Analysis of Topoisomerase IIa and HER2 Status in 126 Patients from the US Oncology 9735 Trial of Adjuvant Chemotherapy with Docetaxel/Cyclophosphamide (TC) vs Doxorubicin/Cyclophosphamide (AC) in Early Breast Cancer.

Background: HER2/neu (HER2) positive breast cancers are associated with worse survival, resistance to cyclophosphamide/methotrexate/fluorouracil, and hypothesized to be sensitive to anthracyclines. It has been postulated that only a subset of HER2 positive breast cancers are sensitive to anthracyclines. Investigators have been working on how to identify this subset of patients, thus sparing patients from anthracyclines that have potential cardiac and bone marrow toxicities. Overexpression of the topoisomerase IIa gene (TOP2A) is the putative biomarker for sensitivity to anthracyclines. Testing tumors for overexpression of this gene may help identify patients who will not benefit from anthracylines. TOP2A is located in the same amplicon as the HER2 gene and can be assessed for overexpression by a FISH assay.Materials and Methods: Paraffin tissue blocks were obtained in 126 patients entered on US Oncology trial 9735 which recruited patients between 1997 and 2000. Data on HER2 status and outcome was previously reported (JCO 27:1177-1183, 2009). TOP2A status was then assessed by fluorescent in situ hybridization (FISH) using the LSI TOP2A Spectrum Orange Probe (Vysis). A total of 20 cells were counted and a gene ratio of greater than 2.0 was considered positive. Clinical data and outcome were available for statistical analysis.Results: We found that none of the 97 HER2 negative cases demonstrated overexpression of TOP2A by FISH analysis. TOP2A was overexpressed in 43% of the 29 HER2 positive cases. An analysis of outcome will be presented at the meeting, although the number of cases limits this observation.Discussion: Our study supports the observation that TOP2A is not overexpressed in HER2 negative disease and is only observed in a subset of cancers overexpressing HER2. Clinical correlation of outcome will be necessary to confirm whether or not TOP2A is a reliable biomarker of sensitivity to anthracyclines. The ongoing US Oncology trial of TC vs. TAC in HER2 negative breast cancer (USOR Trial 06-090) should provide that evidence.Supported in part by a grant from sanofi-aventis. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2134.