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Enhanced Benefit from Adjuvant Chemotherapy in Breast Cancer Patients Classified High-Risk according to Urokinase-type Plasminogen Activator (uPA) and Plasminogen Activator Inhibitor Type 1 (n = 3424)¹

Department of Obstetrics and Gynecology [N. H., R. E. K., M. K., M. S.] and Department of Experimental Oncology [A. K.], Technical University, D-81675 Munich, Germany; Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 Rotterdam, The Netherlands [M. P. L., M. E. M-v. G., J. G. M. K., J. A. F.]; and Department of Obstetrics and Gynecology, University of Hamburg, D-20246 Hamburg, Germany [F. J.]

Risk assessment and prediction of response to treatment are prerequisites for individualized adjuvant therapy decisions in breast cancer. The strong prognostic impact of the two invasion factors urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), in breast cancer has recently been validated at level-I evidence. This article considers the predictive impact of uPA/PAI-1 on response to adjuvant chemo- and endocrine therapy in 3424 primary breast cancer patients from two different data sets. uPA and PAI-1 antigen levels were measured by ELISA in primary tumor tissue extracts. After a median follow-up of 83 months, uPA/PAI-1 has a significant impact on disease-free survival in Cox multivariate analysis (P < 0.001; hazard ratio, 2.0; 95% confidence interval, 1.8–2.3). Patients with high uPA/PAI-1 levels benefit more strongly from adjuvant chemotherapy than those with low levels. This effect is seen as a significant interaction between chemotherapy and uPA/PAI-1 for the entire collective (P < 0.003; hazard ratio, 0.68; 95% confidence interval, 0.53–0.88) and separately within nodal subgroups. This enhanced benefit in the high uPA/PAI-1 patients occurs over and above the significant impact of both therapies in all patients. We find no corresponding significant interaction between endocrine therapy and uPA/PAI-1; i.e., no significant difference in benefit between patients with high and low uPA/PAI-1. In conclusion, uPA and PAI-1 levels in primary tumor tissue provide clinically relevant information on relapse risk and treatment response that will help to tailor adjuvant therapy concepts in breast cancer, accounting for individual biological tumor characteristics.

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