title: Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients.
abstract: BACKGROUND
  Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG).
  
  
  METHODS
  The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided.
  
  
  RESULTS
  Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001).
  
  
  CONCLUSIONS
  This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies.
authors.affiliation: Department of Medical Oncology, University Hospital Rotterdam, The Netherlands. look@bidh.azr.nl
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: Wim L J
authors.initials: WL
authors.lastname: van Putten
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Ib Jarle
authors.initials: IJ
authors.lastname: Christensen
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomssen
authors.forename: Ronald
authors.initials: R
authors.lastname: Kates
authors.forename: Frédérique
authors.initials: F
authors.lastname: Spyratos
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.forename: Serenella
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.forename: C G J Fred
authors.initials: CG
authors.lastname: Sweep
authors.forename: Kurt
authors.initials: K
authors.lastname: Ulm
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Peyrat
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Martin
authors.forename: Henri
authors.initials: H
authors.lastname: Magdelenat
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Catherine
authors.initials: C
authors.lastname: Duggan
authors.forename: Björn W
authors.initials: BW
authors.lastname: Lisboa
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.forename: Véronique
authors.initials: V
authors.lastname: Quillien
authors.forename: Alain
authors.initials: A
authors.lastname: Daver
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ricolleau
authors.forename: Marion E
authors.initials: ME
authors.lastname: Meijer-van Gelder
authors.forename: Peggy
authors.initials: P
authors.lastname: Manders
authors.forename: W Edward
authors.initials: WE
authors.lastname: Fiets
authors.forename: Marinus A
authors.initials: MA
authors.lastname: Blankenstein
authors.forename: Philippe
authors.initials: P
authors.lastname: Broët
authors.forename: Sylvie
authors.initials: S
authors.lastname: Romain
authors.forename: Günter
authors.initials: G
authors.lastname: Daxenbichler
authors.forename: Gudrun
authors.initials: G
authors.lastname: Windbichler
authors.forename: Tanja
authors.initials: T
authors.lastname: Cufer
authors.forename: Simona
authors.initials: S
authors.lastname: Borstnar
authors.forename: Willy
authors.initials: W
authors.lastname: Kueng
authors.forename: Louk V A M
authors.initials: LV
authors.lastname: Beex
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Niall
authors.initials: N
authors.lastname: O'Higgins
authors.forename: Urs
authors.initials: U
authors.lastname: Eppenberger
authors.forename: Fritz
authors.initials: F
authors.lastname: Jänicke
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator