Breast Cancer Research and Treatment

, Volume 82, Issue 2, pp 113–123 | Cite as

Studies of the Potential Utility of Ki67 as a Predictive Molecular Marker of Clinical Response in Primary Breast Cancer

  • L. Assersohn
  • J. Salter
  • T.J. Powles
  • R. A'hern
  • A. Makris
  • R.K. Gregory
  • J. Chang
  • M. Dowsett


Introduction. Objectives were to characterise the relationship of the proliferation marker Ki67 with response to systemic treatment in early breast cancer and to assess its clinical utility, using fine needle aspirates.

Materials and methods. Hundred and six women were treated with primary tamoxifen (n = 33), chemotherapy (n = 33) or chemotherapy and tamoxifen (n = 40). Treatment was not randomised and response was assessed clinically. Ki67 was evaluated prior to treatment and at Day 14 or 21 after commencing treatment. To assess reproducibility, Ki67 was evaluated in repeat FNAs taken from 37 untreated patients.

Results. The percentage change in Ki67 in first 21 days was different between responders and non-responders for patients treated with tamoxifen (p = 0.007) and chemotherapy (p = 0.005) but not for chemoendocrine treatment (p = 0.062). The reproducibility study indicated that a decrease to 36% or less of the pre-treatment Ki67 value in an individual patient was required for it to be regarded as a statistically significant change. A significant decrease in Ki67 was seen in responding patients treated with chemotherapy (p = 0.026) and chemoendocrine treatment (p = 0.041). Positive and negative predictive values for response were 85 and 59% for chemotherapy patients and 88 and 54% for chemoendocrine patients, respectively.

Conclusion. Ki67 is unlikely to be useful as a predictive marker in individual patients. Further molecular markers that predict lack of response continue to be required.

