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 Hall; Robert Huddart; Nicholas D. James; Peter J. Hoskin; Catharine M.L. 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 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)

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

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

23 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 language	English
Pages (from-to)	809-818
Number of pages	10
Journal	International Journal of Radiation Oncology Biology Physics
Volume	104
Issue number	4
Early online date	15 Jun 2019
DOIs	https://doi.org/10.1016/j.ijrobp.2019.03.015
Publication status	Published - 15 Jul 2019

Bibliographical note

Funding Information:
Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work.This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant (C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre (C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work. This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant ( C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre ( C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/ Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Publisher Copyright:
© 2019 The Authors

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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. W., 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

Walker, AK, Karaszi, K, Valentine, H, Strauss, VY, Choudhury, A, McGill, S, Wen, K, Brown, MD, Ramani, V, Bhattarai, S, Teo, MTW, 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, CML & 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

@article{4f664d96b11b4987aabb91b7f1c9f89d,

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

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.",

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 T.W.} 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 M.L.} and Kiltie, {Anne E.}",

note = "Funding Information: Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work.This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant (C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre (C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work. This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant ( C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre ( C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/ Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jul,

day = "15",

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

language = "English",

volume = "104",

pages = "809--818",

journal = "International Journal of Radiation Oncology Biology Physics",

issn = "0360-3016",

publisher = "Elsevier Inc.",

number = "4",

}

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 T.W.

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 M.L.

AU - Kiltie, Anne E.

N1 - Funding Information: Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work.This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant (C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre (C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Disclosures: S.B., L.B., A.C., E.H., R.H., N.J., A.E.K., V.S., and C.W. report grant funding from Cancer Research UK during the conduct of the study. A.C. is a Senior Editor of IJROBP and reports nonfinancial support from ASCO and ESTRO; personal fees and nonfinancial support from Bayer PLC; grants from Prostate Cancer UK, Medical Research Council UK, and National Institute for Health Research UK; grants, personal fees, and nonfinancial support from Elekta AB; and personal fees from ASTRO, outside the submitted work. E.H. reports grants from Merck Sharp & Dohm, grants and nonfinancial support from AstraZeneca, grants from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Aventis Pharma Limited (Sanofi), and grants from Accuray Inc., outside the submitted work. R.H. reports grants and personal fees from MSD and Roche; personal fees from Bristol Myers Squibb and Janssen; and grants from Elekta, outside the submitted work. G.I. reports personal fees from Bayer Pharmaceuticals, outside the submitted work. This work was funded by CRUK Biomarkers and Imaging Discovery and Development grant ( C15140/A13492). The BC2001 trial was supported by grants (C547/A2606, C547/A6845, C9764/A9904, and C1491/A9895) from Cancer Research UK. The work was also supported by CRUK grant C2094/A11365, CRUK grant C5529/A16895, CRUK grant C5255/A15935, an MRC studentship MR/K501256/1, CRUK funding to the Cancer Research Manchester Centre ( C147/A18083, C147/A25254), the NIHR Manchester, NIHR Oxford (Molecular Diagnostics Theme/Multimodal Pathology Theme), and Royal Marsden/ Institute of Cancer Research Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: © 2019 The Authors

PY - 2019/7/15

Y1 - 2019/7/15

N2 - 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.

AB - 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.

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U2 - 10.1016/j.ijrobp.2019.03.015

DO - 10.1016/j.ijrobp.2019.03.015

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SN - 0360-3016

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JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

IS - 4

ER -

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

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