Organ-confined muscle-invasive bladder cancer (MIBC) is treated with cystectomy or bladder preservation techniques, including radiotherapy. There are currently no biomarkers to inform management decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome following radiotherapy but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from two major clinical trials.
Samples from the BCON and BC2001 randomised controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in three UK centres.
Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor inter-centre scoring agreement (Kappa 0.32, 95% CI 0.17-0.47). There were no significant associations between MRE11 scores and cause-specific survival (CSS) identified in BCON (n=132) and BC2001 (n=221) samples. Re-optimised staining improved agreement between scores from BCON tissue microarrays (n=116), but MRE11 expression was not prognostic for CSS.
Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods and/or a reassessment of how DNA-damage response relates to clinical outcomes.
International journal of radiation oncology, biology, physics. 2019 Mar 15 [Epub ahead of print]
Alexandra K Walker, Katalin Karaszi, Helen Valentine, Victoria Y Strauss, Ananya Choudhury, Shaun McGill, Kaisheng Wen, Michael D Brown, Vijay Ramani, Selina Bhattarai, Mark Tw Teo, Lingjian Yang, Kevin A Myers, Nayneeta Deshmukh, Helen Denley, Lisa Browning, Sharon B Love, Gopa Iyer, Noel W Clarke, Emma Hall, Robert Huddart, Nicholas D James, Peter J Hoskin, Catharine Ml West, Anne E Kiltie
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK., Translational Radiobiology Group, Division of Cancer Sciences, Christie Hospital NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester M20 4BX, UK., Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Diseases, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK., School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK., Genito Urinary Cancer Research Group, Division of Cancer Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester M20 4GJ, UK., Department of Urology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK., Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK., Leeds Cancer Centre, St James's University Hospital, Leeds LS9 7TF, UK., Experimental Cancer Medicine Centre, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK., Department of Cellular Pathology, Manchester University Foundation Trust, Manchester M13 9WL, UK., Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Oxford, OX3 9DU, UK., Weill Cornell Medical College, Cornell University, New York, NY, USA., Genito Urinary Cancer Research Group, Division of Cancer Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester M20 4GJ, UK; Department of Urology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK., Clinical Trials and Statistics Unit, Institute of Cancer ReseZarch, London SM2 5NG, UK., Academic Uro-Oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, London, SM2 5PT, UK; The Institute of Cancer Research, London, SM2 5NG, UK., Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK; Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK., CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: .