title: Potential of molecular targeted therapy of HER-2 and Cox-2 for invasive transitional cell carcinoma of the urinary bladder.
abstract: Expression of HER-2 and COX-2 was determined to assess the potential of molecular-targeted therapy against human epidermal growth factor receptor-2 (HER-2) and cyclooxygenase-2 (COX-2) for the treatment of invasive bladder cancer. The subjects were 46 patients who attended Aichi Medical University Hospital between January 2001 and August 2008, underwent total cystectomy with a diagnosis of M0 bladder cancer, and received a pathological diagnosis of invasive transitional cell carcinoma of the urinary bladder (pT2-pT4). Expression of HER-2 and COX-2 was determined by immunohistochemical staining, and the results were interpreted by two pathologists by classifying HER-2 expression into four grades, and considering COX-2 positive when 10% or more of the tumor cells were stained. In HER-2 immunostaining, 10 subjects (21.7%) were positive, all of whom had a Grade 3 tumor. Staging classification identified 2 subjects (2/22, 9.1%) with pT2 stage, 3 (3/16, 18.8%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was a correlation between HER-2 positivity and tumor stage (P=0.007). Lymph node metastasis was detected in 13 subjects, 3 of them (3/8, 37.5%) with pN2 metastasis were HER-2 positive. The 5-year cause-specific survival rate was 51.4% for HER-2-positive subjects and 83.4% for HER-2-negative subjects. The outcome was poorer in HER-2-positive subjects, but the difference in survival rate was not statistically significant (P=0.218). In COX-2 immunostaining, 27 subjects (58.7%) were found to be positive. Three (3/4, 75.0%) showed a Grade 2 tumor and 24 (24/42, 57.1%) a Grade 3 tumor. Staging classification identified 13 subjects (13/22, 59.1%) with pT2 stage, 9 (9/16, 56.3%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was no correlation between COX-2 positivity and tumor grade or stage (P=0.488 and 0.089, respectively). Classification by the extent of lymph node metastasis revealed that 6 subjects (6/8, 75.0%) with pN2 were COX-2 positive. There was a correlation between COX-2 positivity and the extent (pN1 or pN2) of lymph node metastasis (P=0.008). The 5-year cause-specific survival rate was 84.0% for COX-2-positive subjects and 71.7% for COX-2-negative subjects. However, the difference in survival rate was not significant (P=0.407). Seven subjects (7/46, 15.2%) were positive for both HER-2 and COX-2, and there was no statistically significant correlation between the status of HER-2 expression and that of COX-2 expression (P=0.2195). The present study failed to show any association between HER-2 or COX-2 positivity and outcome in subjects with invasive bladder cancer. However, HER-2-positive subjects tended to have a poorer outcome. This finding suggests that molecular-targeted therapy against HER-2 could be an effective therapy. Further studies involving a larger number of subjects are required.
authors.affiliation: Department of Urology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Naruse
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kogenta
authors.initials: K
authors.lastname: Nakamura
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Aoki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Taki
authors.forename: Kenji
authors.initials: K
authors.lastname: Zennami
authors.forename: Remi
authors.initials: R
authors.lastname: Katsuda
authors.forename: Masahito
authors.initials: M
authors.lastname: Watanabe
authors.forename: Genya
authors.initials: G
authors.lastname: Nishikawa
authors.forename: Youko
authors.initials: Y
authors.lastname: Itoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Mitsui
authors.forename: Hatsuki
authors.initials: H
authors.lastname: Hibi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Honda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015996:Survival Rate; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor; D051546:Cyclooxygenase 2; D018719:Erb-b2 Receptor Tyrosine Kinases; C496540:PTGS2 protein, human