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.

Figure 1

Kaplan–Meier curves of recurrence-free survival according to chemotherapy and TOP2A status. A) Recurrence-free survival for women with amplified or deleted TOP2A. B) Recurrence-free survival for women with normal TOP2A. In each graph, the solid line indicates the number of breast cancer patients surviving without recurrence after CEF therapy and the dotted line indicates the number of breast cancer patients surviving after CMF therapy. At 0, 5, and 10 years after random assignment to therapy, the number of patients at risk of death from breast cancer are shown. TOP2A = topoisomerase II alpha; CEF = cyclophosphamide, epirubicin, and 5-fluorouracil; CMF = cyclophosphamide, methotrexate, and epirubicin.

Figure 2

Kaplan–Meier curves of overall survival according to chemotherapy and TOP2A status. A) Overall survival for women with amplified or deleted TOP2A. B) Overall survival for women with normal TOP2A. In each graph, the solid line indicates the number of breast cancer patients surviving after CEF therapy and the dotted line indicates the number of breast cancer patients surviving after CMF therapy. At 0, 5, and 10 years after random assignment to therapy, the number of patients at risk of death from all causes are shown. TOP2A = topoisomerase II alpha; CEF = cyclophosphamide, epirubicin, and 5-fluorouracil; CMF  =  cyclophosphamide, methotrexate, and epirubicin.