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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | 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

Authors: Charlotte Levin Tykjær Jørgensen, Christina Bjerre, Bent Ejlertsen, Karsten D Bjerre, Eva Balslev, Annette Bartels, Nils Brünner, Dorte L Nielsen

Published in: BMC Cancer | Issue 1/2014

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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.
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Metadata
Title
TIMP-1 and responsiveness to gemcitabine in advanced breast cancer; results from a randomized phase III trial from the Danish breast cancer cooperative group
Authors
Charlotte Levin Tykjær Jørgensen
Christina Bjerre
Bent Ejlertsen
Karsten D Bjerre
Eva Balslev
Annette Bartels
Nils Brünner
Dorte L Nielsen
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-360

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