Amplification and Overexpression of Topoisomerase IIα Predict Response to Anthracycline-based Therapy in Locally Advanced Breast Cancer

Purpose: The putative association between erbB-2 overexpression and favorable response to anthracyline-based therapy in breast cancer is controversial, and the mechanism unclear. We sought to determine whether coamplification and overexpression of the topoisomerase II α gene, near erbB-2 on chromosome 17, and a known anthracycline target, may underlie the association. Experimental Design: Thirty-five patients who had locally advanced breast cancer (LABC) and who had received neoadjuvant, anthracycline-based therapy were studied. Copy number of topoisomerase II α and erbB-2 was determined by fluorescence in situ hybridization, and expression by immunohistochemistry. Results: Of 8 patients with erbB-2 amplification, 5 had a complete response (CR) or minimal residual disease (MRD), 3 had a partial response (PR), and none had stable (StD) or progressive disease (PD) at the time of mastectomy, versus 3 CR or MRD, 16 PR, and 8 StD or PD for patients without amplification ( P = 0.008). In contrast, erbB-2 overexpression was not significantly associated with response ( P = 0.114). Of 6 patients with topoisomerase II α amplification, 4 had CR or MRD, 2 PR, and none StD or PD, versus 4 CR or MRD, 17 PR, and 8 StD or PD for patients without amplification ( P = 0.034). All of the tumors with topoisomerase II α amplification also had erbB-2 amplification, but not vice versa . Overexpression of topoisomerase IIα (9 patients) was also associated with favorable response ( P = 0.021). Conclusions: Coamplification of erbB-2 and topoisomerase II α is significantly associated with favorable local response to anthracycline-based therapy in LABC. The expression data favor a plausible mechanism based on topoisomerase IIα biology.