Originally published as JCO Early Release 10.1200/JCO.2005.02.9264 on May 8 2006

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Topoisomerase II Gene Amplification Predicts Favorable Treatment Response to Tailored and Dose-Escalated Anthracycline-Based Adjuvant Chemotherapy in HER-2/neu–Amplified Breast Cancer: Scandinavian Breast Group Trial 9401

Minna Tanner, Jorma Isola, Tom Wiklund, Björn Erikstein, Pirkko Kellokumpu-Lehtinen, Per Malmström, Nils Wilking, Jonas Nilsson, Jonas Bergh

From the Laboratory of Cancer Biology, Institute of Medical Technology, and Department of Oncology, Tampere University and Tampere University Hospital, Tampere; Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland; The Norwegian Radium Hospital, Oslo, Norway; Department of Oncology, Lund University Hospital, Lund; and Cancer Centre Karolinska and Radiumhemmet Karolinska Institute and University Hospital, Stockholm, Sweden

Address reprint requests to Jorma Isola, MD, PhD, Institute of Medical Technology, Tampere University and University Hospital, FIN-33014 Tampere University, Tampere, Finland; e-mail: Jorma.Isola{at}uta.fi

PURPOSE: Amplification of the HER-2/neu and topoisomerase II (TOP2A) genes has been linked to the effects of anthracyclines. Their role in predicting the outcome of anthracycline-based adjuvant chemotherapy for breast cancer patients has remained controversial.

PATIENTS AND METHODS: The present substudy of the Scandinavian Breast Group trial 9401, in which an epirubicin-based regimen (nine courses of tailored and dose-escalated fluorouracil, epirubicin, and cyclophosphamide [FEC]) was compared with three or four courses of standard FEC followed by bone marrow–supported high-dose chemotherapy (cyclophosphamide, thiotepa, and carboplatin), included high-risk breast cancer patients (with eight or more positive axillary lymph nodes or at least five nodes with additional poor prognostic indicators). Amplification of HER-2/neu was determined retrospectively in paraffin-embedded tumor tissue sections by chromogenic in situ hybridization. TOP2A was tested only in HER-2/neu–amplified tumors.

RESULTS: HER-2/neu amplification alone, which was present in 32.7% of the tumors, was a strong prognostic factor for short relapse-free (P = .0034) and overall survival (P = .0008) but showed no direct association with treatment assignment. TOP2A coamplification, which was present in 37% of HER-2/neu–amplified tumors, was associated with better relapse-free survival in patients treated with tailored and dose-escalated FEC (hazard ratio [HR] = 0.45; P = .049). A statistical multivariate Cox's regression analysis confirmed the predictive significance of TOP2A coamplification (HR = 0.30; P = .020) in HER-2/neu–amplified tumors. There was no such association in patients with HER-2/neu–amplified tumors without TOP2A gene amplification.

CONCLUSION: Coamplification of HER-2/neu and TOP2A may define a subgroup of high-risk breast cancer patients who benefit from individually tailored and dose-escalated adjuvant anthracyclines.

Supported by grants from Amgen Inc, Roche Inc, the former Pharmacia Inc (presently Pfizer Inc), the Nordic Cancer Union, and the Swedish Cancer Society. J.I. and M.T. have been supported by grants from the Finnish Cancer Society, the Finnish Medical Foundation, the Sigrid Jusélius Foundation, the Scientific Foundation of Tampere University Hospital, and the European Union Research contract No. QL G1-2000-1260.

Both M.T. and J.I. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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