breast cancer Ki67 marker predictive response 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 352: 930–942, 1998Google Scholar
  2. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher E, Wickerham D, Begovic M, DeCillis A, Robidoux A, Margolese R, Cruz AJ, Hoehn J, Lees AW, Dimitrov NV, Bear HD: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16: 2672–2685, 1998Google Scholar
  3. Mauriac L, MacGrogan G, Avril A, Durand M, Floquet A, Debled M, Dilhuydy JM, Bonichon F: Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Institut Bergonie Bordeaux Groupe Sein (IBBGS). Ann Oncol 10: 47–52, 1999Google Scholar
  4. Makris A, Powles T, Ashley S, Chang J, Hickish T, Tidy V, Nash A, Ford H: A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol 9: 1179–1184, 1998Google Scholar
  5. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, Theriault RL, Singh G, Binkley SM, Sneige N, Buchholz TA, Ross MI, McNeese MD, Buzdar AU, Hortobagyi GN, Singletary SE: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17: 460–469, 1999Google Scholar
  6. Henderson IC, Patek AJ: The relationship between prognostic and predictive factors in the management of breast cancer. Breast Cancer Res Treat 52: 261–288, 1998Google Scholar
  7. Pierga JY, Leroyer A, Viehl P, Mosseri V, Chevillard S, Magdelenat H: Long term prognostic value of growth fraction determination by Ki67 immunostaining in primary operable breast cancer. Breast Cancer Res Treat 37: 57–64, 1996Google Scholar
  8. Railo M, Lundin J, Haglund C, von Smitten K, von Boguslawsky K, Nordling S: Ki67, p53, Er-receptors, ploidy and S-phase as prognostic factors in T1 node negative breast cancer. Acta Oncol 36: 369–374, 1997Google Scholar
  9. Lee AK, Loda M, Mackarem G, Bosari S, DeLellis RA, Heatley GJ, Hughes K: Lymph node negative invasive breast carcinoma 1 centimeter or less in size (T1a,bNOMO): clinicopathologic features and outcome. Cancer 79: 761–771, 1997Google Scholar
  10. Clarke RB, Laidlaw IJ, Jones LJ, Howell A, Anderson E: Effect of tamoxifen on Ki67 labelling index in human breast tumours and its relationship to oestrogen and progesterone receptor status. Br J Cancer 67: 606–611, 1993Google Scholar
  11. Bottini A, Berruti A, Bersiga A, Brunelli A, Brizi MP, DiMarco B, Cirillo F, Bertoli G, Alquati P, Dogliotti L: Relationship between estrogen receptor status and antiproliferative effect of neoadjuvant chemotherapy in primary breast cancer. Proc Annu Meet Am Soc Clin Oncol 15: 1996 (Meeting abstract)Google Scholar
  12. MacGrogan G, Mauriac L, Durand M, Bonichon F, Trojani M, de Mascarel I, Coindre JM: Primary chemotherapy in breast invasive carcinoma: predictive value of the immunohistochemical detection of hormonal receptors, p53, c-erbB-2, MiB1, pS2 and GST pi. Br J Cancer 74: 1458–1465, 1996Google Scholar
  13. Honkoop AH, Van Diest PJ, De Jong JS, Linn SC, Giaccone G, Hoekman K, Wagstaff J, Pinedo HM: Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer. Br J Cancer 77: 621–626, 1998Google Scholar
  14. Bottini A, Berruti A, Bersiga A, Brunelli A, Brizzi MP, Marco BD, Cirillo F, Bolsi G, Bertoli G, Alquati P, Dogliotti L: Effect of neoadjuvant chemotherapy on Ki67 labelling index, c-erbB-2 expression and steroid hormone receptor status in human breast tumours. Anticancer Res 16: 3105–3110, 1996Google Scholar
  15. Ellis PA, Smith IE, Detre S, Burton SA, Salter J, A'Hern R, Walsh G, Johnston SR, Dowsett M: Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy. Breast Cancer Res Treat 48: 107–116, 1998Google Scholar
  16. Makris A, Powles TJ, Allred DC, Ashley S, Ormerod MG, Titley JC, Dowsett M: Changes in hormone receptors and proliferation markers in tamoxifen treated breast cancer patients and the relationship with response. Breast Cancer Res Treat 48: 11–20, 1998Google Scholar
  17. Makris A, Powles TJ, Dowsett M, Osborne CK, Trott PA, Fernando IN, Ashley SE, Ormerod MG, Titley JC, Gregory RK, Allred DC: Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas. Clin Cancer Res 3: 593–600, 1997Google Scholar
  18. Dardes R, Horiguchi J, Jordan V: A pilot study of the effects of short-term tamoxifen therapy on Ki67 labelling index in women with primary breast cancer. Int J Oncol 16: 2000Google Scholar
