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: Pernille Braemer Hertel, Dongsheng Tu, Bent Ejlertsen, Maj-Britt Jensen, Eva Balslev, Shan Jiang, Frances P O'Malley, Kathleen I Pritchard, Lois E Shepherd, Annette Bartels, Nils Brünner, Torsten O Nielsen
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 132 Issue 1 Pg. 225-34 (Feb 2012) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 22160637 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor
• DNA-Binding Proteins
• Poly-ADP-Ribose Binding Proteins
• TIMP1 protein, human
• Tissue Inhibitor of Metalloproteinase-1
• Epirubicin
• Cyclophosphamide
• ERBB2 protein, human
• Receptor, ErbB-2
• DNA Topoisomerases, Type II
• TOP2A protein, human
• Fluorouracil
• Methotrexate

Topics

• Antigens, Neoplasm (genetics, metabolism)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (drug therapy, metabolism, mortality, surgery)
• Chemotherapy, Adjuvant
• Combined Modality Therapy
• Cyclophosphamide (administration & dosage)
• DNA Topoisomerases, Type II (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Disease-Free Survival
• Epirubicin (administration & dosage)
• Female
• Fluorouracil (administration & dosage)
• Humans
• Kaplan-Meier Estimate
• Methotrexate (administration & dosage)
• Middle Aged
• Multivariate Analysis
• Mutation
• Poly-ADP-Ribose Binding Proteins
• Proportional Hazards Models
• Receptor, ErbB-2 (genetics, metabolism)
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Treatment Outcome