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Plasminogen Activator Inhibitor-2: Prognostic Relevance in 1012 Patients with Primary Breast Cancer¹

Division of Endocrine Oncology (Department of Medical Oncology) [J. A. F., H. A. P., M. P. L., J. G. M. K.] and Department of Statistics [W. L. J. v. P.], Dr. Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterda, the Netherlands, and Institute for Immunology [F. B., U. K., M. D. K.], Laboratory for Immunopathology, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany

The antigen levels of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor (PAI) 1, as detected in tumor extracts by ELISA, have been reported to be correlated with a poor prognosis in primary breast cancer. In the present study we have characterized a novel PAI-2-specific ELISA, designed to measure PAI-2 antigen levels in tumor cytosols. We determined PAI-2 antigen levels along with those of uPA and PAI-1 in 1012 routinely prepared tumor cytosols of patients with primary breast cancer (median follow-up, 71 months). In the overall population there was no significant association between the level of PAI-2 and prognosis, while in tumors with high uPA values, PAI-2 (test for trend) was associated with a prolonged relapse-free survival, metastasis-free survival, and overall survival (for all analyses, P < 0.02). In Cox's multivariate analysis for relapse-free survival, metastasis-free survival, and overall survival in tumors with high uPA values (including patient's age, menopausal status, lymph node status, tumor size, estrogen and progesterone receptor status, uPA, and PAI-1), PAI-2 either dichotomized or, as a continuous variable, was independently associated with a favorable relapse-free survival, metastasis-free survival, and overall survival. We conclude that the PAI-2-specific ELISA described herein is well suited for the measurement of PAI-2 levels in cytosols routinely prepared for analysis of steroid hormone receptors. We speculate that PAI-2 may serve as an inhibitor for uPA in human primary breast cancers.

¹ Supported by Grant DDHK 92-04 of the Dutch Cancer Society (N. K. B.), by Grants Kr 931/2-2 and Kr 931/3-1 of the Deutsche Forschungsgemeinschaft, and in part by the BIOMED-1 Project BMH1-CT93-1346.

² To whom requests for reprints should be addressed, at Dr. Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, the Netherlands.

Received 12/16/94. Accepted 2/20/95.

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