The antigen levels of components of the urokinase-type plasminogen
activator (uPA) system of plasminogen activation are correlated with
prognosis in several types of cancers, including breast cancer. In the
present study involving 2780 patients with primary invasive breast cancer,
we have evaluated the prognostic importance of the four major components
of the uPA system [uPA, the receptor uPAR (CD87), and the inhibitors PAI-1
and PAI-2]. The antigen levels were determined by ELISA in cytosols
prepared from primary breast tumors. The levels of the four factors
significantly correlated with each other; the Spearman rank correlation
coefficients (r(s)) ranged from 0.32 (between PAI-2 and PAI-1 or uPAR) to
0.59 (between uPA and PAI-1). The median duration of follow-up of patients
still alive was 88 months. In the multivariate analyses for relapse-free
survival (RFS) and overall survival (OS), we defined a basic model
including age, menopausal status, tumor size and grade, lymph node status,
adjuvant therapy, and steroid hormone receptor status. uPA, uPAR, PAI-1,
and PAI-2 were considered as categorical variables, each with two cut
points that were established by isotonic regression analysis. Compared
with tumors with low levels, those with intermediate and high levels
showed a relative hazard rate (RHR) and 95% confidence interval (95% CI)
of 1.22 (1.02-1.45) and 1.69 (1.39-2.05) for uPA, and 1.32 (1.14-1.54) and
2.17 (1.74-2.70) for PAI-1, respectively, in multivariate analysis for RFS
in all patients. Compared with tumors with high PAI-2 levels, those with
intermediate and low levels showed a poor RFS with a RHR (95% CI) of 1.30
(1.14-1.48) and 1.76 (1.38-2.24), respectively. Similar results were
obtained in the multivariate analysis for OS in all patients. Furthermore,
uPA and PAI-1 were independent predictive factors of a poor RFS and OS in
node-negative and node-positive patients. PAI-2 also added to the
multivariate models for RFS in node-negative and node-positive patients,
and in the analysis for OS in node-negative patients. uPAR did not further
contribute to any of the multivariate models. A prognostic score was
calculated based on the estimates from the final multivariate model for
RFS. Using this score, the difference between the highest and lowest 10%
risk groups was 66% in the analysis for RFS at 10 years and 61% in the
analysis for OS. Moreover, separate prognostic scores were calculated for
node-negative and node-positive patients. In the 10% highest risk groups,
the proportion of disease-free patients was only 27 +/- 6% and 9 +/- 3% at
10 years for node-negative and node-positive patients, respectively. These
proportions were 86 +/- 4% and 61 +/- 6% for the corresponding 10% lowest
risk groups of relapse. We conclude that several components of the uPA
system are potential predictors of RFS and OS in patients with primary
invasive breast cancer. Knowledge of these factors could be helpful to
assess the individual risk of patients, to select various types of
adjuvant treatment and to identify patients who may benefit from targeted
therapies that are currently being developed