LOW CATHEPSIN-D AND LOW PLASMINOGEN-ACTIVATOR TYPE-1 INHIBITOR IN TUMOR CYTOSOLS DEFINES A GROUP OF NODE-NEGATIVE BREAST-CANCER PATIENTS WITH LOW-RISK OF RECURRENCE

Prognostic factors are highly needed to divide node negative breast ca ncer patients into groups of low versus high risk of recurrence and de ath. In order to invade and spread, cancer cells must degrade extracel lular matrix proteins. Accordingly, tumor levels of molecules involved in this degradation might be associated with patient outcome. Previou s work has demonstrated that high levels of the aspartyl protease cath epsin D in breast cancer are associated with a poor prognosis and simi lar findings have been reported for molecules involved in the urokinas e pathway of plasminogen activation. Interactions between different pr otease systems have been described and data suggest that several prote olytic enzymes may be operable at the same time in a tumor. In the pre sent study we measured cathepsin D (n = 162), uPA (n = 116), uPAR (n = 109) and PAI-1 (n = 135) in tumor cytosols obtained from a population of node negative breast cancer patients. A significant correlation wa s found between levels of uPA, uPAR, and PAI-1, Levels of cathepsin D were directly related to levels of uPA and uPAR, With a median observa tion time of 4.81 years, univariate survival analyses showed that high levels of uPA and cathepsin D significantly predicted a shorter disea se free survival, while only high levels of cathepsin D were able to s ignificantly predict a shorter overall survival. Tumor levels of uPAR and PAI-1 gave mixed results depending on the cut-off point choosen. I nterestingly, multivariate analysis demonstrated that PAI-1 and cathep sin D were independent significant prognostic indicators for disease-f ree survival while only cathepsin D was helpful in overall survival. T he five year relapse rate of patients with low PAI-1 and low cathepsin D was 13 % while patients who had greater than the median value for b oth of these molecules had a 5 year relapse rate of 40 %. These data w ould indicate that at least two different protease systems are active in spread of node negative breast cancer and that measurement of these molecules may aid in the decisions to be made when offering adjuvant treatment to these patients.