title: A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High-Risk Bladder Cancer Patients.
abstract: Purpose:Hypoxia modification improves overall survival in muscle-invasive bladder cancer patients who undergo radiotherapy. There is evidence that hypoxic tumors benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer.Experimental Design:Published hypoxia signatures were tested and a new one derived by analyzing bladder cancer transcriptomic data from public databases. Tumor samples were available from the BCON phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Gene expression data were generated for 151 tumors using Affymetrix Human 1.0 Exon ST arrays and used for independent validation.Results:A 24-gene signature was derived, which was prognostic in four of six independent surgical cohorts (n= 679; meta HR, 2.32; 95% CI, 1.73-3.12;P< 0.0001). The signature was also prognostic in BCON patients receiving radiotherapy alone (n= 75; HR for local relapse-free survival, 2.37; 95% CI, 1.26-4.47;P= 0.0076). The signature predicted benefit from CON (n= 76; HR, 0.47; 95% CI, 0.26-0.86;P= 0.015). Prognostic significance (P= 0.017) and predictive significance (P= 0.058) remained after adjusting for clinicopathologic variables. A test for interaction between hypoxia status and treatment arms was significant (P= 0.0094).Conclusions:A 24-gene hypoxia signature has strong and independent prognostic and predictive value for muscle-invasive bladder cancer patients. The signature can aid identification of patients likely to benefit from the addition of carbogen and nicotinamide to radiotherapy.Clin Cancer Res; 23(16); 4761-8. ©2017 AACR.
authors.affiliation: Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.
authors.forename: Lingjian
authors.initials: L
authors.lastname: Yang
authors.affiliation: Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.|Applied Computational Biology and Bioinformatics Group, CRUK-MI, Manchester, United Kingdom.|HMDS, Leeds Cancer Centre, St James University Hospital, Leeds, United Kingdom.
authors.forename: Janet
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Eustace
authors.affiliation: Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.
authors.forename: Joely J
authors.initials: JJ
authors.lastname: Irlam
authors.affiliation: Department of Cellular Pathology, Manchester Royal Infirmary, Manchester, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Denley
authors.affiliation: Cancer Centre, Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hoskin
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Alsner
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.
authors.forename: Ananya
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom. catharine.west@manchester.ac.uk.
authors.forename: Catharine M L
authors.initials: CML
authors.lastname: West
mesh_terms: D000368:Aged; D002245:Carbon Dioxide / Q000008:administration & dosage; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D000860:Hypoxia; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage; D010100:Oxygen / Q000008:administration & dosage; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000532:radiotherapy*
chemical_list: D002245:Carbon Dioxide; D009536:Niacinamide; C011700:carbogen; D010100:Oxygen