epirubicin versus methotrexate differs according to TIMP-1 tumour cell immunoreactivity. Experimental design: Tissue micro arrays from 647 patients randomly assigned to CMF or CEF in DBCG trial 89D were included. The primary end-point was invasive disease-free survival (IDFS). A central assessment of tissue inhibitor of metalloproteinases I (TIMP-1) status was performed using immunohistochemistry (IHC). Tumours were regarded as TIMP-1 positive if epithelial breast cancer cells were stained using the anti-TIMP-1 monoclonal antibody VT7. Results: By central assessment 75% of tumours were classified as tumour cell TIMP-1 positive. Among CEF-treated patients, individuals with TIMP-1 negative tumours; had a significant longer IDFS than patients with TIMP-1 positive tumours; (p = 0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumours (hazard ratio (HR) = 0.51; 95% confidence interval (Cl): 0.31-0.84, p = 0.0085), while no significant difference could be demonstrated among patients with TIMP-1 positive tumours (HR = 0.88; 95% Cl: 0.68-1.13, p = 0.32). A non-significant TIMP-1 status (positive or negative) versus treatment (CMF or CEF) interaction was detected for IDFS (p = 0.06) and OS (p = 0.21). Conclusion: Lack of TIMP-1 tumour cell immunoreactivity seems to predict a favourable effect of epirubicin-containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity. (C) 2009 Elsevier Ltd. All rights reserved.