title: uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies.
abstract: Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease involved in cancer invasion and metastasis, interacting with plasminogen activator inhibitor-1 (PAI-1), which was originally identified as a blood-derived endogenous fast-acting inhibitor of uPA. At concentrations found in tumor tissue, however, both PAI-1 and uPA promote tumor progression and metastasis. Consistent with the causative role of uPA and PAI-1 in cancer dissemination, several retrospective and prospective studies have shown that elevated levels of uPA and PAI-1 in breast tumor tissue are statistically independent and potent predictors of poor patient outcome, including adverse outcome in the subset of breast cancer patients with lymph node-negative disease. In addition to being prognostic, high levels of uPA and PAI-1 have been shown to predict benefit from adjuvant chemotherapy in patients with early breast cancer. The unique clinical utility of uPA/PAI-1 as prognostic biomarkers in lymph node-negative breast cancer has been confirmed in two independent level-of-evidence-1 studies (that is, in a randomized prospective clinical trial in which the biomarker evaluation was the primary purpose of the trial and in a pooled analysis of individual data from retrospective and prospective studies). Thus, uPA and PAI-1 are among the best validated prognostic biomarkers currently available for lymph node-negative breast cancer, their main utility being the identification of lymph node-negative patients who have HER-2-negative tumors and who can be safely spared the toxicity and costs of adjuvant chemotherapy. Recently, a phase II clinical trial using the low-molecular-weight uPA inhibitor WX-671 reported activity in metastatic breast cancer.
authors: Michael J
authors: MJ
authors: Duffy
authors: Patricia M
authors: PM
authors: McGowan
authors: Nadia
authors: N
authors: Harbeck
authors: Christoph
authors: C
authors: Thomssen
authors: Manfred
authors: M
authors: Schmitt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism*; D011379:Prognosis; D015203:Reproducibility of Results; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator