Plasminogen activator inhibitor-1 and prognosis in primary breast cancer.
OBJECTIVE
Evaluation of the relationship between plasminogen activator inhibitor-1 (PAI-1) and the metastatic potential of primary breast cancer, and to compare the prognostic impact of PAI-1 in multivariate analysis with those of conventional prognostic factors, including steroid-hormone receptors, and those of urokinase plasminogen activator (uPA), pS2-protein (PS2), and cathepsin D.


METHODS
Cell biologic prognostic factors were analyzed in 657 cytosols routinely prepared from frozen-tissue biopsies that were submitted to our laboratory for the assessment of steroid-hormone receptor status. The median duration of follow-up in patients still alive at the time of analysis was 48 months. Estrogen receptor (ER) and progesterone receptor (PgR) status were assessed by radioligand binding assay, PS2, and cathepsin D by radiometric immunoassay, and uPA and PAI-1 by enzyme-linked immunosorbent assay (ELISA).


RESULTS
PAI-1 levels were found to be strongly positively correlated with the rates of relapse (P < .0001) and death (P < .001). Relating the levels of PAI-1 with those of other cytosolic prognostic factors, we found a positive association with the metastasis-related proteases uPA (P < .0001) and cathepsin D (P < .0001). On the other hand, PAI-1 levels were found to be negatively correlated with ER (P < .005) and PgR (P < .001), and the estrogen-regulated pS2-protein (P < .001), which are proteins associated with a favorable prognosis. In multivariate regression analysis for 5-year relapse-free survival, and using an optimized cutoff point for discrimination between PAI-1-positive and -negative, independent predictors of the rate of relapse were found to be PAI-1 (P < .0001) and uPA (P = .01) of the cytosolic parameters, and tumor size, lymph node status, and premenopausal age of the clinical parameters. In multivariate analysis in patients with node-negative disease, only PAI-1 (P < .001) and tumor size (P = .03) were positively and premenopausal age negatively (P < .001) associated with the rate of relapse. In patients with node-positive disease, PAI-1 (P < .001), uPA (P = .02), tumor size (P < .001), and the number of positive lymph nodes (P < .001) were all positively associated with the rate of relapse.


CONCLUSIONS
We conclude that the PAI-1 level measured in routinely prepared cytosols is an important parameter to predict the metastatic potential in both node-negative and node-positive human primary breast cancer.
Foekens
J A
JA
Department of Medical Oncology, Dr Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Schmitt
M
M
van Putten
W L
WL
Peters
H A
HA
Kramer
M D
MD
Jänicke
F
F
Klijn
J G
JG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D002402:Cathepsin D / Q000032:analysis; D003600:Cytosol / Q000737:chemistry; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012008:Recurrence; D012016:Reference Values; D016019:Survival Analysis; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
D009363:Neoplasm Proteins; D017395:Plasminogen Activator Inhibitor 1; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014568:Urokinase-Type Plasminogen Activator; D002402:Cathepsin D