  19. Chang J, Powles T, Allred D, Ashley S, Clark G, Makris A, Assersohn L, Gregory R, Osborne C, Dowsett M: Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol 17: 3058–3063, 1999Google Scholar
  20. Makris A, Powles TJ, Allred DC, Ashley SE, Trott PA, Ormerod MG, Titley JC, Dowsett M: Quantitative changes in cytological molecular markers during primary medical treatment of breast cancer: a pilot study. Breast Cancer Res Treat 53: 51–59, 1999Google Scholar
  21. Chang J, Powles T, Allred D, Ashley S, Makris A, Gregory R, Osborne C, Dowsett M: Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients. Clin Cancer Res 6: 616–621, 2000Google Scholar
  22. Hayward J, Carbone P, Heuson J, Kumaoka S, Segaloff A, Rubens R: Assessment of response to therapy in advanced breast cancer. Br J Cancer 35: 292–298, 1977Google Scholar
  23. Powles TJ, Hickish TF, Makris A, Ashley SE, O'Brien MER, Tidy VA, Casey S, Nash AG, Sacks N, Cosgrove D, MacVicar D, Fernando I, Ford HT: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13: 547–552, 1995Google Scholar
  24. Iqbal S, Anderson TJ, Marson LP, Prescott RJ, Dixon JM, Miller WR: MIB-1 assessments in breast cancers. The Breast 11: 252–256, 2002Google Scholar
  25. Iqbal S, Anderson TJ, Marson LP, Prescott RJ, Dixon JM, Miller WR: MIB-1 assessments in breast cancers. The Breast 11: 252–256, 2002Google Scholar
  26. Nizzoli R, Bozzetti C, Naldi N, Guazzi A, Babrielli M, Michiara M, Camisa R, Barilli A, Cocconi G: Comparison of the results of immunocytochemical assays for biologic variables on preoperative fine-needle aspirates and on surgical specimens of primary breast carcinomas. Cancer (Cancer Cytopathology) 90: 61–66, 2000Google Scholar
  27. Kenny F, Willsher P, Gee J, Nicholson R, Pinder S, Ellis I, Robertson J: Change in expression of ER, bcl-2 and MIB1 on primary tamoxifen and relation to response in ER positive breast cancer. Breast Cancer Res Treat 65: 135–144, 2001Google Scholar
  28. Dowsett M, Bundred N, Decensi A, Sainsbury R, Lu Y, Hills M, Cohen F, Veronesi P, O'Brien M, Scott T, Muchmore D: Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients. Cancer Epidemiology, Biomarkers Prevent 10: 961–966, 2001Google Scholar
  29. Altman DG, Lyman GH: Methodological challenges in the evaluation of prognostic factors in breast cancer. Breast Cancer Res Treat 52: 289–303, 1998Google Scholar
  30. Shipp M, Ross K, Tamayo P, Weng A, Kutok J, Aguiar R, Gaasenbeek M, Angelo M, Reich M, Pinkus G, Ray T, Koval M, Last K, Norton A, Lister T, Mesirov J, Neuberg D, Lander E, Aster J, Golub T: Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nature Med 8: 68–74, 2002Google Scholar
  31. Rosenwald A, Wright G, Chan W, Connors JE, Fisher R, Gascoyne R, Muller-Hermelink H, Smeland E, Staudt L: The use of molecular profiling to predict survival after chemotherapy for diffuse large B cell lymphoma. N Engl J Med 346: 1937–1947, 2002Google Scholar
  32. Perou C, Sorlie T, Eisen M, van de Rijn M, Jeffrey S, Rees C, Pollack J, Ross D, Johnsen H, Akslen L, Fluge O, Pergamenschikov A, Williams C, Zhu S, Lonning P, Borresen-Dale A, Brown P, Botstein D: Molecular portraits of human breast tumours. Nature 406: 747–752, 2000Google Scholar
  33. Alizadeh A, Eisen M, Davis R, Ma C, Lossos I, Rosenwald A, Boldrick J, Sabet H, Tran T, Yu X, Powell J, Yang L, Marti G, Moore T, Hudson J, Lu L, Lewis D, Tabshirani R, Sherlock G, Chan W, Greiner T, Weisenburger D, Armitae J, Warnke R, Levy R, Wilson W, Grever M, Byrd J, Botstein D, Brown P, Staudt L: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403: 503–511, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • L. Assersohn
    • 1
  • J. Salter
    • 2
  • T.J. Powles
    • 1
  • R. A'hern
    • 2
  • A. Makris
    • 3
  • R.K. Gregory
    • 4
  • J. Chang
    • 5
  • M. Dowsett
    • 1
  1. 1.Breast UnitRoyal Marsden HospitalSutton, SurreyUK
  2. 2.Academic BiochemistryRoyal Marsden HospitalLondonUK
  3. 3.Marie Curie Research WingMount Vernon HospitalNorthwood, MiddlesexUK
  4. 4.Southampton University Hospitals TrustShirley, SouthamptonUK
  5. 5.Breast CenterBaylor College of MedicineHoustonUSA

Personalised recommendations