title: Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group.
abstract: OBJECTIVE
  Erb-1 (epidermal growth factor receptor, EGFR) and Erb-2 (Her-2) are two of the best characterized members in the EGFR pathway. In many tumor types, overexpression of these proteins is associated with enhanced malignant potential. Our objective in this study was to investigate the clinical relevance of EGFR and Her-2 expression in bladder cancer cases from four prospective Radiation Therapy Oncology Group (RTOG) bladder preservation trials using cisplatin-containing chemoradiation (RTOG 8802, 8903, 9506, and 9706).
  
  
  METHODS
  Tumors from 73 cases from patients with muscle-invading T2-T4a bladder cancers had slides interpretable for EGFR staining; 55 cases had slides interpretable for Her-2 staining. Additionally, the respective prognostic values of p53, pRB, and p16 immunostaining were concomitantly examined. Staining and interpretation of staining were done in a blinded manner, without knowledge of clinical outcome. Staining was judged as positive or negative. Subsequently, staining was correlated with clinical outcome.
  
  
  RESULTS
  On univariate analysis, EGFR positivity was significantly associated with improved overall survival (p = 0.044); disease-specific survival (DSS) (p = 0.042); and DSS with intact bladder (p = 0.021). There was also a trend for association between EGFR expression and reduced frequency of distant metastasis (p = 0.06). On multivariate analysis adding tumor stage, tumor grade, whether a visibly complete transurethral resection of bladder tumor (TURBT) was done or not, and patient age to the model, EGFR positivity was significantly associated with improved DSS. On univariate analysis, Her-2 positivity was significantly associated with reduced complete response (CR) rates (50% vs. 81%, p = 0.026) after chemoradiation which remained significant on multivariate analysis. The other markers examined in this study were not found to have any prognostic value in this setting.
  
  
  CONCLUSIONS
  Epidermal growth factor receptor expression appears to correlate significantly with improved outcome in bladder cancer, whereas Her-2 expression is significantly associated only with reduced CR rates after chemoradiation. Further investigations are warranted into how EGFR family members regulate response to chemoradiation in bladder cancer and their potential therapeutic implications.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. achakravarti@partners.org
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Kathryn
authors.initials: K
authors.lastname: Winter
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.forename: Donald
authors.initials: D
authors.lastname: Kaufman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hammond
authors.forename: Matthew
authors.initials: M
authors.lastname: Parliament
authors.forename: William
authors.initials: W
authors.lastname: Tester
authors.forename: Michael
authors.initials: M
authors.lastname: Hagan
authors.forename: David
authors.initials: D
authors.lastname: Grignon
authors.forename: Niall
authors.initials: N
authors.lastname: Heney
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
authors.forename: Howard
authors.initials: H
authors.lastname: Sandler
authors.forename: William
authors.initials: W
authors.lastname: Shipley
mesh_terms: D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53