The prognostic value of components of the
urokinase-type plasminogen activator (uPA) system, its
receptor uPAR (CD87), and
plasminogen activator inhibitors PAI-1 and
PAI-2 is well established. We studied the predictive value of these proteolytic factors by evaluating the association of their
tumor expression level and the efficacy of
tamoxifen therapy in patients with recurrent
breast cancer. The
antigen levels of the four factors were determined by ELISA in cytosols prepared from
estrogen receptor-positive primary
breast tumors of 691
hormone-naive
breast cancer patients with recurrent disease and treated with
tamoxifen as first-line systemic
therapy. High
tumor levels of uPA (P < 0.001), uPAR (P < 0.01), and
PAI-1 (P = 0.01) were associated with a lower efficacy of
tamoxifen therapy. In the multivariable analysis, uPA (P < 0.001) provided additional information independent of the traditional predictive factors to predict benefit from
tamoxifen therapy. High levels of uPA, uPAR, and
PAI-1 predicted a shorter progression-free survival (PFS) on
tamoxifen in an analysis of the first 9 months of
therapy. However in the analysis during the total follow-up period, high
PAI-2 levels (P = 0.01) showed a longer response to
tamoxifen. In conclusion, uPA, uPAR, and
PAI-1, components of the
urokinase system, are predictive for the efficacy of
tamoxifen therapy in patients treated for recurrent
breast cancer. Knowledge of their
tumor expression levels might be helpful for future individualized
therapy protocols, including possible new-targeted
therapies based on the interference in the
urokinase system.