A hypoxia transcriptomic signature to predict benefit from hypoxia-modifying treatment for muscle-invasive bladder cancer patients.

301 Background: Hypoxia modification improves overall survival (OS) in muscle invasive bladder cancer (MIBC) patients treated with radical radiotherapy. There is evidence that hypoxic tumours benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in MIBC. Methods: Bladder cancer transcriptomic data were available from public datasets and generated for 152 tumour samples from the BCON phase III trial of radiotherapy (RT) alone or RT with carbogen and nicotinamide (CON) using Affymetrix Human 1.0 Exon ST arrays. Published hypoxia signatures were tested. A novel signature was then derived by identifying candidate hypoxia genes from the literature and evaluating their bladder cancer specificity in the publically available datasets. A gene co-expression network was built and hub genes identified to generate a signature. Results: None of the published hypoxia signatures were prognostic in public datasets or predicted benefit from hypoxia modification in the BCON patients. A novel 24-gene signature was derived and its prognostic significance was validated in 7 surgical cohorts. The signature was then independently validated in BCON patients. Patients categorised as high- versus low-hypoxia by the signature had a poor local progression free survival (LPFS) following radiotherapy alone (HR 2.37, 95% CI 1.26-4.47, P= 0.0076). The signature also predicted benefit from CON with high-hypoxia patients receiving CON having a better LPFS than those receiving radiotherapy alone (HR 0.47, 95% CI 0.26-0.86, P= 0.0147). Prognostic and predictive significance remained after adjusting for clinicopathological variables (including gender, necrosis, age, stage and carcinoma in situ). Conclusions: A 24-gene hypoxia signature has strong, independent prognostic and predictive value with the potential for stratifying patients with MIBC for treatment with hypoxia-modification strategies.