title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 1 (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 (CI): 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% CI: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Gro L
authors.initials: GL
authors.lastname: Willemoe
authors.forename: Pernille B
authors.initials: PB
authors.lastname: Hertel
authors.forename: Annette
authors.initials: A
authors.lastname: Bartels
authors.forename: Maj-Britt
authors.initials: MB
authors.lastname: Jensen
authors.forename: Eva
authors.initials: E
authors.lastname: Balslev
authors.forename: Birgitte B
authors.initials: BB
authors.lastname: Rasmussen
authors.forename: Henning
authors.initials: H
authors.lastname: Mouridsen
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage; D003718:Denmark; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis* / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D009363:Neoplasm Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate