Proliferation marker Ki-67 in early breast cancer.

Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer. Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67. The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake. High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios. However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs.

[1]  S. Hilsenbeck,et al.  Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  M. J. van de Vijver,et al.  The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer. , 1999, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[3]  H. Rochefort,et al.  The antiproliferative effect of tamoxifen in breast cancer cells: mediation by the estrogen receptor , 1984, Molecular and Cellular Endocrinology.

[4]  R. Broll,et al.  Colorectal carcinomas with high MIB‐1 labelling indices but low pKi67 mRNA levels correlate with better prognostic outcome , 2003, Histopathology.

[5]  W. Weikel,et al.  Growth fractions (Ki-67) in primary breast cancers, with particular reference to node-negative tumors. , 1995, Cancer detection and prevention.

[6]  T. Powles,et al.  Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[7]  I. Kill Localisation of the Ki-67 antigen within the nucleolus. Evidence for a fibrillarin-deficient region of the dense fibrillar component. , 1996, Journal of cell science.

[8]  A. Antón,et al.  Weekly docetaxel as neoadjuvant chemotherapy for stage II and III breast cancer: efficacy and correlation with biological markers in a phase II, multicenter study. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  M. Fernö,et al.  Differential prognostic impact of the cyclins E and B in premenopausal and postmenopausal women with lymph node‐negative breast cancer , 2003, International journal of cancer.

[10]  S. Chevillard,et al.  Long term prognostic value of growth fraction determination by Ki-67 immunostaining in primary operable breast cancer , 2005, Breast Cancer Research and Treatment.

[11]  K. Zedeler,et al.  Correlation of growth fraction by Ki-67 and proliferating cell nuclear antigen (PCNA) immunohistochemistry with histopathological parameters and prognosis in primary breast carcinomas , 2005, Breast Cancer Research and Treatment.

[12]  M. Dowsett,et al.  Preoperative chemotherapy induces apoptosis in early breast cancer , 1997, The Lancet.

[13]  G. Hortobagyi,et al.  Ki‐67 immunostaining in node‐negative stage I/II breast carcinoma. Significant correlation with prognosis , 1991, Cancer.

[14]  A. Harris,et al.  Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  R. Gelber,et al.  Ki‐67 expression in breast carcinoma , 2003, Cancer.

[16]  M. Mitze,et al.  Immunohistochemical evaluation of growth fractions in human breast cancers using monoclonal antibody Ki-67 , 1991, Breast Cancer Research and Treatment.

[17]  F Pozza,et al.  Breast cancer cell kinetics: immunocytochemical determination of growth fractions by monoclonal antibody Ki-67 and correlation with flow cytometric S-phase and with some features of tumor aggressiveness. , 1991, Anticancer research.

[18]  M. Dowsett,et al.  Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  J. Cuzick,et al.  Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early‐stage breast cancer , 2003, Cancer.

[20]  T. Powles,et al.  Comparison of MIB-1 proliferation index with S-phase fraction in human breast carcinomas. , 1996, British Journal of Cancer.

[21]  S. Bruno,et al.  Cell cycle dependent expression and stability of the nuclear protein detected by Ki‐67 antibody in HL‐60 cells , 1992, Cell proliferation.

[22]  L. Skoog,et al.  Prognostic Significance of Tumor Cell Proliferation Analyzed in Fine Needle Aspirates from Primary Breast Cancer , 2004, Breast Cancer Research and Treatment.

[23]  M. Dowsett,et al.  Idoxifene antagonizes estradiol-dependent MCF-7 breast cancer xenograft growth through sustained induction of apoptosis. , 1999, Cancer research.

[24]  T. Powles,et al.  Studies of the Potential Utility of Ki67 as a Predictive Molecular Marker of Clinical Response in Primary Breast Cancer , 2003, Breast Cancer Research and Treatment.

[25]  W. Weikel,et al.  Usefulness of immunohistochemical staining for p53 in the prognosis of breast carcinomas: correlations with established prognosis parameters and with the proliferation marker, MIB-1. , 1995, Gynecologic oncology.

[26]  R. Jakesz,et al.  Expression of Cell Cycle Regulatory Proteins in Breast Carcinomas Before and After Preoperative Chemotherapy , 2003, Breast Cancer Research and Treatment.

[27]  M. Dowsett,et al.  The biology of neoadjuvant chemotherapy for breast cancer. , 2002, Endocrine-related cancer.

[28]  F. Spyratos,et al.  Correlation between MIB‐1 and other proliferation markers , 2002, Cancer.

[29]  G. Pelosi,et al.  Ki‐67 immunostaining in 322 primary breast cancers: Associations with clinical and pathological variables and prognosis , 1997, International journal of cancer.

[30]  C. Cornelisse,et al.  Nuclear distribution of the Ki-67 antigen during the cell cycle: comparison with growth fraction in human breast cancer cells. , 1989, Cancer research.

[31]  A. Howell,et al.  Dissociation between steroid receptor expression and cell proliferation in the human breast. , 1997, Cancer research.

