title: Long-term follow-up confirms prognostic impact of PAI-1 and cathepsin D and L in primary breast cancer.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Technical University, Munich. nadia.harbeck@lrz.tum.de
authors.forename: N
authors.initials: N
authors.lastname: Harbeck
authors.forename: U
authors.initials: U
authors.lastname: Alt
authors.forename: U
authors.initials: U
authors.lastname: Berger
authors.forename: R
authors.initials: R
authors.lastname: Kates
authors.forename: A
authors.initials: A
authors.lastname: Krüger
authors.forename: C
authors.initials: C
authors.lastname: Thomssen
authors.forename: F
authors.initials: F
authors.lastname: Jänicke
authors.forename: H
authors.initials: H
authors.lastname: Graeff
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D002401:Cathepsin B / Q000032:analysis; D002402:Cathepsin D / Q000032:analysis*; D056668:Cathepsin L; D002403:Cathepsins / Q000032:analysis*; D003546:Cysteine Endopeptidases; D018572:Disease-Free Survival; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis*; D011379:Prognosis; D012008:Recurrence; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; D002402:Cathepsin D