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 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

doi:10.1016/j.ijrobp.2019.03.015

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 Tw 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 Ml West, Anne E Kiltie

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

PURPOSE: 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.

METHODS AND MATERIALS: 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.

RESULTS: 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.

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 and/or a reassessment of how DNA-damage response relates to clinical outcomes.

Original language	English
Pages (from-to)	809-818
Journal	International journal of radiation oncology, biology, physics
Volume	104
Issue number	4
Early online date	15 Mar 2019
DOIs	https://doi.org/10.1016/j.ijrobp.2019.03.015
Publication status	Published - 15 Mar 2019

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Manchester Cancer Research Centre

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Walker, A. K., Karaszi, K., Valentine, H., Strauss, V. Y., Choudhury, A., McGill, S., Wen, K., Brown, M. D., Ramani, V., Bhattarai, S., Teo, M. T., Yang, L., Myers, K. A., Deshmukh, N., Denley, H., Browning, L., Love, S. B., Iyer, G., Clarke, N. W., ... Kiltie, A. E. (2019). MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer. International journal of radiation oncology, biology, physics, 104(4), 809-818. https://doi.org/10.1016/j.ijrobp.2019.03.015

@article{7385846c498644cfb8e00a4021a0cc1c,

title = "MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer",

abstract = "PURPOSE: 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.METHODS AND MATERIALS: 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.RESULTS: 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.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 and/or a reassessment of how DNA-damage response relates to clinical outcomes.",

author = "Walker, {Alexandra K} and Katalin Karaszi and Helen Valentine and Strauss, {Victoria Y} and Ananya Choudhury and Shaun McGill and Kaisheng Wen and Brown, {Michael D} and Vijay Ramani and Selina Bhattarai and Teo, {Mark Tw} and Lingjian Yang and Myers, {Kevin A} and Nayneeta Deshmukh and Helen Denley and Lisa Browning and Love, {Sharon B} and Gopa Iyer and Clarke, {Noel W} and Emma Hall and Robert Huddart and James, {Nicholas D} and Hoskin, {Peter J} and West, {Catharine Ml} and Kiltie, {Anne E}",

year = "2019",

month = mar,

day = "15",

doi = "10.1016/j.ijrobp.2019.03.015",

language = "English",

volume = "104",

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Walker, AK, Karaszi, K, Valentine, H, Strauss, VY, Choudhury, A, McGill, S, Wen, K, Brown, MD, Ramani, V, Bhattarai, S, Teo, MT, Yang, L, Myers, KA, Deshmukh, N, Denley, H, Browning, L, Love, SB, Iyer, G, Clarke, NW, Hall, E, Huddart, R, James, ND, Hoskin, PJ , West, CM & Kiltie, AE 2019, 'MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer', International journal of radiation oncology, biology, physics, vol. 104, no. 4, pp. 809-818. https://doi.org/10.1016/j.ijrobp.2019.03.015

TY - JOUR

T1 - MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer

AU - Walker, Alexandra K

AU - Karaszi, Katalin

AU - Valentine, Helen

AU - Strauss, Victoria Y

AU - Choudhury, Ananya

AU - McGill, Shaun

AU - Wen, Kaisheng

AU - Brown, Michael D

AU - Ramani, Vijay

AU - Bhattarai, Selina

AU - Teo, Mark Tw

AU - Yang, Lingjian

AU - Myers, Kevin A

AU - Deshmukh, Nayneeta

AU - Denley, Helen

AU - Browning, Lisa

AU - Love, Sharon B

AU - Iyer, Gopa

AU - Clarke, Noel W

AU - Hall, Emma

AU - Huddart, Robert

AU - James, Nicholas D

AU - Hoskin, Peter J

AU - West, Catharine Ml

AU - Kiltie, Anne E

PY - 2019/3/15

Y1 - 2019/3/15

N2 - PURPOSE: 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.METHODS AND MATERIALS: 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.RESULTS: 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.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 and/or a reassessment of how DNA-damage response relates to clinical outcomes.

AB - PURPOSE: 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.METHODS AND MATERIALS: 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.RESULTS: 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.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 and/or a reassessment of how DNA-damage response relates to clinical outcomes.

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U2 - 10.1016/j.ijrobp.2019.03.015

DO - 10.1016/j.ijrobp.2019.03.015

M3 - Article

C2 - 30885775

VL - 104

SP - 809

EP - 818

JO - International Journal of Radiation: Oncology - Biology - Physics

JF - International Journal of Radiation: Oncology - Biology - Physics

SN - 0360-3016

IS - 4

ER -

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

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