TOP2A, TIMP-1 and responsiveness to adjuvant anthracycline containing chemotherapy in high risk breast cancer patients.
Authors: Ejlertsen B , Jensen M , Nielsen KV , Balslev E , Willemoe GL , Hertel PB , Knoop AS , Mouridsen HT , Brünner N 
Published: December 2010

Abstract
Abstract #36
Background: Anthracyclins are potent poisons for topoisomerase II, an indispensable enzyme for DNA replication, repair and transcription. Apoptosis is often the consequence of anthracycline induced DNA breaks but cancer cells may escape through activation of the cell survival pathway by Tissue Inhibitor of Metalloproteinases-1 (TIMP-1). The aim of the present study was to determine the predictive value of the combination of the two biomarkers (TOP2A and TIMP-1) for benefits observed with CEF compared to CMF in DBCG trial 89D.&#x2028; Material and Methods: The DBCG 89-D trial randomized 980 high-risk Danish breast cancer patients to nine series of CMF or CEF, without endocrine therapy. Overall CEF was superior to CMF in terms of DFS and OS (Ejlertsen et al, EJC 2007). TOP2A copy number changes were determined with the TOP2A FISH pharmDx™ Kit (Dako A/S, Glostrup) as described previously (Knoop et al, JCO 2005). TMAs were constructed and analyzed centrally for TIMP-1 expression using the anti-TIMP-1 monoclonal antibody VT7 (Sørensen et al, J. Hist. Cytochem. 2006). A combined marker (2T) for anthracycline sensitivity was constructed as follows: 2T non-responsive (TOP2A normal and TIMP-1 positive) and 2T responsive (TOP2A abnormal and/or TIMP-1 negative). Relationships between IDFS, OS and the 2T profile were analyzed using multivariate regression analysis.&#x2028; Results: The assessable 623 patients differed significantly (P&lt;0.05) from the non-assessable patients with regard to menopausal status, tumor size, malignancy grade, ER and HER2 status. Among the 347 patients treated with CMF 150 (43%) had tumors with a 2T responsive profile, compared with 119 (43%) of the 276 patients treated with CEF.&#x2028; Among patients with a 2T responsive profile the Cox regression analysis showed that treatment with CEF was superior to CMF in terms of both invasive disease-free survival (IDFS) (adjusted hazard ratio 0.48; 95% CI 0.34 to 0.69; P&lt;0.001) and overall survival (OS) (adjusted hazard ratio 0.54; 95% CI, 0.38 to 0.77; P&lt;0.001). In contrast, among patients with a 2T non-responsive profile, no significant difference between CEF and CMF was demonstrated in terms of IDFS (hazard ratio 1.18; 95% CI 0.87 to 1.60; P=0.29) or OS (hazard ratio 1.07; 95% CI, 0.78 to 1.47; P=0.68). A highly significant 2T profile (responsive or non-responsive) versus treatment (CEF or CMF) interaction was detected in the Cox analysis by the Wald-test for both IDFS (P&lt;0.001) and OS (P=0.004). Discussion: TOP2A aberrations and absence of TIMP-1 immunoreactivity are associated with clinical benefits from anthracycline-containing therapy in patients with early breast cancer. In combination the two biomarkers identify a substantial part of the patients (43%) and the use of the 2T profile seems advantageous compared to using either marker alone.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 36.