title: Immunohistochemistry to enhance prognostic allocation and guide decision-making of patients with advanced urothelial cancer receiving first-line chemotherapy.
abstract: BACKGROUND
  Knowledge of the expression of molecular drivers and potentially druggable targets might enhance prognostic classification of M UC.
  
  
  METHODS
  We analyzed archival tissue from patients with UC who underwent first-line chemotherapy for locally advanced (LA) and M disease between the years 2000 and 2013. The following biomarkers were evaluated using IHC: excision repair cross complementation (ERCC) group 1 (ERCC1), epidermal growth factor receptor (EGFR), HER2, VEGFR-3, PDGFRα, p53, and p63. Expression of ERCC1, EGFR, and HER2 was dichotomized as positive (2+, 3+) or negative (≤ 1+). Cox regression models were used to evaluate the association of biomarker expression with progression-free (PFS) and overall survival (OS), after controlling for known prognostic factors.
  
  
  RESULTS
  Since June of 2009, tissues of 88 cases (27 LA, 61 M) were stained. Rates of positive IHC/number evaluable were as follows: ERCC1: 30 of 66 (45%); HER2: 24 of 52 (46%); EGFR: 31 of 54 (57%); VEGFR-3: 50 of 66 (76%); PDGFRα: 10 of 63 (16%); p53: 25 of 56 (45%); and p63: 46 of 53 (87%). In the multivariable model, PDGFRα was significantly prognostic for poorer PFS (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.01-6.37; P = .047) and trended to significance for poorer OS (HR, 2.66; 95% CI, 0.96-7.42; P = .060) and VEGFR-3 was significantly prognostic for better PFS (HR, 0.33; 95% CI, 0.15-0.74; P = .007) and OS (HR, 0.36; 95% CI, 0.15-0.85; P = .019). The c-index of the model was 0.67 and 0.68 for the 2 end points, respectively.
  
  
  CONCLUSIONS
  Tumor VEGFR-3 and PDGFRα expression appeared to confer a divergent prognostic effect. These data underscore the hurdles in defining the role of angiogenesis as a molecular driver and therapeutic target, and the controversial role of IHC to guide therapeutic decision-making.
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: andrea.necchi@istitutotumori.mi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Necchi
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannatempo
authors.affiliation: Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: Paolini
authors.affiliation: Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lo Vullo
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Marongiu
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Farè
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Raggi
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Nicolai
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Piva
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Catanzaro
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Biasoni
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Torelli
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stagni
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Maffezzini
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: De Braud
authors.affiliation: Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.affiliation: UAB Comprehensive Cancer Center, Birmingham, AL.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
authors.affiliation: Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Colecchia
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvioni
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C581309:FLT4 protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Advanced disease; Chemotherapy; Immunohistochemistry; Transitional cell carcinoma; Urothelial cancer