Lars Dyrskjøt1, Thomas Reinert2, Ferran Algaba3, Emil Christensen2, Daan Nieboer4, Gregers G Hermann5, Karin Mogensen5, Willemien Beukers6, Mirari Marquez7, Ulrika Segersten8, Søren Høyer9, Benedicte P Ulhøi9, Arndt Hartmann10, Robert Stöhr10, Sven Wach11, Roman Nawroth12, Kristina Schwamborn13, Cane Tulic14, Tatjana Simic15, Kerstin Junker16, Niels Harving17, Astrid C Petersen18, Jørgen B Jensen19, Bastian Keck11, Marc-Oliver Grimm20, Marcus Horstmann20, Tobias Maurer12, Ewout W Steyerberg4, Ellen C Zwarthoff6, Francisco X Real21, Núria Malats7, Per-Uno Malmström8, Torben F Ørntoft2. 1. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. Electronic address: lars@clin.au.dk. 2. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. 3. Section of Pathology, Fundació Puigvert, University Autonoma de Barcelona, Barcelona, Spain. 4. Department of Public Health, Erasmus MC, Rotterdam, The Netherlands. 5. Department of Urology, Frederiksberg Hospital, Frederiksberg, Denmark. 6. Department of Pathology, Erasmus MC, Rotterdam, The Netherlands. 7. Spanish National Cancer Research Centre, Madrid, Spain. 8. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. 9. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark. 10. Institute of Pathology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen, Germany. 11. Department of Urology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen, Germany. 12. Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 13. Institute of Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 14. Clinic of Urology, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 15. Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 16. Department of Urology, Saarland University, Homburg, Germany. 17. Department of Urology, Aalborg University Hospital, Aalborg, Denmark. 18. Department of Pathology, Aalborg University Hospital, Aalborg, Denmark. 19. Department of Urology, Aarhus University Hospital, Aarhus, Denmark. 20. Department of Urology, Friedrich-Schiller-University Jena, Jena, Germany. 21. Spanish National Cancer Research Centre, Madrid, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Abstract
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 (R2=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.
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 (R2=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.
Authors: Yu-Cheng Lee; Hung-Ming Lam; Charles Rosser; Dan Theodorescu; William C Parks; Keith Syson Chan Journal: Nat Rev Urol Date: 2022-06-28 Impact factor: 16.430
Authors: Joshua J Meeks; Hikmat Al-Ahmadie; Bishoy M Faltas; John A Taylor; Thomas W Flaig; David J DeGraff; Emil Christensen; Benjamin L Woolbright; David J McConkey; Lars Dyrskjøt Journal: Nat Rev Urol Date: 2020-03-31 Impact factor: 14.432
Authors: Joaquim Bellmunt; Jaegil Kim; Brendan Reardon; Júlia Perera-Bel; Anna Orsola; Alejo Rodriguez-Vida; Stephanie A Wankowicz; Michaela Bowden; Justine A Barletta; Juan Morote; Inés de Torres; Nuria Juanpere; Josep Lloreta-Trull; Silvia Hernandez; Kent W Mouw; Mary-Ellen Taplin; Paloma Cejas; Henry W Long; Eliezer M Van Allen; Gad Getz; David J Kwiatkowski Journal: Cancer Res Date: 2020-08-31 Impact factor: 13.312