The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer.
A variety of serine proteases, including urokinase-type plasminogen activator (uPA), plasmin,and polymorphonuclear leukocyte elastase (PMN-E), have been implicated in the processes of tumor cell invasion and metastasis. Besides degrading of matrix proteins, PMN-E has been shown to be able to cleave and inactivate plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of uPA, and alpha2-antiplasmin, the natural inhibitor of plasmin, thus enabling an uncontrolled matrix degradation by the fibrinolytic enzymes. Because only limited data are available on a relationship between the tumor level of PMN-E and prognosis in primary breast cancer patients, in the present study we have measured with an ELISA the levels of PMN-E (in complex with alpha1-proteinase inhibitor) in cytosolic extracts of 1143 primary breast tumors. Levels of complexed PMN-E have been correlated with the lengths of metastasis-free survival (MFS), relapse-free survival, and overall survival, and a comparison was made with data previously obtained for uPA and PAI-1. Our results show that patients with a high PMN-E level in their primary tumor had a rapid relapse and an early death compared with patients with a low tumor level of PMN-E. This held true for node-negative and node-positive subgroups of patients as well. The relationship of PMN-E with a poor prognosis was especially obvious during short-term follow-up (0-60 months). In Cox multivariate regression analysis, corrected for the traditional prognostic factors, PMN-E was an independent prognostic factor, and high levels of PMN-E were associated with a poor MFS [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.23-2.16; P < 0.001], relapse-free survival (HR, 1.45; 95% CI, 1.10-1.89; P = 0.01), and overall survival (HR, 1.64; 95% CI, 1.20-2.23; P = 0.003). Furthermore, in all three multivariate models, PMN-E still added significantly to the model after the additional inclusion of the uPA. PMN-E was an independent prognostic factor for MFS even in the multivariate analysis including the traditional clinical prognostic factors and the strong established biochemical prognostic factors uPA and PAI-1. Our present study suggests that PMN-E is associated with breast cancer metastasis, and knowledge of the tumor PMN-E status might be helpful in selecting the appropriate individualized (adjuvant) treatment for patients with breast cancer.
Foekens
John A
JA
Erasmus MC-Daniel den Hoed, Department of Medical Oncology, 3000 DR Rotterdam, The Netherlands. Foekens@bidh.azr.nl
Ries
Christian
C
Look
Maxime P
MP
Gippner-Steppert
Cornelia
C
Klijn
Jan G M
JG
Jochum
Marianne
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015996:Survival Rate; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D019272:Leukocyte Elastase; D014568:Urokinase-Type Plasminogen Activator