[32]  M. Dowsett,et al.  Time‐related effects of estrogen withdrawal on proliferation‐ and cell death‐related events in MCF‐7 xenografts , 1999, International journal of cancer.

[33]  A. Thor,et al.  Measures of cell turnover (proliferation and apoptosis) and their association with survival in breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  J. Sloane,et al.  Estrogen receptor-positive proliferating cells in the normal and precancerous breast. , 1999, The American journal of pathology.

[35]  I. Ellis,et al.  Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: associations with other prognostic factors and survival. , 1995, British Journal of Cancer.

[36]  M. Fernö,et al.  Immunologic proliferation marker Ki-S2 as prognostic indicator for lymph node-negative breast cancer. , 1999, Journal of the National Cancer Institute.

[37]  T. Powles,et al.  Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma , 2000, Cancer.

[38]  C. Bartoli,et al.  Effects of short-term pre-operative tamoxifen on steroid receptor and Ki-67 expression in primary breast cancer: an immunocytochemical study. , 1998, International journal of oncology.

[39]  U. Veronesi,et al.  Changes in biological markers after primary chemotherapy for breast cancers , 1995, International journal of cancer.

[40]  T. Powles,et al.  Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[41]  Johannes Gerdes,et al.  Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation , 1983, International journal of cancer.

[42]  S. Singletary,et al.  Phase II clinical trial of N-(4-Hydroxyphenyl)retinamide and tamoxifen administration before definitive surgery for breast neoplasia. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  K. Maclennan,et al.  Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen. , 1994, European journal of cancer.

[44]  M. Dowsett,et al.  Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[45]  E. Petru,et al.  T1 Breast Cancer: Identification of Patients at Low Risk of Axillary Lymph Node Metastases , 2002, Breast Cancer Research and Treatment.

[46]  J. Gerdes,et al.  New Ki-67-equivalent murine monoclonal antibodies (MIB 1-3) generated against bacterially expressed parts of the Ki-67 cDNA containing three 62 base pair repetitive elements encoding for the Ki-67 epitope. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[47]  A. Luini,et al.  A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. , 2003, Journal of the National Cancer Institute.

[48]  I. Ellis,et al.  Relationship between EGF-R, c-erbB-2 protein expression and Ki67 immunostaining in breast cancer and hormone sensitivity. , 1993, European journal of cancer.

[49]  B. Iacopetta,et al.  Analysis of p53 gene mutation by polymerase chain reaction-single strand conformation polymorphism provides independent prognostic information in node-negative breast cancer. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[50]  G. Giaccone,et al.  Expression of drug resistance proteins in breast cancer, in relation to chemotherapy , 1997, International journal of cancer.

[51]  V. Kosma,et al.  The important prognostic value of Ki-67 expression as determined by image analysis in breast cancer , 2005, Journal of Cancer Research and Clinical Oncology.

[52]  M. Dowsett,et al.  Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy , 1998, Breast Cancer Research and Treatment.

[53]  M. Starborg,et al.  The murine Ki-67 cell proliferation antigen accumulates in the nucleolar and heterochromatic regions of interphase cells and at the periphery of the mitotic chromosomes in a process essential for cell cycle progression. , 1996, Journal of cell science.

[54]  M. Dowsett,et al.  Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  M. Gnant,et al.  Thymidine labeling index and Ki-67 growth fraction in breast cancer: Comparison and correlation with prognosis , 2004, Breast Cancer Research and Treatment.

[56]  M. Dowsett,et al.  Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[57]  T. Powles,et al.  Changes in hormone receptors and proliferation markers in tamoxifen treated breast cancer patients and the relationship with response , 1998, Breast Cancer Research and Treatment.

[58]  M. J. van de Vijver,et al.  Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome , 2003, British Journal of Cancer.

[59]  M. Ellis,et al.  Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. , 2003, Cancer research.

[60]  L. Skoog,et al.  Proliferating fraction during neoadjuvant chemotherapy of primary breast cancer in relation to objective local response and relapse-free survival. , 1999, Acta oncologica.

[61]  P. Boracchi,et al.  Value of epidermal growth factor receptor status compared with growth fraction and other factors for prognosis in early breast cancer. , 1992, British Journal of Cancer.

[62]  M. Dowsett,et al.  HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer. , 2001, Cancer research.

[63]  P. Bruzzi,et al.  Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer , 2001, British Journal of Cancer.

[64]  M. Hidalgo,et al.  Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[65]  M. Dowsett,et al.  Coordinate expression of apoptosis-associated proteins in human breast cancer before and during chemotherapy. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[66]  T. Venesio,et al.  Cell proliferation of breast cancer evaluated by anti-BrdU and anti-Ki-67 antibodies: its prognostic value on short-term recurrences. , 1993, European journal of cancer.

[67]  K. Sasaki,et al.  Measurement of bromodeoxyuridine labeling index, Ki-67 score and Ag-NOR count in breast carcinomas. Comparison with DNA ploidy. , 1992, Oncology.

