. 2015 Mar;12(5).
doi: 10.1038/nrclinonc.2015.46.

Ki67--no evidence for its use in node-positive breast cancer

Fabrice Andre 1 Monica Arnedos 1 Aicha Goubar 2 Amal Ghouadni 1 Suzette Delaloge 1 
  • PMID: 25781576
  •     34 References
  •     27 citations


The expression of Ki67 in breast cancer has been associated with the luminal B phenotype, a high risk of relapse, and likelihood of good response to neoadjuvant chemotherapy. Several guidelines propose assays to determine Ki67 expression levels to select which patients with early stage breast cancer and 1-3 positive axillary nodes should not receive adjuvant chemotherapy. We discuss why oncologists should not rely on the use of this biomarker for patients with early stage breast cancer and only 1-3 positive axillary nodes. First, Ki67 staining lacks analytical validity. Second, the performance of the biomarker for prognostic purposes is poor, with no compelling evidence to indicate that patients with oestrogen receptor (ER)-positive disease, low Ki67 expression and 1-3 positive axillary nodes have a very low risk of disease relapse. Finally, no robust evidence indicates that Ki67 staining predicts the efficacy of adjuvant chemotherapy. Overall, evidence does not support withholding adjuvant chemotherapy in patients with ER-positive, Ki67-low breast cancer and 1-3 positive nodes without risk in daily practice.

Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer.
Frédérique Penault-Llorca, Fabrice André, +11 authors, Henri Roché.
J Clin Oncol, 2009 Apr 22; 27(17). PMID: 19380452
Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), R Peto, +15 authors, K Pritchard.
Lancet, 2011 Dec 14; 379(9814). PMID: 22152853    Free PMC article.
Highly Cited.
Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer.
Einar Gudlaugsson, Ivar Skaland, +5 authors, Jan P A Baak.
Histopathology, 2012 Sep 12; 61(6). PMID: 22963617
Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.
J Ferlay, E Steliarova-Foucher, +5 authors, F Bray.
Eur J Cancer, 2013 Mar 15; 49(6). PMID: 23485231
Highly Cited.
Molecular portraits of human breast tumours.
C M Perou, T Sørlie, +15 authors, D Botstein.
Nature, 2000 Aug 30; 406(6797). PMID: 10963602
Highly Cited.
Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.
Mitch Dowsett, Jack Cuzick, +11 authors, Steven Shak.
J Clin Oncol, 2010 Mar 10; 28(11). PMID: 20212256
Highly Cited.
A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors.
Martin Filipits, Margaretha Rudas, +25 authors, EP Investigators.
Clin Cancer Res, 2011 Aug 03; 17(18). PMID: 21807638
Highly Cited.
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.
Jack Cuzick, Mitch Dowsett, +10 authors, John F Forbes.
J Clin Oncol, 2011 Oct 13; 29(32). PMID: 21990413
Highly Cited.
Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients.
E de Azambuja, F Cardoso, +7 authors, M Paesmans.
Br J Cancer, 2007 Apr 25; 96(10). PMID: 17453008    Free PMC article.
Highly Cited.
Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.
A Goldhirsch, E P Winer, +5 authors, Panel members.
Ann Oncol, 2013 Aug 07; 24(9). PMID: 23917950    Free PMC article.
Highly Cited.
How reliable is Ki-67 immunohistochemistry in grade 2 breast carcinomas? A QA study of the Swiss Working Group of Breast- and Gynecopathologists.
Zsuzsanna Varga, Joachim Diebold, +16 authors, Hans-Anton Lehr.
PLoS One, 2012 Jun 05; 7(5). PMID: 22662150    Free PMC article.
Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group.
Mitch Dowsett, Torsten O Nielsen, +19 authors, International Ki-67 in Breast Cancer Working Group.
J Natl Cancer Inst, 2011 Oct 01; 103(22). PMID: 21960707    Free PMC article.
Highly Cited.
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
Patricia Cortazar, Lijun Zhang, +34 authors, Gunter von Minckwitz.
Lancet, 2014 Feb 18; 384(9938). PMID: 24529560
Highly Cited. Review.
An international Ki67 reproducibility study.
Mei-Yin C Polley, Samuel C Y Leung, +16 authors, International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group.
