MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer

Alexandra K. Walker, Katalin Karaszi, Helen Valentine, Victoria Y. Strauss, Ananya Choudhury, Shaun McGill, Kaisheng Wen, Michael D. Brown, Vijay Ramani, Selina Bhattarai, Mark T.W. Teo, Lingjian Yang, Kevin A. Myers, Nayneeta Deshmukh, Helen Denley, Lisa Browning, Sharon B. Love, Gopa Iyer, Noel W. Clarke, Emma HallRobert Huddart, Nicholas D. James, Peter J. Hoskin, Catharine M.L. West, Anne E. Kiltie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Purpose: Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. 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 after radiation therapy, 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 2 major clinical trials. Methods and Materials: Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom. Results: Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival. Conclusions: 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 or a reassessment of how DNA-damage response relates to clinical outcomes.

Original languageEnglish
Pages (from-to)809-818
Number of pages10
JournalInternational Journal of Radiation Oncology Biology Physics
Volume104
Issue number4
Early online date15 Mar 2019
DOIs
Publication statusPublished - 15 Jul 2019

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