Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2013

Open Access 01-06-2013 | Epidemiology

Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry

Authors: E. C. Inwald, M. Klinkhammer-Schalke, F. Hofstädter, F. Zeman, M. Koller, M. Gerstenhauer, O. Ortmann

Published in: Breast Cancer Research and Treatment | Issue 2/2013

Login to get access

Abstract

The proliferation marker Ki-67 is one of the most controversially discussed parameters for treatment decisions in breast cancer patients. The purpose of this study was to evaluate the routine use and value of Ki-67 as a prognostic marker, and to analyze the associations between Ki-67 and common histopathological parameters in the routine clinical setting. Data from the clinical cancer registry Regensburg (Bavaria, Germany) were analyzed. Within the total data pool of 4,692 female patients, who had been diagnosed between 2005 and 2011, in 3,658 cases Ki-67 was routinely determined. Thus, a total of 3,658 patients with invasive breast cancer were included in the present study and used for statistical analysis. Ki-67 expression was associated with the common histopathological parameters. The strongest correlation was found between grading and Ki-67 (P < 0.001). In terms of survival analyses, Ki-67 was categorized into five categories (reference category Ki-67 ≤15 %) due to a nonlinear relationship to overall survival (OS). In multivariable analysis, Ki-67 was an independent prognostic parameter both for disease-free survival (DFS) (Ki-67 > 45 %, HR = 1.96, P = 0.001) as well as for OS (Ki-67: 26–35 %, HR = 1.71, P = 0.017; Ki-67: 36–45 %, HR = 2.05, P = 0.011; Ki-67 > 45 %, HR = 2.06, P = 0.002) independent of common clinical and histopathological factors. The 5-year DFS (OS) rate was 86.7 % (89.3 %) in patients with a Ki-67 value ≤15 % compared to 75.8 % (82.8 %) in patients with a Ki-67 value >45 %. Based on the data from a large cohort of a clinical cancer registry, it was demonstrated that Ki-67 is frequently determined in routine clinical work. Ki-67 expression is associated with common histopathological parameters, but is an additional independent prognostic parameter for DFS and OS in breast cancer patients. Future work should focus on standardization of Ki-67 assessment and specification of its role in treatment decisions.
Literature
1.
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ (2011) Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22:1736–1747PubMedCrossRef
2.
3.
Milde-Langosch K, Karn T, Müller V, Witzel I, Rody A, Schmidt M, Wirtz RM (2013) Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer. Breast Cancer Res Treat 137(1):57–67. doi:10.​1007/​s10549-012-2296-x PubMedCrossRef
4.
Wirapati P, Sotiriou C, Kunkel S, Farmer P, Pradervand S, Haibe-Kains B, Desmedt C, Ignatiadis M, Sengstag T, Schutz F et al (2008) Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures. Breast Cancer Res 10:R65PubMedCrossRef
5.
Garcia RL, Coltrera MD, Gown AM (1989) Analysis of proliferative grade using anti-PCNA/cyclin monoclonal antibodies in fixed, embedded tissues. Comparison with flow cytometric analysis. Am J Pathol 134(4):733–739PubMed
6.
7.
Stuart-Harris R, Caldas C, Pinder SE, Pharoah P (2008) Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients. Breast 17:323–334PubMedCrossRef
8.
Gerdes J, Schwab U, Lemke H, Stein H (1983) Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 31(1):13–20PubMedCrossRef
9.
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133(4):1710–1715PubMed
10.
Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182(3):311–322PubMedCrossRef