[68]  Mikael Lundin,et al.  Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[69]  D B Evans,et al.  Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  G. Brugal,et al.  Ki-67 labeling in postmitotic cells defines different Ki-67 pathways within the 2c compartment. , 1991, Cytometry.

[71]  H. Müller-Hermelink,et al.  Cell cycle dependent distribution of the proliferation-associated Ki-67 antigen in human embryonic lung cells , 1988, Virchows Archiv. B, Cell pathology including molecular pathology.

[72]  H. Hara,et al.  Proliferation marker MIB‐1 correlates well with proliferative activity evaluated by BrdU in breast cancer: An immunohistochemical study including correlation with PCNA, p53, c‐erbB‐2 and estrogen receptor status , 1996, Pathology international.

[73]  K. Sasaki,et al.  Relationship between labeling indices of KI‐67 and brdurd in human malignant tumors , 1988, Cancer.

[74]  N. Bundred,et al.  Short‐term biologic response to withdrawal of hormone replacement therapy in patients with invasive breast carcinoma , 2003, Cancer.

[75]  V. Jordan,et al.  Effects of low dose tamoxifen on normal breast tissue from premenopausal women. , 2003, European journal of cancer.

[76]  J. Schulte‐Mönting,et al.  Ki‐67 immunostaining in human breast tumors and its relationship to prognosis , 1991, Cancer.

[77]  P. Lønning,et al.  Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels and proliferation markers in patients with locally advanced breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[78]  M. Fernö,et al.  Concurrent overexpression of p53 and c-erbB-2 correlates with accelerated cycling and concomitant poor prognosis in node-negative breast cancer. , 2001, Human pathology.

[79]  J. Gerdes,et al.  Assignment of the human Ki-67 gene (MKI67) to 10q25−qter , 1991 .

[80]  R. Parwaresch,et al.  Monoclonal antibodies Ki‐S3 and Ki‐S5 yield new data on the ‘Ki‐67’proteins , 1996, Cell proliferation.

[81]  J. Horiguchi,et al.  A pilot study of the effects of short-term tamoxifen therapy on Ki-67 labelling index in women with primary breast cancer. , 2000, International journal of oncology.

[82]  C. Osborne,et al.  Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  M. Fernö,et al.  Correlation between p53, c‐erbB‐2, and topoisomerase IIα expression, DNA ploidy, hormonal receptor status and proliferation in 356 node‐negative breast carcinomas: prognostic implications , 1999, The Journal of pathology.

[84]  Michael A. Gonzalez,et al.  Minichromosome maintenance protein 2 is a strong independent prognostic marker in breast cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[85]  I. Ellis,et al.  Ki67 immunostaining in primary breast cancer: pathological and clinical associations. , 1989, British Journal of Cancer.

[86]  I. Ellis,et al.  Change in Expression of ER, bcl-2 and MIB1 on Primary Tamoxifen and Relation to Response in ER Positive Breast Cancer , 2004, Breast Cancer Research and Treatment.

[87]  M. Dowsett,et al.  Comparison of the Short-Term Biological Effects of 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17β-diol (Faslodex) versus Tamoxifen in Postmenopausal Women with Primary Breast Cancer , 2001 .

[88]  A. Howell,et al.  Effect of tamoxifen on Ki67 labelling index in human breast tumours and its relationship to oestrogen and progesterone receptor status. , 1993, British Journal of Cancer.

[89]  P. Lipponen Apoptosis in breast cancer: relationship with other pathological parameters. , 1999, Endocrine-related cancer.

[90]  D. Horsfall,et al.  Relationship between p53 gene abnormalities and other tumour characteristics in breast‐cancer prognosis , 1996, International journal of cancer.

[91]  T. Petit,et al.  Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. , 2004, European journal of cancer.

[92]  F. Lacombe,et al.  Modalities of synthesis of Ki67 antigen during the stimulation of lymphocytes. , 1991, Cytometry.

[93]  H Stein,et al.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. , 1984, Journal of immunology.

[94]  M. Dowsett,et al.  Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[95]  A. Thor,et al.  Comparison of mitotic index, in vitro bromodeoxyuridine labeling, and MIB-1 assays to quantitate proliferation in breast cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  J. Gerdes,et al.  Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. , 1991, The American journal of pathology.

[97]  M. Dowsett,et al.  Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[98]  S. Nordling,et al.  Ki-67, p53, Er-receptors, ploidy and S-phase as prognostic factors in T1 node negative breast cancer. , 1997, Acta oncologica.

[99]  A. Howell,et al.  Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. , 1994, Cancer research.

[100]  M. Dowsett,et al.  Fulvestrant, an estrogen receptor downregulator, reduces cell turnover index more effectively than tamoxifen. , 2002, Anticancer research.

[101]  M. Key,et al.  Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. , 1991, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[102]  E. Prosperi Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control. , 1997, Progress in cell cycle research.

[103]  J. Gerdes,et al.  The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins , 1993, The Journal of cell biology.