title: An international study to increase concordance in Ki67 scoring.
abstract: Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.
authors.affiliation: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Mei-Yin C
authors.initials: MY
authors.lastname: Polley
authors.affiliation: Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Samuel C Y
authors.initials: SC
authors.lastname: Leung
authors.affiliation: Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Gao
authors.affiliation: Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors.forename: Mauro G
authors.initials: MG
authors.lastname: Mastropasqua
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Lila A
authors.initials: LA
authors.lastname: Zabaglo
authors.affiliation: Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.affiliation: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Lisa M
authors.identifier: 0000000181953206
authors.initials: LM
authors.lastname: McShane
authors.affiliation: The Emmes Corporation, Rockville, Maryland, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Enos
authors.affiliation: Indiana University Simon Cancer Center, Indianapolis, Indiana, USA.
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Badve
authors.affiliation: Department of Pathology and Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Bane
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Signe
authors.initials: S
authors.lastname: Borgquist
authors.affiliation: Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Fineberg
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ming-Gang
authors.initials: MG
authors.lastname: Lin
authors.affiliation: PhenoPath Laboratories, Seattle, Washington, USA.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Gown
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Grabau
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Carolina
authors.identifier: 0000000229413461
authors.initials: C
authors.lastname: Gutierrez
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Alberta, Canada.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Hugh
authors.affiliation: Department of Pathology, Kawasaki Medical School, Kurashiki City, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
authors.affiliation: Department of Pathology, Hakuaikai Sagara Hospital, Matsubaracho, Kagoshima, Japan.
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Ohi
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: Department of Pathology, Centre Jean Perrin and Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: Frédérique M
authors.initials: FM
authors.lastname: Penault-Llorca
authors.affiliation: Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK.
authors.forename: Tammy
authors.initials: T
authors.lastname: Piper
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Porter
authors.affiliation: Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakatani
authors.affiliation: Institut Jules Bordet, Brussels, Belgium.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Birmingham Heart of England, National Health Service, Birmingham, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Starczynski
authors.affiliation: Slagelse Hospital, Slagelse, Region Sjælland, Denmark.
authors.forename: Anne-Vibeke
authors.initials: AV
authors.lastname: Lænkholm
authors.affiliation: Division of Pathology and Laboratory Medicine, European Institute of Oncology, and University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.affiliation: Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000592:standards*; D019394:Ki-67 Antigen / Q000032:analysis*; D046888:Tissue Array Analysis / Q000592:standards*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen