PRONOSTIC VALUE OF UROKINASE-TYPE PLASMIN OGEN-ACTIVATOR (UPA) AND PLASMINOGEN-ACTIVATOR INHIBITORS PAI-1 AND PAI-2 IN BREAST CARCINOMAS

It is now clearly established that proteolytic enzymes, and in particu lar plasminogen activator (uPA), play an important role in breaking do wn the extracellular matrix, wich is considered to be a step in metast asis formation. Plasminogen activators are controlled at various level s. Two inhibitors, PAI-1 and PAI-2, have been identified, the latter b eing more specific for uPA. In attempts to determine their prognostic value, it is essential to investigate the relative importance of these parameters and their interactions. We used an immunoenzymatic method to assay uPA, PAI-1 and PAI-2 antigens in cytosols prepared from 314 p rimary breast tumors. The patients were followed up for a minimum of s ix years and all relevant clinical and laboratory findings had been re corded. Univariate analysis confirmed the poor outcome of patients who se tumors contained large amounts of uPA and PAI-1. In addition, low l evels of PAI-2 correlated with shorter disease-free survival in the ov erall population (P = 0.02), post-menopausal women (P = 0.02) and wome n without lymph node involvement (P = 0.02). Multivariate analysis usi ng the ''Main Effects'' Cox model identified node involvement, macrosc opic tumor size and PAI-2 as significant variables. The ''interactive' ' Cox model, taking into account interactions between uPA and its two inhibitors, identified a first subgroup with a very poor prognosis ass ociating either high levels of PAI-1 with low-levels of PAI-2 in the o verall population as well as following stratification for axillary nod e negative disease, or high levels of uPA with low levels of PAI-2 in the group of menopausal women. We conclude that PAI-I provides the sam e prognostic informations as uPA, and does not appear to play its role as an inhibitor. In contrast, PAI-2 increased the prognostic value of both uPA, particularly in post-menopausal women, as well as PAI-1 in a subgroup of axillary node negative patients.