11.
Urruticoechea A, Smith IE, Dowsett M (2005) Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 23:7212–7220PubMedCrossRef
12.
Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA (2010) Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 11:174–183PubMedCrossRef
13.
Luporsi E, André F, Spyratos F, Martin PM, Jacquemier J, Penault-Llorca F, Tubiana-Mathieu N, Sigal-Zafrani B, Arnould L, Gompel A et al (2012) Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review. Breast Cancer Res Treat 132(3):895–915. doi:10.​1007/​s10549-011-1837-z PubMedCrossRef
14.
Gnant M, Harbeck N, Thomssen C (2011) St. Gallen Summary of the Consensus Discussion. Breast Care (Basel) 6(2):136–141CrossRef
15.
Untch M, Gerber B, Möbus V, Schneeweiss A, Thomssen C, von Minckwitz G, Beckmann MW, Blohmer JU, Costa SD, Diedrich K et al (2011) Zurich Consensus: Statement of German Experts on St. Gallen Conference 2011 on Primary Breast Cancer (Zurich 2011). Breast Care 6:144–152. doi:10.​1159/​000327999 CrossRef
16.
Untch M, Gerber B, Harbeck N, Jackisch C, Marschner N, Möbus V, von Minckwitz G, Loibl S (2013) 13th St. Gallen International Breast Cancer Conference 2013: Primary Therapy of Early Breast Cancer Evidence, Controversies, Consensus. Breast Care 03/2013: in press
17.
de Azambuja E, Cardoso F, de Castro G, Colozza M Jr, Mano MS, Durbecq V, Sotiriou C, Larsimont D, Piccart-Gebhart MJ, Paesmans M (2007) Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer 96(10):1504–1513PubMedCrossRef
18.
Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287–5312PubMedCrossRef
19.
Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T et al (2011) Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst 103:1656–1664PubMedCrossRef
20.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef
21.
22.
Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826PubMedCrossRef
23.
24.
van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009PubMedCrossRef
25.
Oakman C, Bessi S, Zafarana E, Galardi F, Biganzoli L, Di Leo A (2009) Recent advances in systemic therapy: new diagnostics and biological predictors of outcome in early breast cancer. Breast Cancer Res 11(2):205. doi:10.​1186/​bcr2238 PubMedCrossRef
26.
Cuzick J, Dowsett M, Pineda S, Wale C, Salter J, Quinn E, Zabaglo L, Mallon E, Green AR, Ellis IO et al (2011) 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. J Clin Oncol 29(32):4273–4278. doi:10.​1200/​JCO.​2010.​31.​2835 PubMedCrossRef
27.
28.
Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410PubMedCrossRef
29.
30.
Sahin AA, Ro J, Ro JY, Blick MB, el-Naggar AK, Ordonez NG, Fritsche HA, Smith TL, Hortobagyi GN, Ayala AG (1991) Ki-67 immunostaining in node-negative stage I/II breast carcinoma. Significant correlation with prognosis. Cancer 68(3):549–557PubMedCrossRef
31.
Rudas M, Gnant MF, Mittlböck M, Neumayer R, Kummer A, Jakesz R, Reiner G, Reiner A (1994) Thymidine labeling index and Ki-67 growth fraction in breast cancer: comparison and correlation with prognosis. Breast Cancer Res Treat 32(2):165–175PubMedCrossRef
32.
Pinder SE, Wencyk P, Sibbering DM, Bell JA, Elston CW, Nicholson R, Robertson JF, Blamey RW, Ellis IO (1995) Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: associations with other prognostic factors and survival. Br J Cancer 71(1):146–149PubMedCrossRef
33.
Pierga JY, Leroyer A, Viehl P, Mosseri V, Chevillard S, Magdelénat H (1996) Long term prognostic value of growth fraction determination by Ki-67 immunostaining in primary operable breast cancer. Breast Cancer Res Treat 37(1):57–64PubMedCrossRef
