title: ErbB2 and NFκB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer.
abstract: Radical cystectomy for muscle-invasive bladder cancer (MIBC) patients frequently impairs their quality of life (QOL) due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR) to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS) were investigated. Of the 35 patients, 11 (31%) achieved pathological CR, while tumors in the remaining 24 patients (69%) were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014), 15.4 (P = 0.024) and 14.3 (P = 0.038). The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001). The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056) along with chemoradiation resistance (P = 0.003) and hydronephrosis (P = 0.018). The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018). Thus, erbB2 and NFκB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC.
authors.affiliation: Department of Urology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan. f-koga.uro@tmd.ac.jp
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Koga
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yoshida
authors.forename: Manabu
authors.initials: M
authors.lastname: Tatokoro
authors.forename: Satoru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujii
authors.forename: Jiro
authors.initials: J
authors.lastname: Kumagai
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kihara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000378:metabolism* / Q000628:therapy; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011836:Radiation Tolerance; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000628:therapy
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002945:Cisplatin; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C107489:BIRC5 protein, human; C495901:TP53 protein, human; C508053:ERBB2 protein, human
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