Long-Term Follow-Up Confirms Prognostic Impact of Pai-1 and Cathepsin D and L in Primary Breast Cancer

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Abstract
After long-term follow-up, the prognostic impact of the following proteolytic factors associated with tumor invasion and metastasis was evaluated in 276 primary breast cancer patients: uPA (urokinase-type plasminogen activator), PAI-1 (uPA inhibitor type 1), and cathepsins B, D and L. The median follow-up of patients still alive at the time of analysis was 109 months. To date 119 patients (43%) have relapsed and 117 (42%) have died. Antigen levels of uPA and PAI-1 were determined by ELISA in detergent extracts; cathepsin B, D, and L content was determined in cytosol fractions of the primary tumor: cathepsin D by ELSA and cathepsin B and L by ELISA. In multivariate analysis (Cox model) for disease-free survival (DFS), lymph node status (p<0.001; RR=3.8), cathepsin L (p<0.001; RR=2.6) and PAI-1 (p=0.027; RR=1.7) were significant factors in all patients. In addition to these factors, grading was significant for overall survival (OS). In another multivariate approach, CART (Classification And Regression Trees) analysis, lymph node status (p<0.001) turned out to be the strongest discriminator for patients at high risk of relapse. In the node-negative patient subset, PAI-1 was the strongest risk group discriminator (p<0.001): in this subset, patients with low levels of both PAI-1 and cathepsin D had a very low relapse rate of only 3.2% compared to 39% in the remaining node-negative patients. In node-positive patients cathepsin L gave the best risk group assessment (p=0.001). In conclusion, tumor-associated PAI-1 and cathepsins D and L provide significant, statistically independent prognostic information for DFS and OS in primary breast cancer, even after a median follow-up period of almost 10 years.