J Natl Cancer Inst, 2013 Nov 10; 105(24). PMID: 24203987    Free PMC article.
Highly Cited.
Breast cancer classification and prognosis based on gene expression profiles from a population-based study.
Christos Sotiriou, Soek-Ying Neo, +7 authors, Edison T Liu.
Proc Natl Acad Sci U S A, 2003 Aug 15; 100(18). PMID: 12917485    Free PMC article.
Highly Cited.
Recommendations from the EGAPP Working Group: can tumor gene expression profiling improve outcomes in patients with breast cancer?
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.
Genet Med, 2009 Jan 07; 11(1). PMID: 19125125    Free PMC article.
Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial.
Judith Hugh, John Hanson, +11 authors, Charles Vogel.
J Clin Oncol, 2009 Feb 11; 27(8). PMID: 19204205    Free PMC article.
Highly Cited.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
A methodology to ensure and improve accuracy of Ki67 labelling index estimation by automated digital image analysis in breast cancer tissue.
Arvydas Laurinavicius, Benoit Plancoulaine, +8 authors, Catherine Bor.
Breast Cancer Res, 2014 Apr 09; 16(2). PMID: 24708745    Free PMC article.
Re-evaluating adjuvant breast cancer trials: assessing hormone receptor status by immunohistochemical versus extraction assays.
Meredith M Regan, Giuseppe Viale, +16 authors, International Breast Cancer Study Group.
J Natl Cancer Inst, 2006 Nov 02; 98(21). PMID: 17077359
Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression.
U Nitz, O Gluz, +22 authors, W Kuhn.
Ann Oncol, 2014 May 16; 25(8). PMID: 24827128
Gene-expression signatures in breast cancer.
Christos Sotiriou, Lajos Pusztai.
N Engl J Med, 2009 Feb 21; 360(8). PMID: 19228622
Highly Cited. Review.
Ki67 and proliferation in breast cancer.
Nirmala Pathmanathan, Rosemary L Balleine.
J Clin Pathol, 2013 Feb 26; 66(6). PMID: 23436927
Highly Cited. Review.
Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil– epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.
S Ohno, L W C Chow, +20 authors, M Toi.
Breast Cancer Res Treat, 2013 Oct 15; 142(1). PMID: 24122389    Free PMC article.
Clinical significance of pretherapeutic Ki67 as a predictive parameter for response to neoadjuvant chemotherapy in breast cancer: is it equally useful across tumor subtypes?
Aiko Sueta, Yutaka Yamamoto, +5 authors, Hirotaka Iwase.
Surgery, 2014 Mar 04; 155(5). PMID: 24582496
Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer.
Maggie C U Cheang, Stephen K Chia, +10 authors, Torsten O Nielsen.
J Natl Cancer Inst, 2009 May 14; 101(10). PMID: 19436038    Free PMC article.
Highly Cited.
Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics.
Matthew J Ellis, Yu Tao, +9 authors, Mitch Dowsett.
J Natl Cancer Inst, 2008 Sep 25; 100(19). PMID: 18812550    Free PMC article.
Highly Cited.
Response-guided neoadjuvant chemotherapy for breast cancer.
Gunter von Minckwitz, Jens Uwe Blohmer, +16 authors, Sibylle Loibl.
J Clin Oncol, 2013 Sep 05; 31(29). PMID: 24002511
Highly Cited.
Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
Kathy S Albain, William E Barlow, +20 authors, Breast Cancer Intergroup of North America.
Lancet Oncol, 2009 Dec 17; 11(1). PMID: 20005174    Free PMC article.
Highly Cited.
Interobserver concordance of Ki67 labeling index in breast cancer: Japan Breast Cancer Research Group Ki67 ring study.
Yoshiki Mikami, Takayuki Ueno, +6 authors, Hironobu Sasano.
Cancer Sci, 2013 Aug 03; 104(11). PMID: 23905924    Free PMC article.
Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.
Giuseppe Viale, Anita Giobbie-Hurder, +18 authors, Breast International Group Trial 1-98.
J Clin Oncol, 2008 Nov 05; 26(34). PMID: 18981464    Free PMC article.
Highly Cited.
Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601).
