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Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial?

Alison F Munro6, Annette Bartels2, Eva Balslev3, Christopher J Twelves4, David A Cameron5, Nils Brünner2 and John MS Bartlett16*

Author Affiliations

1 Transformative Pathology, Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 800, Toronto, ON M5G 0A3, Canada

2 Section of Pathobiology, Institute of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

3 Department of Pathology, Herlev Hospital, Copenhagen, Denmark

4 University of Leeds and Cancer Research UK Centre, St James' University Hospital, Leeds, LS2 9JT, UK

5 Edinburgh Cancer Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK

6 Biomarkers and Companion Diagnostics Group, Edinburgh Cancer Research UK Centre, MRC IGMM, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK

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Breast Cancer Research 2013, 15:R31  doi:10.1186/bcr3411

Published: 9 April 2013



Predictive cancer biomarkers to guide the right treatment to the right patient at the right time are strongly needed. The purpose of the present study was to validate prior results that tissue inhibitor of metalloproteinase 1 (TIMP-1) alone or in combination with either HER2 or TOP2A copy number can be used to predict benefit from epirubicin (E) containing chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil (CMF) treatment.


For the purpose of this study, formalin fixed paraffin embedded tumor tissue from women recruited into the BR9601 clinical trial, which randomized patients to E-CMF versus CMF, were analyzed for TIMP-1 immunoreactivity. Using previously collected data for HER2 amplification and TOP2A gene aberrations, we defined patients as "anthracycline non-responsive", that is, 2T (TIMP-1 immunoreactive and TOP2A normal) and HT (TIMP-1 immunoreactive and HER2 negative) and anthracycline responsive (all other cases).


In total, 288 tumors were available for TIMP-1 analysis with (183/274) 66.8%, and (181/274) 66.0% being classed as 2T and HT responsive, respectively. TIMP-1 was neither associated with patient prognosis (relapse free survival or overall survival) nor with a differential effect of E-CMF and CMF. Also, TIMP-1 did not add to the predictive value of HER2, TOP2A gene aberrations, or to Ki67 immunoreactivity.


This study could not confirm the predictive value of TIMP-1 immunoreactivity in patients randomized to receive E-CMF versus CMF as adjuvant treatment for primary breast cancer.