Functional evaluation of plasmin formation in primary breast cancer

Purpose: Plasmin generation is controlled by the plasminogen activators (PA )/plasmin system, which comprises proteases (urokinase-type PA [uPA] and ti ssue-type PA [tPA]) and antiproteases (PA inhibitors, PAI-1 and PAI-2). The tumoral content of uPA and PAI-I has been shown to carry prognostic valve in breast cancer; however, because most assays used so far have relied on i mmunometric determinations, we have explored the enzymatic activities gover ning plasmin formation in breast cancer specimens. Patients and Methods: We applied semiquantitative histochemical zymography to 201 primary breast cancer tissue sections. Enzymatic activities were cor related with histopathologic parameters and clinical outcome. The median fo llow-up was 91 months. Results: A wide range of PA-mediated catalytic activities was detected, The overall survival was significantly worse for patients with tumors showing tPA in the lowest quartile of activity (P = .003). The 5-year overall survi val of patients with tPA activity in the lowest quartile was 58% compared w ith 81% for patients with tPA value in the other three quartiles, Tumor siz e, axillary lymph node metastasis, histologic grade, lymphovascular infiltr ation, TP53 mutation, and tPA activity were all major risk factors in univa riate analysis, tPA activity was an independent prognostic factor in a mult ivariate Cox regression model, both in the whole population (relative risk = 0.5, 95% confidence interval, 0.3 to 0.9; P = .02) and in the node-negati ve subgroup (relative risk = 0.2, 95% confidence interval, 0.08 to 0.6; P = .004). Conclusion: By using a zymographic assay performed directly on primary tumo r tissue sections, we demonstrate that reduced tpA-mediated plasmin product ion is an independent adverse prognostic factor in breast cancer. (C) 2001 by American Society of Clinical Oncology.