Topoisomerase IIα as a Marker Predicting the Efficacy of Anthracyclines in Breast Cancer: Are We at the End of the Beginning?

Abstract

This article attempts to provide the reader with a complete overview of topoisomerase (topo) IIα as a marker for predicting the efficacy of anthracyclines in patients with breast cancer. In the first section of this article, in vitro data supporting the predictive value of topo IIα are reviewed. Interestingly, these data suggest that the interaction between HER2 and anthracycline efficacy, which has been hypothesized in several clinical studies performed in the past decade, might depend on the concomitant topo IIα status. Molecular pathology studies further reinforce the concept that HER2 might not be directly involved in the prediction of response to anthracyclines. They report that topo IIα gene amplification can be found in 25%–40% of HER2/neu-amplified tumors, while no topo II gene amplification is detected in the absence of HER2/neugene amplification. In the second part of this article, a series of clinical studies are reviewed and interpreted. These studies have attempted to correlate topo IIα status with anthracycline efficacy in the adjuvant, neoadjuvant, and metastatic settings. All of the studies evaluating the topo IIα gene suggest that gene amplification might be associated with an increased efficacy of anthracyclines, and some of the studies evaluating topo IIα protein find that protein overexpression might correlate with an increased sensitivity to these compounds. Despite these findings, however, the reported studies do not provide the proof of principle needed to authorize the use of topo IIα as a predictive marker for standard practice. A new generation of research is currently testing the predictive value of topo IIα. It is hoped that these projects, which are described in the last section of the article, will clarify the role of topo IIα in the prediction of response to anthracyclines.