title: TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients.
abstract: HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark. pernille@dr-hertel.dk
authors.forename: Pernille Braemer
authors.initials: PB
authors.lastname: Hertel
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.forename: Maj-Britt
authors.initials: MB
authors.lastname: Jensen
authors.forename: Eva
authors.initials: E
authors.lastname: Balslev
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Frances P
authors.initials: FP
authors.lastname: O'Malley
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.forename: Annette
authors.initials: A
authors.lastname: Bartels
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D015251:Epirubicin; D005472:Fluorouracil; D008727:Methotrexate; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D019715:Tissue Inhibitor of Metalloproteinase-1; C560822:TIMP1 protein, human; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human