title: Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer.
abstract: Combined determination of urokinase-type plasminogen activator (uPA) and its inhibitor, activator inhibitor type 1 (PAI-1), supports risk-adapted individualized therapy concepts, particularly in node-negative breast cancer. The prognostic impact of both factors in primary breast cancer was substantiated by a pooled analysis of > 8000 patients with breast cancer and a multicenter prospective randomized therapy trial in node-negative breast cancer; findings achieved the highest level of evidence for tumor biomarkers. Patients with node-negative breast cancer with low antigen levels of uPA and PAI-1 in their primary tumor tissue have a very good prognosis and therefore may be spared the burden of adjuvant chemotherapy, whereas those with elevated uPA/PAI-1 antigen levels carry an increased risk of disease recurrence. Recent retrospective analysis of > 3000 patients indicated that patients with breast cancer with high uPA/PAI-1 values derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1 levels. Similarly, in the multicenter prospective Chemo N0 trial, administration of cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy led to a substantial reduction in risk of disease recurrence in patients with high uPA/PAI-1. However, benefit from adjuvant endocrine therapy appears to be independent of a patient's uPA/PAI-1 status. In metastatic breast cancer, retrospective studies showed that elevated uPA or PAI-1 present in the primary tumor tissue are associated with a poor response to later palliative endocrine therapy. These findings suggest that high levels of uPA and/or PAI-1 do reflect an aggressive phenotype that may be overcome or suppressed by early systemic therapy in the adjuvant setting but may be too advanced for response to palliative therapy at a later stage.
authors.affiliation: Department of Obstetrics and Gynecology, Technical University of Munich, Germany. nadia.harbeck@lrz.tum.de
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Roanld E
authors.initials: RE
authors.lastname: Kates
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Katja
authors.initials: K
authors.lastname: Gauger
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Fritz
authors.initials: F
authors.lastname: Janicke
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomassen
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator