An international Ki67 reproducibility study.
2013 Dec 18
Journal Article
Authors:
Polley, M.Y.C.;
C Y Leung, S.;
McShane, L.M.;
Gao, D.;
Hugh, J.C.;
Mastropasqua, M.G.;
Viale, G.;
Zabaglo, L.A.;
Penault-Llorca, F.;
Bartlett, J.M.S.;
Gown, A.M.;
Symmans, F.;
Piper, T.;
Mehl, E.;
Enos, R.A.;
Hayes, D.F.;
Dowsett, M.;
Nielsen, T.O.
Secondary:
J Natl Cancer Inst
Volume:
105
Pagination:
1897-906
Issue:
24
PMID:
24203987
Keywords:
Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Immunohistochemistry; International Cooperation; Ki-67 Antigen; Laboratories; Observer Variation; Reproducibility of Results; Tissue Array Analysis
Abstract:
BACKGROUND: In 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.METHODS: Eight 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.RESULTS: Intralaboratory 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.CONCLUSIONS: Substantial 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.
