Journal of the National Cancer Institute Advance Access published online on April 28, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp067
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© The Author 2009. Published by Oxford University Press.
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Topoisomerase II Alpha and Responsiveness of Breast Cancer to Adjuvant Chemotherapy
Affiliations of authors: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (FPO, ILA); Department of Laboratory Medicine and Pathobiology (FPO, ILA), Sunnybrook Odette Cancer Centre (KIP), and Department of Medicine (KIP), University of Toronto, Toronto, Ontario, Canada; Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada (SC); Department of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada (SC); Department of Medical Oncology, National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada (DT, LES); Department of Medical Oncology, McMaster University, Hamilton, Ontario, Canada (MNL); Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada (VHB); Department of Medical Oncology, University of Calgary, Calgary, Alberta, Canada (VHB); Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (ILA)
Correspondence to: Kathleen I. Pritchard, MD, Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5 (e-mail: kathy.pritchard{at}sunnybrook.ca).
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.
| CONTEXT AND CAVEATS Prior knowledge In Mammary 5 (MA.5) and other randomized breast cancer trials, women with amplification or overexpression of human epidermal growth factor receptor type 2 (HER2) were reported to benefit more from adjuvant therapies that included anthracyclines than from therapies without them. Because HER2 lies near the gene for topoisomerase II alpha (TOP2A), it was hypothesized that responsiveness to anthracyclines might be associated with TOP2A gene alterations. Study design Tissue microarrays were able to be constructed from 438 of 710 tumor blocks accrued in 1989–1993 from MA.5 patients. TOP2A and HER2 amplification were measured by fluorescence in situ hybridization on the arrays. The association of each with recurrence-free survival and with overall survival was statistically tested. Contribution Patients whose tumors had alterations (either amplification or deletion) of TOP2A had statistically significantly longer overall survival and recurrence-free survival in response to chemotherapy with epirubicin than to chemotherapy without this anthracycline, whereas patients without TOP2A alterations showed no difference in responsiveness. Implications TOP2A alteration (amplification or deletion) is associated with a degree of responsiveness to anthracyclines that is similar to that observed in patients with HER2 amplification. Limitations There is close but not complete concordance between TOP2A alteration and HER2 amplification. A larger number of patients will be needed to determine which measurement is most closely associated with responsiveness to anthracycline-containing regimens. From the Editors
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Manuscript received December 27, 2008; revised February 2, 2009; accepted February 27, 2009.
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J Natl Cancer Inst 2009 101: 613.
J Natl Cancer Inst 2009 101: 613.
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