Lack of TIMP-1 tumor cell immunoreactivity predicts effect of adjuvant anthracycline based chemotherapy in patients (n=647) with primary breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #6042 Background: Randomized trials have in general demonstrated that anthracycline-based chemotherapy prolongs disease-free and overall survival as compared to CMF-based regimens. In the Danish Breast Cancer Cooperative Group (DBCG) 89D randomised trial a 21% improvement in overall survival was observed from substitution of methotrexate in the CMF combination with epirubicin. This suggests that the additional effect of anthracyclines is confined to a subset of the patients. We have previously shown that in vitro grown cancer cells devoid of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) are more sensitive towards chemotherapy than cells expressing TIMP-1 (Davidsen et al., Br J Cancer, 2005). In addition, we have recently published (Schrohl et al., Clin Cancer Res., 2006), that patients with metastatic breast cancer and high levels of TIMP-1 in their primary tumor tissues, have a significantly reduced likelihood of obtaining an objective response to chemotherapy. Purpose: The aim of the present study was to evaluate if Tissue Inhibitor of Metalloproteinses-1 (TIMP-1) tumor cell immunoreactivity could be used to identify a subset of patients who benefits from adjuvant chemotherapy. Patients and Methods: Formalin fixed paraffin embedded tissue micro arrays from 647 patients who were enrolled in the Danish Breast Cancer Cooperative Group randomized trial 89D comparing adjuvant CMF versus adjuvant CEF were analysed for tumor cell TIMP-1 immunoreactivity. The primary end-point was invasive disease free survival (IDFS). Immunohistochemistry was performed using the anti-TIMP-1 monoclonal antibody VT7 as described previously (Sorensen et al., J. Hist. Cytochem., 2006) and the slides were scored as + or – for positive immunoreactivity. Results: Tumor cell TIMP-1 immunoreactivity was found in 75% of the tumor samples. In the CEF treated patients, individuals with TIMP-1 negative tumors had a significant longer IDFS than patients with TIMP-1 positive tumors (p=0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumors (HR: 0.51; 95%CI: 0.31 to 0.84, p=0.008), while no significant difference could be demonstrated among patients with TIMP-1 positive tumors (HR: 0.86; 95%CI: 0.66 to 1.11, p=0.24). However, only a non-significanct trend could be demonstrated between TIMP-1 status and CEF versus CMF (p=0.07 for interaction). Conclusion: Lack of TIMP-1 tumor cell immunoreactivity seems to predict a favourable effect of epirubicin containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6042.