Prospective Evaluation of Topoisomerase II Alpha Gene Amplification and Protein Overexpression as Markers Predicting the Efficacy of Epirubicin in the Primary Treatment of Breast Cancer Patients

Clinical evaluation of topo II a as a predictive marker: Preliminary results from a clinical study suggest that complete remission after treatment with anthracyclines for advanced breast cancer is observed only in case of topo II a gene amplification (7 complete remissions, all in patients with topo II a gene amplified tumors, no complete remissions in patients with a normal or deleted topo II a gene).

Moreover, our group has analyzed the predictive value of topo II a in a population of node-positive breast cancer patients randomly treated either with anthracyclines or with CMF (Belgian cooperative trial). In a first study, topo II a was evaluated by immunohistochemistry, which allows the detection of topo II a protein expression. The results of this study suggested that patients deriving the highest benefit from anthracyclines were those in which topo II a protein is immunostained in more than 10% of tumor cells. The main findings of this study should be seen as hypothesis-generating because of the limited number of patients evaluated (about fifty in each study arm) and because topo II a protein levels depend on gene amplification as well as on tumor proliferation rate. Therefore, topo II a protein expression does not necessarily reflect topo II a gene status.

The second study run by our group was based on the same series of patients evaluated in the first study, but, this time, both HER-2 and topo II a genes were evaluated by fluorescence in-situ hybridization (FISH), which allows the detection of gene aberrations. The main findings of the second study were quite consistent with the pre-clinical data suggesting that only HER-2 amplified/topo II a amplified tumours show great sensitivity to anthracyclines while the efficacy of these same agents in HER-2 amplified/topo II a non-amplified tumors is comparable to the efficacy of other drugs or regimens like CMF.

Nevertheless, although the results reported in this study bring some additional support to the hypothesis of topo II a as a marker predicting the efficacy of anthracyclines, no definitive conclusions can be drawn because of the fairly limited number of patients evaluated, and the retrospective nature of the analyses.

The present study protocol: Supported by "in-vitro" and preliminary "in-vivo" data, briefly summarized above, this study is designed to test prospectively the value of topo II alpha gene amplification and protein overexpression in predicting the efficacy of anthracyclines. To our knowledge this is the only prospective trial worldwide which is attempting to prospectively clarify the predictive value of this interesting biological marker. This study could have important practical implications in the daily clinical management of early breast cancer patients because, if the trial confirms that topo II a gene amplification and/or protein overexpression are associated with high efficacy of anthracyclines, while topo II a normal/deleted gene and low protein content are associated with modest efficacy, an important step forward in the direction of anthracycline "tailoring" would be accomplished.