Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients.
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.
Look
Maxime P
MP
Department of Medical Oncology, University Hospital Rotterdam, The Netherlands. look@bidh.azr.nl
van Putten
Wim L J
WL
Duffy
Michael J
MJ
Harbeck
Nadia
N
Christensen
Ib Jarle
IJ
Thomssen
Christoph
C
Kates
Ronald
R
Spyratos
Frédérique
F
Fernö
Mårten
M
Eppenberger-Castori
Serenella
S
Sweep
C G J Fred
CG
Ulm
Kurt
K
Peyrat
Jean-Philippe
JP
Martin
Pierre-Marie
PM
Magdelenat
Henri
H
Brünner
Nils
N
Duggan
Catherine
C
Lisboa
Björn W
BW
Bendahl
Pär-Ola
PO
Quillien
Véronique
V
Daver
Alain
A
Ricolleau
Gabriel
G
Meijer-van Gelder
Marion E
ME
Manders
Peggy
P
Fiets
W Edward
WE
Blankenstein
Marinus A
MA
Broët
Philippe
P
Romain
Sylvie
S
Daxenbichler
Günter
G
Windbichler
Gudrun
G
Cufer
Tanja
T
Borstnar
Simona
S
Kueng
Willy
W
Beex
Louk V A M
LV
Klijn
Jan G M
JG
O'Higgins
Niall
N
Eppenberger
Urs
U
Jänicke
Fritz
F
Schmitt
Manfred
M
Foekens
John A
JA
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*
D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator