Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group

Overview

Journal J Natl Cancer Inst

Publisher Oxford University Press

Specialty Oncology

Date 2020 Dec 28

PMID 33369635

Citations 240

Authors

Torsten O Nielsen

Samuel C Y Leung

David L Rimm

Andrew Dodson

Balazs Acs

Sunil Badve

Carsten Denkert

Matthew J Ellis

Susan Fineberg

Margaret Flowers

Hans H Kreipe

Anne-Vibeke Laenkholm

Hongchao Pan

Frederique M Penault-Llorca

Mei-Yin Polley

Roberto Salgado

Ian E Smith

Tomoharu Sugie

John M S Bartlett

Lisa M McShane

Mitch Dowsett

Daniel F Hayes

Affiliations

Soon will be listed here.

Abstract

Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor-positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.

Citing Articles

A bottom-up initiated digital external quality assessment scheme for the state-of-the-art pathology in Sweden: reduced variability between pathology departments.

Rask G, Olofsson H, Bauer A, Boden A, van Brakel J, Colon-Cervantes E Virchows Arch. 2025; .

PMID: 40019543 DOI: 10.1007/s00428-025-04059-9.

Exploring the Potential of Adjuvant CDK4/6 Inhibitors in Hormone Receptor-Positive Early Breast Cancer: A Consistent Approach for All.

Li J Cancers (Basel). 2025; 17(4).

PMID: 40002156 PMC: 11852482. DOI: 10.3390/cancers17040561.

The association between Ki-67 expression and survival in breast cancer subtypes: a cross-sectional study of Ki-67 cut-point in northern Thailand.

Wongmaneerung P, Chitapanarux I, Traisathit P, Prasitwattanaseree S, Rottuntikarn W, Somwangprasert A BMC Cancer. 2025; 25(1):346.

PMID: 40000991 PMC: 11863483. DOI: 10.1186/s12885-025-13724-w.

Mucin 4 expression is associated with metastasis in triple-negative breast cancer and can be tackled by soluble TNF blockade, improving immunotherapy outcome.

Mauro F, Bruni S, Dupont A, Schey A, Badalini A, Inurrigarro G Transl Oncol. 2025; 54:102325.

PMID: 39987883 PMC: 11904514. DOI: 10.1016/j.tranon.2025.102325.

The Relationship Between KI67 Expression and Grading with Chemotherapy Response in Triple-Negative Breast Cancer Patients at Haji Adam Malik General Hospital, Medan.

Putra E, Hermansyah D, Pasaribu E, Eyanoer P Med Arch. 2025; 78(4):285-289.

PMID: 39981154 PMC: 11838830. DOI: 10.5455/medarh.2024.78.285-289.

References

Peto R, Davies C, Godwin J, Gray R, Pan H, Clarke M . Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2011; 379(9814):432-44. PMC: 3273723. DOI: 10.1016/S0140-6736(11)61625-5. View

Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C . Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020; 21(11):1443-1454. PMC: 7606901. DOI: 10.1016/S1470-2045(20)30458-7. View

Ma C, Gao F, Luo J, Northfelt D, Goetz M, Forero A . NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2017; 23(15):4055-4065. PMC: 5555232. DOI: 10.1158/1078-0432.CCR-16-3206. View

Mengel M, von Wasielewski R, Wiese B, Rudiger T, Muller-Hermelink H, Kreipe H . Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial. J Pathol. 2002; 198(3):292-9. DOI: 10.1002/path.1218. View

Dowsett M, Smith I, Ebbs S, Dixon J, Skene A, AHern R . Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007; 99(2):167-70. DOI: 10.1093/jnci/djk020. View

Harris L, Ismaila N, McShane L, Andre F, Collyar D, Gonzalez-Angulo A . Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016; 34(10):1134-50. PMC: 4933134. DOI: 10.1200/JCO.2015.65.2289. View