John M S Bartlett, Alison F Munro, +13 authors, Christopher J Poole.
Lancet Oncol, 2010 Jan 19; 11(3). PMID: 20079691
Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study.
M V Dieci, C Criscitiello, +8 authors, F Andre.
Ann Oncol, 2014 Jan 10; 25(3). PMID: 24401929    Free PMC article.
Highly Cited.
Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
E Senkus, S Kyriakides, +5 authors, ESMO Guidelines Working Group.
Ann Oncol, 2013 Aug 24; 24 Suppl 6. PMID: 23970019
Highly Cited.
High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer.
Emilio Alba, Ana Lluch, +18 authors, Federico Rojo.
Oncologist, 2016 Jan 21; 21(2). PMID: 26786263    Free PMC article.
Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.
Luisa Carbognin, Isabella Sperduti, +13 authors, Emilio Bria.
J Exp Clin Cancer Res, 2016 Mar 24; 35. PMID: 27000271    Free PMC article.
Mitosis in circulating tumor cells stratifies highly aggressive breast carcinomas.
Daniel L Adams, Diane K Adams, +7 authors, R Katherine Alpaugh.
Breast Cancer Res, 2016 May 05; 18(1). PMID: 27142282    Free PMC article.
The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis.
Daniel G Stover, Jonathan L Coloff, +3 authors, Laura M Selfors.
Clin Cancer Res, 2016 Jun 23; 22(24). PMID: 27330058    Free PMC article.
Value of Ki-67 expression in triple-negative breast cancer before and after neoadjuvant chemotherapy with weekly paclitaxel plus carboplatin.
Ruo-Xi Wang, Sheng Chen, Xi Jin, Zhi-Ming Shao.
Sci Rep, 2016 Jul 19; 6. PMID: 27426056    Free PMC article.
Prognostic values of negative estrogen or progesterone receptor expression in patients with luminal B HER2-negative breast cancer.
Chansub Park, Kyeongmee Park, +8 authors, Geumhee Gwak.
World J Surg Oncol, 2016 Sep 14; 14(1). PMID: 27619909    Free PMC article.
Alteration in cellular turnover and progenitor cell population in lacrimal glands from thrombospondin 1-/- mice, a model of dry eye.
Marie A Shatos, Robin R Hodges, +9 authors, Darlene A Dartt.
Exp Eye Res, 2016 Nov 05; 153. PMID: 27697548    Free PMC article.
Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer.
Xiaolan Feng, Haocheng Li, +9 authors, Alexander Paterson.
Oncotarget, 2016 Oct 16; 7(52). PMID: 27741524    Free PMC article.
Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups.
Mustapha Abubakar, Nick Orr, +38 authors, Montserrat Garcia-Closas.
Breast Cancer Res, 2016 Oct 21; 18(1). PMID: 27756439    Free PMC article.
Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy.
Balázs Ács, Veronika Zámbó, +9 authors, Anna-Mária Tőkés.
Diagn Pathol, 2017 Feb 23; 12(1). PMID: 28222768    Free PMC article.
Power of PgR expression as a prognostic factor for ER-positive/HER2-negative breast cancer patients at intermediate risk classified by the Ki67 labeling index.
Sasagu Kurozumi, Hiroshi Matsumoto, +6 authors, Masafumi Kurosumi.
BMC Cancer, 2017 May 24; 17(1). PMID: 28532429    Free PMC article.
High expression of Ki-67 is an independent favorable prognostic factor for esophageal small cell carcinoma.
Han-Yu Deng, Zi-Hang Chen, +5 authors, Long-Qi Chen.
Oncotarget, 2017 Sep 15; 8(33). PMID: 28903420    Free PMC article.
High brain acid soluble protein 1(BASP1) is a poor prognostic factor for cervical cancer and promotes tumor growth.
Huiru Tang, Yan Wang, +5 authors, Heping Li.
Cancer Cell Int, 2017 Nov 02; 17. PMID: 29089860    Free PMC article.
First Prospective Multicenter Italian Study on the Impact of the 21-Gene Recurrence Score in Adjuvant Clinical Decisions for Patients with ER Positive/HER2 Negative Breast Cancer.
