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

It is now clearly established that proteolytic enzymes, including plas minogen activator (uPA), play an important role in breaking down the e xtracellular matrix, which is considered to be a step in metastasis fo rmation. Plasminogen activators are controlled at various levels. Two inhibitors, PAI-1 and PAI-2, have been identified, the latter being mo re specific for uPA. In attempts to determine their prognostic value, it is essential to investigate the relative importance of these parame ters and their interactions. We used an immunoenzymatic method to assa y uPA, PAI-I and PAI-2 antigens in cytosols prepared from 314 primary breast tumours. The patients were followed up for a minimum of 6 years and all relevant clinical and laboratory findings were recorded. Univ ariate analysis confirmed the poor outcome of patients whose tumours c ontained large amounts of uPA and PAI-1. In addition, low levels of PA I-2 correlated with shorter disease-free survival in the overall popul ation (P = 0.02), post-menopausal women (P = 0.02) and women without l ymph node involvement (P = 0.02). Multivariate analysis in the 'main e ffects' Cox model identified node involvement, macroscopic tumour size and PAI-2 as significant variables. The 'interactive' model, taking i nto account interactions between uPA and its two inhibitors, identifie d a first subgroup with a very poor prognosis associating either high levels of PAI-I with low levels of PAI-2 in the overall population and the women with no node involvement or high levels of uPA with low lev els of PAI-2 in the group of menopausal women. We conclude that PAI-I provides the same prognostic information as uPA, and does not appear t o play a role as an inhibitor. In contrast, PAI-2 increases the progno stic value of uPA, particularly in post-menopausal women, and PAI-1 in patients with no node involvement.