© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 12, 913-920,
June 20, 2001
© 2001 Oxford University Press
Randomized Adjuvant Chemotherapy Trial in High-Risk, Lymph Node-Negative Breast Cancer Patients Identified by Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1
Affiliations of authors: F. Jänicke, C. Thomssen, Universitäts-Frauenklinik Eppendorf, Hamburg, Germany; A. Prechtl, N. Harbeck, H. Graeff, M. Schmitt, Frauenklinik der Technischen Universität München, Germany; C. Meisner, H.-K. Selbmann, Institut für Medizinische Informationsverarbeitung der Universität Tübingen, Germany; M. Untch, Frauenklinik Grosshadern der Ludwig-Maximilians-Universität München, Germany; C. G. J. F. Sweep, Department of Chemical Endocrinology, University Medical Center Sint Radboud, Nijmegen, The Netherlands.
Correspondence to: Manfred Schmitt, Ph.D., Klinische Forschergruppe, Frauenklinik der Technischen Universität München, Ismaninger Str. 22, D-81675 München, Germany (e-mail: manfred.schmitt{at}lrz.tum.de).
Background: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo N0 prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis. Methods: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA (
3 ng/mg of protein) and of PAI-1 (14 ng/mg of protein) were observed. Patients with high tumor levels of uPA (>3 ng/mg of protein) and/or of PAI-1 (>14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided. Results: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = .006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but further follow-up is needed for confirmation. Conclusions: Using uPA and PAI-1, we have been able to classify about half of the patients with lymph node-negative breast cancer as low risk, for whom adjuvant chemotherapy may be avoided, and half as high risk, who appear to benefit from adjuvant chemotherapy.
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