Background: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. Objective: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. Design, setting, and participants: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. Outcome measurements and statistical analysis: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. Results and limitations: The progression score was significantly (p <0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p <0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p <0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R 2 =0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). Conclusions: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. Patient summary: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens. In a large prospective European study of non-muscle-invasive bladder cancer we successfully validated a 12-gene real-time qualitative polymerase chain reaction test for disease aggressiveness. The test showed independent prognostic power beyond established risk factors, and may help in stratifying patients to optimal treatment and follow-up regimens.

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Keywords Bladder cancer, Non-muscle-invasive bladder cancer, Prognostic biomarker, Progression risk, Prospective study, Real-time qualitative polymerase chain reaction, Validation
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Journal European Urology : Official Journal of the European Association of Urology
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/201663 - Prediction of bladder cancer disease course using risk scores that combine molecular and clinical risk factors (UROMOL)
Dyrskjot, L, Reinert, T, Algaba, F, Christensen, E. (Emil), Nieboer, D, Hermann, G.G. (Gregers G.), … Orntoft, T.F. (2017). Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study. European Urology : Official Journal of the European Association of Urology. doi:10.1016/j.eururo.2017.05.040