Leary A, Evans A, Johnston S, AHern R, Bliss J, Sahoo R . Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039). Clin Cancer Res. 2014; 21(13):2932-40. DOI: 10.1158/1078-0432.CCR-14-1428. View

Arima N, Nishimura R, Osako T, Nishiyama Y, Fujisue M, Okumura Y . The importance of tissue handling of surgically removed breast cancer for an accurate assessment of the Ki-67 index. J Clin Pathol. 2015; 69(3):255-9. PMC: 4789709. DOI: 10.1136/jclinpath-2015-203174. View

Leung S, Nielsen T, Zabaglo L, Arun I, Badve S, Bane A . Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration. NPJ Breast Cancer. 2017; 2:16014. PMC: 5515324. DOI: 10.1038/npjbcancer.2016.14. View

10.

Mikami Y, Ueno T, Yoshimura K, Tsuda H, Kurosumi M, Masuda S . Interobserver concordance of Ki67 labeling index in breast cancer: Japan Breast Cancer Research Group Ki67 ring study. Cancer Sci. 2013; 104(11):1539-43. PMC: 7656544. DOI: 10.1111/cas.12245. View

11.

Gluz O, Kolberg-Liedtke C, Prat A, Christgen M, Gebauer D, Kates R . Efficacy of deescalated chemotherapy according to PAM50 subtypes, immune and proliferation genes in triple-negative early breast cancer: Primary translational analysis of the WSG-ADAPT-TN trial. Int J Cancer. 2019; 146(1):262-271. DOI: 10.1002/ijc.32488. View

12.

Johnston S, Puhalla S, Wheatley D, Ring A, Barry P, Holcombe C . Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial. J Clin Oncol. 2018; 37(3):178-189. DOI: 10.1200/JCO.18.01624. View

13.

Vyberg M, Nielsen S . Proficiency testing in immunohistochemistry--experiences from Nordic Immunohistochemical Quality Control (NordiQC). Virchows Arch. 2015; 468(1):19-29. PMC: 4751198. DOI: 10.1007/s00428-015-1829-1. View

14.

Visvanathan K, Fabian C, Bantug E, Brewster A, Davidson N, DeCensi A . Use of Endocrine Therapy for Breast Cancer Risk Reduction: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2019; 37(33):3152-3165. DOI: 10.1200/JCO.19.01472. View

15.

Hofmann D, Nitz U, Gluz O, Kates R, Schinkoethe T, Staib P . WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized,.... Trials. 2013; 14:261. PMC: 3765940. DOI: 10.1186/1745-6215-14-261. View

16.

Ellis M, Suman V, Hoog J, Goncalves R, Sanati S, Creighton C . Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol. 2017; 35(10):1061-1069. PMC: 5455353. DOI: 10.1200/JCO.2016.69.4406. View

17.

TUBIANA M, Pejovic M, Chavaudra N, Contesso G, Malaise E . The long-term prognostic significance of the thymidine labelling index in breast cancer. Int J Cancer. 1984; 33(4):441-5. DOI: 10.1002/ijc.2910330404. View

18.

Romero Q, Bendahl P, Ferno M, Grabau D, Borgquist S . A novel model for Ki67 assessment in breast cancer. Diagn Pathol. 2014; 9:118. PMC: 4069280. DOI: 10.1186/1746-1596-9-118. View

19.

Arnaout A, Robertson S, Pond G, Lee H, Jeong A, Ianni L . A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients. Breast Cancer Res Treat. 2019; 178(2):327-335. DOI: 10.1007/s10549-019-05381-y. View

20.

Bartlett J, Christiansen J, Gustavson M, Rimm D, Piper T, van de Velde C . Validation of the IHC4 Breast Cancer Prognostic Algorithm Using Multiple Approaches on the Multinational TEAM Clinical Trial. Arch Pathol Lab Med. 2015; 140(1):66-74. DOI: 10.5858/arpa.2014-0599-OA. View