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

MRE11 作为膀胱癌放射治疗后结果的预测生物标志物

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作者: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

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.

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.

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.

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