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Open Access Research article

TIMP-1 and responsiveness to gemcitabine in advanced breast cancer; results from a randomized phase III trial from the Danish breast cancer cooperative group

Charlotte Levin Tykjær Jørgensen1*, Christina Bjerre2, Bent Ejlertsen34, Karsten D Bjerre3, Eva Balslev1, Annette Bartels2, Nils Brünner2 and Dorte L Nielsen5

Author Affiliations

1 Department of Pathology, Herlev University Hospital, Herlev Ringvej 75, Herlev 2730, Denmark

2 Sino-Danish Breast Cancer Research Centre, Section for Molecular Disease Biology, Institute of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Strandboulevarden 49, Copenhagen Ø 2100, Denmark

3 Danish Breast Cancer Cooperative Group, Strandboulevarden 49, Copenhagen 2100 Ø, Denmark

4 Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen 2100 Ø, Denmark

5 Department of Oncology, Herlev University Hospital, Herlev Ringvej 75, Herlev 2730, Denmark

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BMC Cancer 2014, 14:360  doi:10.1186/1471-2407-14-360

Published: 22 May 2014

Abstract

Background

Tissue inhibitor of metalloproteinases-1 (TIMP-1) has anti-apoptotic functions, which may protect TIMP-1 positive cancer cells from the effects of chemotherapy such as docetaxel and gemcitabine. The purpose of the present study was to evaluate TIMP-1 immunoreactivity as a prognostic and predictive marker in advanced breast cancer patients receiving docetaxel (D) or gemcitabine plus docetaxel (GD).

Methods

Patients with locally advanced or metastatic breast cancer who were assigned to D or GD by participation in a randomized phase III trial were included in the study. Assessment of TIMP-1 status was performed retrospectively on primary tumor whole-tissue sections by immunohistochemistry and tumor samples were considered positive if epithelial breast cancer cells were stained by the anti-TIMP-1 monoclonal antibody VT7. Time to progression (TTP) was the primary endpoint. Overall survival (OS) and response rate (RR) were secondary endpoints. Associations between TIMP-1 status and outcome after chemotherapy were analyzed by Kaplan-Meier estimates and Cox proportional hazards regression models.

Results

TIMP-1 status was available from 264 of 337 patients and 210 (80%) of the tumors were classified as cancer cell TIMP-1 positive. No significant difference for TTP between TIMP-1 positive versus TIMP-1 negative patients was observed in multivariate analysis, and RR did not differ according to TIMP-1 status. However, patients with TIMP-1 positive tumors had a significant reduction in OS events (hazard ratio = 0.71, 95% confidence interval (CI) = 0.52-0.98, P = 0.03). Additionally, a borderline significant interaction for OS was observed between TIMP-1 status and benefit from GD compared to D (Pinteraction = 0.06) such that median OS increased by nine months for TIMP-1 negative patients receiving GD.

Conclusions

TIMP-1 status was an independent prognostic factor for OS but not TTP in patients with advanced breast cancer receiving either D or GD. There was no statistically significant interaction between TIMP-1 status and treatment, but a trend towards an incremental OS from the addition of gemcitabine to docetaxel in patients with TIMP-1 negative tumors suggests further investigation.

Keywords:
TIMP-1; Gemcitabine; Docetaxel; Breast cancer; Prediction; Prognosis