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Clinical Cancer Research Vol. 8, 1107-1116, May 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

HER-2 Amplification and Topoisomerase II{alpha} Gene Aberrations as Predictive Markers in Node-positive Breast Cancer Patients Randomly Treated Either with an Anthracycline-based Therapy or with Cyclophosphamide, Methotrexate, and 5-Fluorouracil1

Angelo Di Leo2, David Gancberg, Denis Larsimont, Minna Tanner, Tero Jarvinen, Ghizlane Rouas, Stella Dolci, Jean-Yves Leroy, Marianne Paesmans, Jorma Isola and Martine J. Piccart

Translational Research Unit, Jules Bordet Institute-Brussels, 1000 Brussels, Belgium [A. D. L., D. G., D. L., G. R., S. D., J-Y. L., M. J. P.]; Jules Bordet Institute Data Center, 1000 Brussels, Belgium [M. P.]; and Laboratory of Cancer Biology, Institute of Medical Technology [M. T., J. I.], Department of Surgery and Institute of Medical Technology [T. J.], Tampere, 33101 Finland

Purpose: The purpose of this study is to evaluate HER-2 and topoisomerase II{alpha} (topo II{alpha}) as candidates for predicting the activity of anthracyclines in the adjuvant treatment of breast cancer patients.

Experimental Design: In this study, we evaluated HER-2 and topo II{alpha} gene aberrations by fluorescence in situ hybridization in a series of 430 primary breast cancer samples. Samples came from node-positive breast cancer patients randomly treated either with one of two anthracycline-based regimens [full-dose epirubicin-cyclophosphamide (HEC) and moderate-dose epirubicin-cyclophosphamide (EC)] or with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in the context of a Phase III adjuvant therapy trial. Event-free survival comparisons were performed between the three study arms in the subgroups of HER-2-amplified and nonamplified tumors. An explorative analysis was also performed to evaluate the predictive value of topo II{alpha} in the cohort of HER-2-amplified patients.

Results: HER-2 amplification was observed in 73 of the 354 evaluable samples (21%), whereas topo II{alpha} amplification was found in 23 of the 61 evaluable HER-2-amplified tumors (38%). The three event-free survival comparisons were CMF versus HEC, CMF versus EC, and EC versus HEC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were as follows: (a) CMF versus HEC, HR = 1.42 for HER-2-amplified tumors (95% CI, 0.54–3.76; P = 0.48) and 0.84 for HER-2-nonamplified tumors (95% CI, 0.49–1.44; P = 0.53); (b) CMF versus EC, HR = 1.65 for HER-2-amplified tumors (95% CI, 0.66–4.13; P = 0.29) and 0.66 for HER-2-nonamplified tumors (95% CI, 0.39–1.10; P = 0.11); and (c) EC versus HEC, HR = 0.93 for HER-2-amplified tumors (95% CI, 0.31–2.77, P = 0.90) and 1.33 for HER-2-nonamplified tumors (95% CI, 0.82–2.14; P = 0.25). Observed HRs suggest that the anthracycline-based therapy could be more effective than CMF in the subgroup of HER-2-amplified patients, whereas treatments could be equally active in the HER-2-nonamplified cohort. topo II{alpha} evaluation suggests that the superiority of anthracyclines over CMF in HER-2-amplified patients could be confined to the subgroup of topo II{alpha}-amplified tumors.

Conclusions: HER-2 could have a predictive value for the activity of anthracycline-based regimens in the adjuvant therapy of breast cancer patients. The predictive value of HER-2 would most likely be related to the concomitant amplification of the topo II{alpha} gene.




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