Maria Vittoria Dieci, Valentina Guarneri, +15 authors, PierFranco Conte.
Oncologist, 2017 Nov 15; 23(3). PMID: 29133514    Free PMC article.
Clinical and pathological factors influencing survival in a large cohort of triple-negative breast cancer patients.
Silvana Anna Maria Urru, Silvano Gallus, +25 authors, Sandra Orrù.
BMC Cancer, 2018 Jan 10; 18(1). PMID: 29310602    Free PMC article.
Assessment of the predictive role of pretreatment Ki-67 and Ki-67 changes in breast cancer patients receiving neoadjuvant chemotherapy according to the molecular classification: a retrospective study of 1010 patients.
Rui Chen, Yin Ye, +9 authors, Shengchun Liu.
Breast Cancer Res Treat, 2018 Feb 27; 170(1). PMID: 29480449    Free PMC article.
Ki67 Changes Identify Worse Outcomes in Residual Breast Cancer Tumors After Neoadjuvant Chemotherapy.
Paula Cabrera-Galeana, Wendy Muñoz-Montaño, +9 authors, Oscar Arrieta.
Oncologist, 2018 Mar 02; 23(6). PMID: 29490940    Free PMC article.
Prognostic Importance of Ki-67 in Breast Cancer and Its Relationship with Other Prognostic Factors.
Gül Kanyılmaz, Berrin Benli Yavuz, +3 authors, Sıddıka Fındık.
Eur J Breast Health, 2019 Oct 18; 15(4). PMID: 31620685    Free PMC article.
Subtypes of Breast Cancer in Lao P.D.R.: A Study in a Limited-Resource Setting
Thitsamay Luangxay, Siriphone Virachith, +8 authors, Motoji Sawabe.
Asian Pac J Cancer Prev, 2019 Feb 26; 20(2). PMID: 30806064    Free PMC article.
The prognostic and predictive potential of Ki-67 in triple-negative breast cancer.
Xiuzhi Zhu, Li Chen, +8 authors, Zhonghua Wang.
Sci Rep, 2020 Jan 16; 10(1). PMID: 31937819    Free PMC article.
Clinical validation of an immunohistochemistry-based CanAssist-Breast test for distant recurrence prediction in hormone receptor-positive breast cancer patients.
Manjiri M Bakre, Charusheila Ramkumar, +10 authors, Mark D Pegram.
Cancer Med, 2019 Mar 09; 8(4). PMID: 30848103    Free PMC article.
Clinical validation of Ki67 by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in HR+/HER2- early breast cancer.
Weiqi Gao, Jiayi Wu, +4 authors, Ou Huang.
J Cancer, 2019 Mar 12; 10(5). PMID: 30854118    Free PMC article.
Assessment of tumour proliferation by use of the mitotic activity index, and Ki67 and phosphohistone H3 expression, in early-stage luminal breast cancer.
Julia E C van Steenhoven, Anne Kuijer, +4 authors, Paul J van Diest.
Histopathology, 2020 Jun 20; 77(4). PMID: 32557844    Free PMC article.
First prospective outcome data for the second-generation multigene test Endopredict in ER-positive/HER2-negative breast cancer.
Johannes Ettl, Sophie-Isabelle Anders, +5 authors, Marion Kiechle.
Arch Gynecol Obstet, 2020 Sep 10; 302(6). PMID: 32902674    Free PMC article.
A comparative study between Ki67 positive versus Ki67 negative females with breast cancer: Cross sectional study.
Mowafak Masoud Bahaddin.
Ann Med Surg (Lond), 2020 Nov 17; 60. PMID: 33194179    Free PMC article.
The Prognostic Value of Lymph Node Involvement after Neoadjuvant Chemotherapy Is Different among Breast Cancer Subtypes.
Lucie Laot, Enora Laas, +12 authors, Anne-Sophie Hamy.
Cancers (Basel), 2021 Jan 10; 13(2). PMID: 33418983    Free PMC article.
Recent Discoveries of Macromolecule- and Cell-Based Biomarkers and Therapeutic Implications in Breast Cancer.
Hsing-Ju Wu, Pei-Yi Chu.
Int J Mol Sci, 2021 Jan 14; 22(2). PMID: 33435254    Free PMC article.