title: PAI-1 and HER2 interaction in advanced breast cancer disease: evidence for added benefit from trastuzumab in HER2-negative patients.
abstract: OBJECTIVE
  The urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor 1 (PAI-1) are associated with an aggressive course in breast cancer and are used to determine whether chemotherapy is needed in node-negative patients. The objective of the study was to evaluate the prognostic value of uPA and PAI-1 protein expression in advanced breast cancer patients treated with trastuzumab.
  
  
  METHODS
  Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 230 patients with advanced breast cancer treated with trastuzumab and 130 patients treated with 1st line taxanes. uPA, PAI-1, ER, PgR, HER2 and Ki67 protein expression was evaluated by immunohistochemistry.
  
  
  RESULTS
  Central review of HER2 status revealed that only 144 (63 %) of the trastuzumab-treated patients were truly HER2-positive. Median survival was 50.7 months for the HER2-positive and 30.1 months for the HER2-negative patients (p = 0.006) treated with trastuzumab. In multivariate Cox regression analysis of the trastuzumab cohort, a significant interaction was found, in terms of survival, between HER2 status and PAI-1 protein expression in the stroma (Wald's p = 0.002). Positive PAI-1 protein expression in the stroma of HER2-negative patients was associated with lower risk of death (HR 0.35, 95 % CI 0.19-0.65, Wald's p = 0.0008). Such an association was not observed in HER2-positive patients treated with trastuzumab or in the non-trastuzumab (validation) cohorts.
  
  
  CONCLUSIONS
  Our results suggest that positive stromal PAI-1 protein expression may identify a subgroup of HER2-negative advanced breast cancer patients who might benefit from treatment with trastuzumab. Further studies are warranted to validate these findings in larger cohorts.
authors.affiliation: Hematology Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, Rimini 1, Haidari, 124 62, Athens, Greece, akoumari@yahoo.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Koumarianou
authors.forename: Georgia
authors.initials: G
authors.lastname: Karayannopoulou
authors.forename: Georgia
authors.initials: G
authors.lastname: Gourgioti
authors.forename: Anna
authors.initials: A
authors.lastname: Batistatou
authors.forename: Mattheos
authors.initials: M
authors.lastname: Bobos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Efstratiou
authors.forename: Dimosthenis
authors.initials: D
authors.lastname: Miliaras
authors.forename: Eleni
authors.initials: E
authors.lastname: Galani
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Aravantinos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.forename: Pavlos
authors.initials: P
authors.lastname: Papakostas
authors.forename: Evangelia
authors.initials: E
authors.lastname: Razis
authors.forename: Haralabos P
authors.initials: HP
authors.lastname: Kalofonos
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Petraki
authors.forename: Maria
authors.initials: M
authors.lastname: Sotiropoulou
authors.forename: Konstantine T
authors.initials: KT
authors.lastname: Kalogeras
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D017395:Plasminogen Activator Inhibitor 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C051321:SERPINE1 protein, human; C508053:ERBB2 protein, human