TIMP-1 Status Measured by Immunohistochemistry in 268 ER Positive Postmenopausal High-Risk Breast Cancer Patients Treated with Adjuvant Tamoxifen: Association to Recurrence Free Survival.

Abstract

Abstract Background: A proportion of ER positive breast cancer patients do not benefit from adjuvant tamoxifen treatment. Tamoxifen has been shown to induce apoptosis in human breast cancer cells in vitro and Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) protects cancer cells against apoptosis. We therefore raised the hypothesis that ER positive breast cancer cells with high TIMP-1 immunoreactivity would show reduced benefit to tamoxifen treatment.Material and methods: Tumor tissue from 268 high-risk postmenopausal ER positive breast cancer patients was used for this study. All patients underwent surgery for primary invasive breast cancer. The majority of the patients were lymph node positive: 92% (246/268). Patients were allocated to 1, 2 or 5 years of adjuvant tamoxifen as mono-therapy. Recurrent disease was diagnosed in 33% (89/268) of the patients. Median time to recurrence was 3.1 years and the median time of follow-up was 12.4 years. Archival formalin-fixed and paraffin-embedded primary tumor tissue was used to generate tissue microarrays comprising two, 2 mm cores from each tumor. TIMP-1 immunoreactivity was evaluated using the mouse monoclonal antibody (clone VT7) raised against recombinant human TIMP-1. This antibody exclusively reacts with TIMP-1. A central assessment of TIMP-1 status was performed. Tumors were analysed by bright field microscopy and scored semi-quantitatively as 0 - 3 with regard to the number of stained tumour cells and intensity of the staining. An index combining the number of positive tumor cells and staining intensity was created: low (0-2), median (3-4) and high expression (5-6).Results: IHC was successfully performed in 266 cases. TIMP-1 IHC negative cases were observed in 39% (105/266) of the tumors and 61% (161/266) were TIMP-1 IHC positive. The index combining the number of positive tumor cells and staining intensity showed low expression in 59% (157/266), median expression in 24% (65/266) and high expression in 17% (44/266) of the tumors. TIMP-1 negativity and low TIMP-1 index showed no significant association with tumor grade, tumor size or lymph node status. When performing Kaplan-Meier plots, TIMP-1 expression was not significantly associated with recurrence free survival in univariate analyses (p = 0.1).Conclusion: This study did not confirm our hypothesis that TIMP-1 immunoreactivity in ER positive breast cancer cells are associated with reduced benefit from adjuvant tamoxifen treatment. This is partly in contrast with prior studies on endocrine therapy of metastatic breast cancer (Lipton et al 2008) where high serum TIMP-1 was associated with reduced response to endocrine therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2025.