Topoisomerase II Alpha and Responsiveness of Breast Cancer to Adjuvant Chemotherapy

Abstract

Background

Amplification or deletion of the topoisomerase II alpha ( TOP2A ) gene in breast cancers has been postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than amplification of the human epidermal growth factor receptor type 2 ( HER2 ) gene.

Methods

We studied 438 tumors from 710 premenopausal women with node-positive breast cancer who received cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant chemotherapy in the randomized National Cancer Institute of Canada Clinical Trials Group Mammary 5 (MA.5) trial. TOP2A alterations and HER2 amplification were quantified by fluorescence in situ hybridization. The association of TOP2A and HER2 status with recurrence-free survival (RFS) and overall survival (OS) in the two treatment groups was analyzed using Kaplan–Meier curves, the log-rank test, and Cox proportional hazard models. All statistical tests were two-sided.

Results

In patients whose tumors showed TOP2A alterations (either amplifications or deletions), treatment with CEF was statistically significantly superior to treatment with CMF in terms of RFS (adjusted hazard ratio [HR]  =  0.35, 95% confidence interval [CI]  =  0.17 to 0.73, P = .005) and OS (adjusted HR  =  0.33, 95% CI  =  0.15 to 0.75, P   =  .008). In patients without TOP2A amplification or deletion, the corresponding adjusted hazard ratios for RFS and OS were 0.90 (95% CI  =  0.66 to 1.23, P   =  .49) and 1.09 (95% CI  =  0.77 to 1.56, P = .62). Adjusted tests of interaction between treatment and TOP2A status were P = .09 for RFS and P = .02 for OS. Adjusted tests of interaction between treatment and HER2 status were P = .008 for RFS and P = .02 for OS.

Conclusion

TOP2A gene alterations (amplifications or deletions) are associated with an increase in responsiveness to anthracycline-containing chemotherapy regimens relative to non-anthracycline regimens that is similar to that seen in patients with HER2 amplification.