34.
Liu S, Edgerton SM, Moore DH 2nd, Thor AD (2001) Measures of cell turnover (proliferation and apoptosis) and their association with survival in breast cancer. Clin Cancer Res 7(6):1716–1723PubMed
35.
Spyratos F, Ferrero-Poüs M, Trassard M, Hacène K, Phillips E, Tubiana-Hulin M, Le Doussal V (2002) Correlation between MIB-1 and other proliferation markers: clinical implications of the MIB-1 cutoff value. Cancer 94(8):2151–2159PubMedCrossRef
36.
Trihia H, Murray S, Price K, Gelber RD, Golouh R, Goldhirsch A, Coates AS, Collins J, Castiglione-Gertsch M, Gusterson BA; International Breast Cancer Study Group (2003) Ki-67 expression in breast carcinoma: its association with grading systems, clinical parameters, and other prognostic factors–a surrogate marker? Cancer 97(5):1321–1331CrossRef
37.
Brown RW, Allred CD, Clark GM, Osborne CK, Hilsenbeck SG (1996) Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res 2(3):585–592PubMed
38.
Haerslev T, Jacobsen GK, Zedeler K (1996) Correlation of growth fraction by Ki-67 and proliferating cell nuclear antigen (PCNA) immunohistochemistry with histopathological parameters and prognosis in primary breast carcinomas. Breast Cancer Res Treat 37(2):101–113PubMedCrossRef
39.
Molino A, Micciolo R, Turazza M, Bonetti F, Piubello Q, Bonetti A, Nortilli R, Pelosi G, Cetto GL (1997) Ki-67 immunostaining in 322 primary breast cancers: associations with clinical and pathological variables and prognosis. Int J Cancer 74(4):433–437PubMedCrossRef
40.
Kontzoglou K, Palla V, Karaolanis G, Karaiskos I, Alexiou I, Pateras I, Konstantoudakis K, Stamatakos M (2013) Correlation between Ki67 and Breast Cancer Prognosis. Oncology 84(4):219–225. doi:10.​1159/​000346475 PubMedCrossRef
41.
Aleskandarany MA, Green AR, Benhasouna AA, Barros FF, Neal K, Reis-Filho JS, Ellis IO, Rakha EA (2012) Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer. Breast Cancer Res 14(1):R3PubMedCrossRef
42.
Viale G, Giobbie-Hurder A, Regan MM, Coates AS, Mastropasqua MG, Dell’Orto P, Maiorano E, MacGrogan G, Braye SG, Ohlschlegel C et al (2008) 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. J Clin Oncol 26(34):5569–5575. doi:10.​1200/​JCO.​2008.​17.​0829 PubMedCrossRef
43.
Jacquemier J, Charafe-Jauffret E, Monville F, Esterni B, Extra JM, Houvenaeghel G, Xerri L, Bertucci F, Birnbaum D (2009) Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer. Breast Cancer Res 11(2):R23. doi:10.​1186/​bcr2249 PubMedCrossRef
44.
45.
Domagala W, Markiewski M, Harezga B, Dukowicz A, Osborn M (1996) Prognostic significance of tumor cell proliferation rate as determined by the MIB-1 antibody in breast carcinoma: its relationship with vimentin and p53 protein. Clin Cancer Res 2(1):147–154PubMed
46.
Jansen RL, Hupperets PS, Arends JW, Joosten-Achjanie SR, Volovics A, Schouten HC, Hillen HF (1998) MIB-1 labelling index is an independent prognostic marker in primary breast cancer. Br J Cancer 78(4):460–465PubMedCrossRef
47.
Viale G, Regan MM, Mastropasqua MG, Maffini F, Maiorano E, Colleoni M, Price KN, Golouh R, Perin T, Brown RW et al (2008) Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Natl Cancer Inst 100(3):207–212. doi:10.​1093/​jnci/​djm289 PubMedCrossRef
48.
Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750. doi:10.​1093/​jnci/​djp082 PubMedCrossRef
49.
Kashiwagi S, Yashiro M, Takashima T, Aomatsu N, Ikeda K, Ogawa Y, Ishikawa T, Hirakawa K (2011) Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67. Breast Cancer Res 13(6):R122. doi:10.​1186/​bcr3068 PubMedCrossRef
50.
