An international ki67 reproducibility study

Mei Yin C Polley, Samuel C Y Leung, Lisa M. McShane, Dongxia Gao, Judith C. Hugh, Mauro G. Mastropasqua, Giuseppe Viale, Lila A. Zabaglo, Frédérique Penault-Llorca, John M S Bartlett, Allen M. Gown, W. Fraser Symmans, Tammy Piper, Erika Mehl, Rebecca A. Enos, Daniel F. Hayes, Mitch Dowsett, Torsten O. Nielsen

Research output: Contribution to journalArticle

285 Citations (Scopus)

Abstract

BackgroundIn breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study.MethodsEight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. ResultsIntralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation.ConclusionsSubstantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited.

Original languageEnglish
Pages (from-to)1897-1906
Number of pages10
JournalJournal of the National Cancer Institute
Volume105
Issue number24
DOIs
Publication statusPublished - Dec 18 2013

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Staining and Labeling
Confidence Intervals
Breast Neoplasms
Neoplasms
Research

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Polley, M. Y. C., Leung, S. C. Y., McShane, L. M., Gao, D., Hugh, J. C., Mastropasqua, M. G., ... Nielsen, T. O. (2013). An international ki67 reproducibility study. Journal of the National Cancer Institute, 105(24), 1897-1906. https://doi.org/10.1093/jnci/djt306

An international ki67 reproducibility study. / Polley, Mei Yin C; Leung, Samuel C Y; McShane, Lisa M.; Gao, Dongxia; Hugh, Judith C.; Mastropasqua, Mauro G.; Viale, Giuseppe; Zabaglo, Lila A.; Penault-Llorca, Frédérique; Bartlett, John M S; Gown, Allen M.; Symmans, W. Fraser; Piper, Tammy; Mehl, Erika; Enos, Rebecca A.; Hayes, Daniel F.; Dowsett, Mitch; Nielsen, Torsten O.

In: Journal of the National Cancer Institute, Vol. 105, No. 24, 18.12.2013, p. 1897-1906.

Research output: Contribution to journalArticle

Polley, MYC, Leung, SCY, McShane, LM, Gao, D, Hugh, JC, Mastropasqua, MG, Viale, G, Zabaglo, LA, Penault-Llorca, F, Bartlett, JMS, Gown, AM, Symmans, WF, Piper, T, Mehl, E, Enos, RA, Hayes, DF, Dowsett, M & Nielsen, TO 2013, 'An international ki67 reproducibility study', Journal of the National Cancer Institute, vol. 105, no. 24, pp. 1897-1906. https://doi.org/10.1093/jnci/djt306
Polley MYC, Leung SCY, McShane LM, Gao D, Hugh JC, Mastropasqua MG et al. An international ki67 reproducibility study. Journal of the National Cancer Institute. 2013 Dec 18;105(24):1897-1906. https://doi.org/10.1093/jnci/djt306
Polley, Mei Yin C ; Leung, Samuel C Y ; McShane, Lisa M. ; Gao, Dongxia ; Hugh, Judith C. ; Mastropasqua, Mauro G. ; Viale, Giuseppe ; Zabaglo, Lila A. ; Penault-Llorca, Frédérique ; Bartlett, John M S ; Gown, Allen M. ; Symmans, W. Fraser ; Piper, Tammy ; Mehl, Erika ; Enos, Rebecca A. ; Hayes, Daniel F. ; Dowsett, Mitch ; Nielsen, Torsten O. / An international ki67 reproducibility study. In: Journal of the National Cancer Institute. 2013 ; Vol. 105, No. 24. pp. 1897-1906.
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abstract = "BackgroundIn breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study.MethodsEight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95{\%} confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. ResultsIntralaboratory reproducibility was high (ICC = 0.94; 95{\%} CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95{\%} CI = 0.47 to 0.78; local staining: ICC = 0.59, 95{\%} CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1{\%} to 23.9{\%} with central staining and 6.1{\%} to 30.1{\%} with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation.ConclusionsSubstantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited.",
author = "Polley, {Mei Yin C} and Leung, {Samuel C Y} and McShane, {Lisa M.} and Dongxia Gao and Hugh, {Judith C.} and Mastropasqua, {Mauro G.} and Giuseppe Viale and Zabaglo, {Lila A.} and Fr{\'e}d{\'e}rique Penault-Llorca and Bartlett, {John M S} and Gown, {Allen M.} and Symmans, {W. Fraser} and Tammy Piper and Erika Mehl and Enos, {Rebecca A.} and Hayes, {Daniel F.} and Mitch Dowsett and Nielsen, {Torsten O.}",
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T1 - An international ki67 reproducibility study

AU - Polley, Mei Yin C

AU - Leung, Samuel C Y

AU - McShane, Lisa M.

AU - Gao, Dongxia

AU - Hugh, Judith C.

AU - Mastropasqua, Mauro G.

AU - Viale, Giuseppe

AU - Zabaglo, Lila A.

AU - Penault-Llorca, Frédérique

AU - Bartlett, John M S

AU - Gown, Allen M.

AU - Symmans, W. Fraser

AU - Piper, Tammy

AU - Mehl, Erika

AU - Enos, Rebecca A.

AU - Hayes, Daniel F.

AU - Dowsett, Mitch

AU - Nielsen, Torsten O.

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Y1 - 2013/12/18

N2 - BackgroundIn breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study.MethodsEight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. ResultsIntralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation.ConclusionsSubstantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited.

AB - BackgroundIn breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study.MethodsEight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. ResultsIntralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation.ConclusionsSubstantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited.

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