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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.

Fig.3

Kaplan–Meier plots for BCON patients stratified as either (A) high-hypoxia or (B) low-hypoxia by the 24-gene signature. In each group, patients received either RT or RT plus CON. Patients with persistent muscle-invasive disease or with no cystoscopy after treatment had their time set to zero.​ 

Author information

Yang L1, Taylor J1,2,3, Eustace A1, Irlam JJ1, Denley H4, Hoskin PJ5, Alsner J6, Buffa FM7, Harris AL7, Choudhury A1, West CML8.​

1 Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.

2 Applied Computational Biology and Bioinformatics Group, CRUK-MI, Manchester, United Kingdom.

3 HMDS, Leeds Cancer Centre, St James University Hospital, Leeds, United Kingdom.

4 Department of Cellular Pathology, Manchester Royal Infirmary, Manchester, United Kingdom.

5 Cancer Centre, Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex, United Kingdom.

6 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

7 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

8 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.