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      Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration

      research-article
      1 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 2 , 9 , 10 , 11 , 1 , 12 , 7 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 13 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 2 , *
      NPJ Breast Cancer
      Nature Publishing Group

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          Abstract

          Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81–0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999–0.93) and hot-spot methods (0.84; 95% CI: 0.77–0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples.

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          Most cited references19

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          Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015

          The 14th St Gallen International Breast Cancer Conference (2015) reviewed new evidence on locoregional and systemic therapies for early breast cancer. This manuscript presents news and progress since the 2013 meeting, provides expert opinion on almost 200 questions posed to Consensus Panel members, and summarizes treatment-oriented classification of subgroups and treatment recommendations.
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            Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients

            The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR=1.93 (95% confidence interval (CI): 1.74–2.14); P<0.001), in node-negative patients (HR=2.31 (95% CI: 1.83–2.92); P<0.001) and in node-positive patients (HR=1.59 (95% CI: 1.35–1.87); P<0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR=1.95 (95% CI: 1.70–2.24; P<0.001)), node-negative patients (HR=2.54 (95% CI: 1.65–3.91); P<0.001) and node-positive patients (HR=2.33 (95% CI: 1.83–2.95); P<0.001). Our meta-analysis suggests that Ki-67/MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC.
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              Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer.

              We recently reported that the mRNA-based, 21-gene Genomic Health recurrence score (GHI-RS) provided additional prognostic information regarding distant recurrence beyond that obtained from classical clinicopathologic factors (age, nodal status, tumor size, grade, endocrine treatment) in women with early breast cancer, confirming earlier reports. The aim of this article is to determine how much of this information is contained in standard immunohistochemical (IHC) markers. The primary cohort comprised 1,125 estrogen receptor-positive (ER-positive) patients from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial who did not receive adjuvant chemotherapy, had the GHI-RS computed, and had adequate tissue for the four IHC measurements: ER, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67. Distant recurrence was the primary end point, and proportional hazards models were used with sample splitting to control for overfitting. A prognostic model that used classical variables and the four IHC markers (IHC4 score) was created and assessed in a separate cohort of 786 patients. All four IHC markers provided independent prognostic information in the presence of classical variables. In sample-splitting analyses, the information in the IHC4 score was found to be similar to that in the GHI-RS, and little additional prognostic value was seen in the combined use of both scores. The prognostic value of the IHC4 score was further validated in the second separate cohort. This study suggests that the amount of prognostic information contained in four widely performed IHC assays is similar to that in the GHI-RS. Additional studies are needed to determine the general applicability of the IHC4 score.
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                Author and article information

