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.
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.
Willemoe
Gro L
GL
Department of Pathology, Rigshospitalet, Copenhagen, Denmark.
Hertel
Pernille B
PB
Bartels
Annette
A
Jensen
Maj-Britt
MB
Balslev
Eva
E
Rasmussen
Birgitte B
BB
Mouridsen
Henning
H
Ejlertsen
Bent
B
Brünner
Nils
N
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
D009363:Neoplasm Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate