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

Alexandra K Walker,Kevin A Myers,Ananya Choudhury,Emma Hall,Selina Bhattarai,Helen Valentine,Michael D Brown,Gopa Iyer,Robert Huddart,Noel W Clarke,Shaun Mcgill,Anne E Kiltie,Nicholas D James,Nayneeta Deshmukh,Lisa Browning,Vijay Ramani,Helen Denley,Lingjian Yang,Katalin Karászi ,Catharine M L West ,Sharon Love ,Peter Hoskin ,Wen Kong ,Victoria Y Strauss ,Mark Teo

doi:10.1016/j.ijrobp.2019.03.015

Abstract

PurposeOrgan-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 MaterialsSamples 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.ResultsDespite 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.ConclusionsManual 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.

Highlights

Nonmetastatic muscle-invasive bladder cancer (MIBC) can be treated with curative intent by either cystectomy or bladder preservation techniques, including radiation therapy (RT) alone or with a radiosensitizing agent if tolerated[1,2]; neoadjuvant cisplatin-based chemotherapy is often used for suitable patients
We previously showed using immunohistochemistry (IHC) on pretreatment transurethral resection of bladder tumor (TURBT) specimens that high levels of MRE11, a DNA-damage signaling protein, predicted outcome after radical RT for MIBC in 2 independent cohorts, but not after cystectomy.[7]
The MRE11 assay was developed in Oxford

Summary

Introduction

Nonmetastatic muscle-invasive bladder cancer (MIBC) can be treated with curative intent by either cystectomy or bladder preservation techniques, including radiation therapy (RT) alone or with a radiosensitizing agent if tolerated[1,2]; neoadjuvant cisplatin-based chemotherapy is often used for suitable patients. These approaches have a 40% to 60% causespecific survival (CSS) rate at 3 years.[3,4] With no randomized data available, treatment is currently based on patient choice after discussion with a urologist, oncologist, and nurse specialist.[5] To date there are no validated biomarkers to predict the likely patient benefit from either approach.[6]. Our results were subsequently independently validated in a Danish/German study.[8]

Objectives

Methods

Results