                Journal
                NPJ Breast Cancer
                NPJ Breast Cancer
                NPJ Breast Cancer
                Nature Publishing Group
                2374-4677
                18 May 2016
                2016
                : 2
                : 16014
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, University of British Columbia , Vancouver, British Columbia, Canada
                [2 ]Academic Department of Biochemistry, Royal Marsden Hospital and Institute of Cancer Research , London, United Kingdom
                [3 ]Department of Pathology, Tata Medical Center , Kolkata, West Bengal, India
                [4 ]Department of Pathology and Laboratory Medicine, Indiana University Simon Cancer Center , Indianapolis, Indiana, USA
                [5 ]Department of Pathology and Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University , Hamilton, Ontario, Canada
                [6 ]Transformative Pathology, Ontario Institute for Cancer Research , Toronto, Ontario, Canada
                [7 ]Department of Clinical Sciences, Division of Oncology and Pathology, Lund University , Lund, Sweden
                [8 ]Department of Pathology, Mount Sinai Hospital , Toronto, Ontario, Canada
                [9 ]The EMMES Corporation , Rockville, Maryland, USA
                [10 ]Department of Pathology, Montefiore Medical Center and the Albert Einstein College of Medicine , Bronx, New York, USA
                [11 ]Department of Pathology, Dietrich-Bonhoeffer Medical Center , Neubrandenburg, Mecklenburg-Vorpommern, Germany
                [12 ]PhenoPath Laboratories , Seattle, Washington, USA
                [13 ]Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine , Houston, Texas, USA
                [14 ]Department of Laboratory Medicine and Pathology, University of Alberta , Edmonton, Alberta, Canada
                [15 ]Department of Pathology and Laboratory Medicine, The Ottawa Hospital , Ottawa, Ontario, Canada
                [16 ]Department of Pathology, Slagelse Hospital , Slagelse, Region Sjælland, Denmark
                [17 ]Fred Hutchinson Cancer Research Center , Seattle, Washington, USA
                [18 ]Division of Pathology and Laboratory Medicine, European Institute of Oncology , Milan, Italy
                [19 ]Department of Pathology, Kawasaki Medical School , Kurashiki, Okayama Prefecture, Japan
                [20 ]Department of Laboratory Medicine, Sunnybrook Health Sciences Centre , Toronto, Ontario, Canada
                [21 ]Department of Pathology, Centre Jean Perrin and Université d'Auvergne , Clermont-Ferrand, France
                [22 ]Biomarkers & Companion Diagnostics Group, Edinburgh Cancer Research Centre, Western General Hospital , Edinburgh, United Kingdom
                [23 ]Department of Pathology, Nippon Medical School , Bunkyo-ku, Tokyo, Japan
                [24 ]Breast Cancer Translational Research Laboratory, Institut Jules Bordet , Brussels, Belgium
                [25 ]Department of Cellular Pathology, Birmingham Heart of England, National Health Service , Birmingham, United Kingdom
                [26 ]Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan , Milan, Italy
                [27 ]Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center , Ann Arbor, Michigan, USA
                [28 ]Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute , Bethesda, Maryland, USA
                Author notes

                S.C.Y.L.: study design, data collection, manuscript drafting and review. T.O.N.: study design, manuscript drafting and review. L.Z.: study design, collection and preparation of samples, data collection, manuscript drafting and review. I.A.: study design, data collection, manuscript drafting and review. S.S.B.: study design, manuscript drafting and review. A.L.B.: study design, data collection, manuscript drafting and review. J.M.S.B.: study design, manuscript drafting and review. S.B.: study design, data collection, manuscript drafting and review. M.C.C.: study design, data collection, manuscript drafting and review. A.D.: study design, data collection, manuscript drafting and review. R.A.E.: study design, data collection, manuscript drafting and review. S.F.: study design, data collection, manuscript drafting and review. C.M.F.: study design, data collection, manuscript drafting and review. D.G.: study design, data collection, manuscript drafting and review. A.M.G.: study design, data collection, manuscript drafting and review. D.G.: study design, data collection, manuscript drafting and review. C.G.: study design, data collection, manuscript drafting and review. J.C.H.: study design, data collection, manuscript drafting and review. Z.K.: study design, data collection, manuscript drafting and review. A-V.L.: study design, data collection, manuscript drafting and review. M-G.L: study design, data collection, manuscript drafting and review. M.G.M.: study design, data collection, manuscript drafting and review. T.M.: study design, data collection, manuscript drafting and review. S.N-M.: study design, data collection, manuscript drafting and review. C.K.O.: study design, manuscript drafting and review. F.M.P-L.: study design, data collection, manuscript drafting and review. T.P.: study design, data collection, manuscript drafting and review. T.S.: study design, data collection, manuscript drafting and review. R.S.: study design, data collection, manuscript drafting and review. J.S.: study design, data collection, manuscript drafting and review. G.V.: study design, manuscript drafting and review. D.F.H.: study design, manuscript drafting and review. L.M.McS.: study design, statistical analysis, manuscript drafting and review. M.D.: study design, manuscript drafting and review.

                Article
                npjbcancer201614
                10.1038/npjbcancer.2016.14
                5515324
                28721378
                a4075828-75a2-461e-a9fc-749ab4670e5e
                Copyright © 2016 Breast Cancer Research Foundation/Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 23 December 2015
                : 22 February 2016
                : 01 April 2016
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