Topoisomerase 2 alpha as a predictor of response to anthracycline neoadjuvant chemotherapy in locally advanced breast cancer

Introduction

Anthracyclines play an important role in the treatment of breast cancer but their beneficial therapeutic effects may not be the same for all breast cancer patients. Side effects, including cardiotoxicity, may be avoided if biomarkers of response could be identified. Topoisomerase 2 alpha (Topo2α) is a target of anthracyclines and has been proposed as a chemosensitivity marker of anthracycline-containing therapies by in vitro and in vivo studies. But the method to detect it remains a controversial issue. Treatment in the neoadjvant setting is a unique opportunity to examine biomarkers of response to chemotherapy.

Objective

To examine the role of Topo2α in response to anthracycline neoadjuvant chemotherapy both at the protein level by immunohistochemistry (IHC) and at the gene level using chromogen in situ hybridisation (CISH).

Patients and methods

This study includes 100 locally advanced breast cancer patients treated by fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy from 1999 to 2008. Pretreatment core biopsy is used to study different biologic markers (basal cytokeratin, EGFR, Ki-67, p53, and Her2) including Topo2α by IHC and to correlate the expression level with the rate of pathological complete response (pCR). CISH is used to determine the level of Topo2α gene amplification.

Results

In the initial analysis of the first 64 patients, the rate of clinical complete response (CR) and pCR were 40.6% and 19.7%, respectively. Prechemotherapy Topo2α protein expression correlated with both clinical CR (P = 0.006) and pCR (P = 0.001). On multivariate analysis, only Topo2α expression correlated with pCR (P = 0.03). A correlation between Topo2α protein expression and gene amplification will be made.

Conclusions

The study demonstrates the importance of Topo2α as a predictor for both clinical CR and pCR to neoadjuvant anthracyclines in locally advanced breast cancer. Furthermore, it could be considered as part of pretreatment evaluation to help in improving the selection of patients for this type of treatment.