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Retrospective Analysis of Topoisomerase IIa Amplifications and Deletions As Predictive Markers in Primary Breast Cancer Patients Randomly Assigned to Cyclophosphamide, Methotrexate, and Fluorouracil or Cyclophosphamide, Epirubicin, and Fluorouracil: Danish Breast Cancer Cooperative Group

From the Department of Oncology, Odense University Hospital, Odense; the Department of Pathology, Herlev Hospital, Herlev; the Department of Pathology, Roskilde County Hospital, Roskilde; the Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus; the DakoCytomation A/S, Glostrup; DBCG Secretariat, Copenhagen; the Department of Pathology, Odense University Hospital, Odense; and the Department of Oncology, Copenhagen, Denmark

Address reprint requests to Ann S. Knoop, MD, PhD, Oncological Department, Odense University Hospital DK-5000, Odense C, Denmark; e-mail: knoop{at}dadlnet.dk

PURPOSE: The aim of the study was to evaluate the predictive value of HER2 and topoisomerase II gene (TOP2A) for the efficacy of epirubicin in the adjuvant setting of breast cancer patients.

PATIENTS AND METHODS: In the Danish Breast Cancer Cooperative Group trial 89D, 980 pre- and postmenopausal primary patients were randomly allocated to either CMF (cyclophosphamide, methotrexate, and fluorouracil; n = 500) or CEF (cyclophosphamide, epirubicin, and fluorouracil; n = 480) times 9, between January 1990 and November 1999. Tumor tissue was retrospectively identified from 805 patients and was analyzed for HER2-positivity and for TOP2A-amplifications and deletions.

RESULTS: HER2-positivity was found in 33% of the 805 investigated tumors and was not a predictive marker for epirubicin sensitivity. TOP2A changes were identified in 23% of the 773 investigated tumors: 12% had TOP2A amplifications and 11% had TOP2A deletions. We found that patients with TOP2A amplification had an increased recurrence-free (RFS; hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.78) and overall survival (OS; HR, 0.57; 95% CI, 0.29 to 1.13), respectively if treated with CEF compared with CMF, and that patients with TOP2A deletions had an almost identical hazard ratio (RFS: HR, 0.63; 95% CI, 0.36 to 1.11; OS: HR, 0.56; 95% CI, 0.30 to 1.04). This is in contrast to patients with a normal TOP2A genotype for whom similar outcome was observed in both treatment arms (RFS: HR, 0.90; 95% CI, 0.70 to 1.17; OS: HR, 0.88; 95% CI, 0.66 to 1.17).

CONCLUSION: TOP2A amplification—and possibly deletion—seems to be predictive markers for the effect of adjuvant epirubicin containing therapy in primary breast cancer, but a final conclusion has to await a confirmative study or a meta-analysis.

Supported by grants from Danish Cancer Society; Danish Medical Research Council; Danish Cancer Research Foundation; The Clinical Oncological Research Unit, Odense University Hospital; The A.P. Moeller Foundation; Dagmar Marshalls Foundation; Grosserer Georg Bjoerkner & Ellen Bjoerkners Fond; and Ambt Balslev’s Foundation. DakoCytomation, Glostrup, Denmark, made all kits available without costs and kindly provided a microscope.

Presented in part as an oral presentation at ECCO 12: The European Cancer Conference, Copenhagen, Denmark, September 21-25, 2003.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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