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

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.

Figure 1

CONSORT diagram. *Tissue samples were unavailable/unsuitable for one of the following reasons: archival tissue not available (n = 39), no tumor cells in available samples (n = 13), only needle biopsies available (n = 12). **Tissue samples were withdrawn for one of the following reasons: IHC analysis done on metastasis only (n = 3), patients with bilateral cancer (n = 4), IHC analysis unsuccessful (n = 2). Abbreviations: D = docetaxel; DBCG = Danish Breast Cancer Cooperative Group; FFPE = formalin-fixed, paraffin-embedded; GD = gemcitabine plus docetaxel; IHC = immunohistochemical staining; TIMP-1 = tissue inhibitor of metalloproteinases-1.

Figure 2

Time to progression and overall survival according to TIMP-1 status. Kaplan-Meier curve for (A) time to progression (165 events) and (B) overall survival (240 events) for all 264 advanced breast cancer patients treated with gemcitabine plus docetaxel or docetaxel alone (study arms combined) according to TIMP-1 immunohistochemical staining status. Abbreviations: CI = confidence interval; TIMP-1 = tissue inhibitor of metalloproteinases-1.

Figure 3

Overall survival according to TIMP-1 status and treatment. Kaplan-Meier curve for overall survival for (A) TIMP-1 negative patients and (B) TIMP-1 positive patients according to treatment allocation. Abbreviations: CI = confidence interval; D = docetaxel; DG = docetaxel plus gemcitabine; TIMP-1 = tissue inhibitor of metalloproteinases-1; trt = treatment.

Figure 4

Subgroup analyses. Forest plots illustrating hazard ratio (HR) estimates of treatment effect with 95% confidence intervals (CI) for (A) time to progression and (B) overall survival comparison between patients with TIMP-1 negative and TIMP-1 positive tumors, basal-like and non-basal-like tumors, TIMP-1 negative and/or basal-like (G responsive) and TIMP-1 positive and non-basal-like tumors (G nonresponsive). Abbreviations: D = docetaxel; G = gemcitabine; TIMP-1 = tissue inhibitor of metalloproteinases-1.