Loehberg CR, Almstedt K, Jud SM, Haeberle L, Fasching PA, Hack CC, Lux MP, Thiel FC, Schrauder MG, Brunner M et al (2013) Prognostic relevance of Ki-67 in the primary tumor for survival after a diagnosis of distant metastasis. Breast Cancer Res Treat 138(3):899–908. doi:10.​1007/​s10549-013-2460-y PubMedCrossRef
51.
Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ (2005) Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol 16:1723–1739PubMedCrossRef
52.
53.
Lüftner D, Lux MP, Maass N, Schütz F, Schwidde I, Fasching PA, Fehm T, Janni W, Kümmel S, Kolberg HC (2012) Advances in Breast Cancer: Looking Back over the year. Geburtsh Frauenheilk 72(12):1117–1129. doi:10.​1055/​s-0032-1328084 CrossRef
54.
Kolberg HC, Lüftner D, Lux MP, Maass N, Schütz F, Fasching PA, Fehm T, Janni W, Kümmel S (2012) Breast Cancer 2012: new aspects. Geburtsh Frauenheilk 72(7):602–615. doi:10.​1055/​s-0032-1315131 CrossRef
55.
Chang J, Ormerod M, Powles TJ, Allred DC, Ashley SE, Dowsett M (2000) Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma. Cancer 89(11):2145–2152PubMedCrossRef
56.
Archer CD, Parton M, Smith IE, Ellis PA, Salter J, Ashley S, Gui G, Sacks N, Ebbs SR, Allum W, Nasiri N, Dowsett M (2003) Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer. Br J Cancer 89(6):1035–1041PubMedCrossRef
57.
Assersohn L, Salter J, Powles TJ, A’hern R, Makris A, Gregory RK, Chang J, Dowsett M (2003) Studies of the potential utility of Ki67 as a predictive molecular marker of clinical response in primary breast cancer. Breast Cancer Res Treat 82(2):113–123PubMedCrossRef
58.
Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, Lee SH, Han W, Kim DW, Kim TY et al (2011) Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res 13(2):R22. doi:10.​1186/​bcr2834 PubMedCrossRef
59.
Bottini A, Berruti A, Bersiga A, Brizzi MP, Bruzzi P, Aguggini S, Brunelli A, Bolsi G, Allevi G, Generali D et al (2001) Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer. Br J Cancer 85(8):1106–1112PubMedCrossRef
60.
Colleoni M, Zahrieh D, Gelber RD, Viale G, Luini A, Veronesi P, Intra M, Galimberti V, Renne G, Goldhirsch A (2003) Preoperative systemic treatment: prediction of responsiveness. Breast 12(6):538–542PubMedCrossRef
61.
Ferguson NL, Bell J, Heidel R, Lee S, Vanmeter S, Duncan L, Munsey B, Panella T, Orucevic A (2013) Prognostic value of breast cancer subtypes, Ki-67 proliferation index, age, and pathologic tumor characteristics on breast cancer survival in Caucasian women. Breast J 19(1):22–30. doi:10.​1111/​tbj.​12059 CrossRef
Metadata
Title
Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry
Authors
E. C. Inwald
M. Klinkhammer-Schalke
F. Hofstädter
F. Zeman
M. Koller
M. Gerstenhauer
O. Ortmann
Publication date
01-06-2013
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-013-2560-8

Other articles of this Issue 2/2013

Breast Cancer Research and Treatment 2/2013 Go to the issue

Preclinical study

Rank-based predictors for response and prognosis of neoadjuvant taxane-anthracycline-based chemotherapy in breast cancer

Epidemiology

Time-dependent resource use and costs associated with different states of disease in patients diagnosed with HER-2-positive metastatic breast cancer

Epidemiology

Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project

Letter to the Editor

What is the clinical significance of the volume of tissue excised in ROLL?

Brief Report

Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer

Epidemiology

Simplifying clinical use of the genetic risk prediction model BRCAPRO
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits