PROGNOSTIC-SIGNIFICANCE OF THE RECEPTOR FOR UROKINASE PLASMINOGEN-ACTIVATOR IN BREAST-CANCER

We have recently described the urokinase-type plasminogen activator (u PA) and its type 1 inhibitor (PAI-1) as strong prognostic variables in breast cancer (J. A. Foekens st al., Cancer Res., 52: 6101-6105, 1992 ; J. Grondahl-Hansen et al., Cancer Res., 53: 2513-2521, 1993; J. A. F oekens et at, J. Clin. Oncol., 11: 899-908, 1994). A specific cell sur face receptor (uPAR) binds uPA and strongly enhances plasmin generatio n, and the amount of uPAR in the tumor tissue might therefore be a rat e-limiting factor in the extracellular proteolysis involved in tumor i nvasion. Here, we report on the prognostic value of uPAR in cytosolic (uPAR(c)) and Triton (uPAR(t)) extracts prepared from 505 primary brea st tumors. The median observation time was 54 (range: 12-125) months. uPAR levels were determined by a sandwich ELISA. Univariate analysis s howed that high uPAR levels (above the median value) were significantl y associated with a shorter overall survival, showing a stronger discr iminatory effect for uPAR(c) [relative hazard rate (RHR): 1.47; P = 0. 012)] as compared with uPAR(t) (RHR, 1.33; P = 0.059), while no statis tically significant differences were found for relapse-free survival. Multivariate analysis including all patients showed that when includin g other biochemical variables (estrogen receptor, progesterone recepto r, PS2, cathepsin D, uPA, and PAI-1), the only retained independent va riable via backward elimination was PAI-1 for both relapse-free surviv al and overall survival. When analyzed separately in clinically releva nt subgroups, the prognostic value of uPAR was particularly strong in a subgroup of 201 node-positive postmenopausal women, showing consider ably shorter overall (RHR: 2.39; P < 0.0001) and relapse free (RHR: 1. 91; P = 0.0006) survival for patients with high uPAR, content. High uP AR, levels were also significantly associated with shorter overall sur vival in this subgroup of patients (RHR: 1.5; P = 0.047), but not with relapse-free survival (P = 0.64). Multivariate analysis, including th e basic model, estrogen and progesterone receptors, PS2, cathepsin D, uPA, PAI-1, uPAR(c), and uPAR(t) in the subgroup of postmenopausal nod e-positive patients, showed that only uPAR, and PAI-1 were significant independent prognostic parameters, with respect to overall survival, RHRs being 2.72 (P < 0.0001) and 1.81 (P = 0.005), respectively. In mu ltivariate analysis of relapse-free survival, uPAR(c), PAI-1, and uPA were independent parameters with respective relative relapse rates of 1.91 (P = 0.002) for uPAR(c), 1.68 (P = 0.02) for PAI-1, and 1.6 (P = 0.03) for uPA. These data lend support to the hypothesis that uPAR is an important molecule in plasmin-mediated extracellular matrix degrada tion leading to cancer cell dissemination and death of the patient.