Cell Kinetics

  • Maria Grazia Daidone
  • Rosella Silvestrini
  • Dino Amadori
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Cell proliferative activity represents one of the biological processes most widely investigated because of its association with tumor progression, and in the past years many laboratories have set up and compared different approaches to measure the proliferation of tumor cells for clinical use. Although available results suggest that the majority of proliferation indices may help clinicians in treatment decision making, their clinical usefulness is still controversial owing to some unresolved technical issues linked to preanalytical and analytical aspects and, most importantly, to interpretation of results. However, some laboratories have dedicated considerable time and effort to develop and optimize reproducible methods and standardized methodologies to quantify cell proliferation in clinical tumors, to assess laboratory performance and reproducibility, and to validate preliminary results. Prospective randomized clinical studies have demonstrated the prognostic and predictive significance of breast cancer proliferative activity in different clinical situations. Novel prospective, multicenter, randomized clinical trials of adjuvant chemotherapy are ongoing to test the utility of cell kinetics to define therapy options for patients with negative or one to three positive nodes presenting rapidly proliferating tumors considered at high risk of relapse. The results will probably help to better establish the predictive role and clinical usefulness of proliferation indices for their transferral to general oncology practice.

Key Words

Assay standardization cell kinetic-based clinical trials posttreatment variations prognostic and predictive relevance 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Clurman BE, Roberts JM. Cell cycle and cancer. J Natl Cancer Inst 1995;87:1499–2005.PubMedCrossRefGoogle Scholar
  2. 2.
    Gillett CE, Barnes DM. Demystified…cell cycle. Mol Pathol 1998;51:310–316.PubMedGoogle Scholar
  3. 3.
    Barnes DM, Gillett CE. Determination of cell proliferation. J Clin Pathol Mol Pathol 1995;48:M2–M5.Google Scholar
  4. 4.
    Amadori D, Silvestrini R. Prognostic and predictive value of thymidine labelling index in breast cancer. Breast Cancer Res Treat 1998;51:267–281.PubMedCrossRefGoogle Scholar
  5. 5.
    Daidone MG, Silvestrini R. Prognostic and predictive role of proliferation indices in adjuvant therapy of breast cancer. J Natl Cancer Inst 2001;30:27–35.Google Scholar
  6. 6.
    Paradiso A, Volpe S, Iacobacci A, et al. Quality control for biomarker determination in oncology: the experience of the Italian Network for Quality Assessment of Tumour Biomarkers (INQAT). Int J Biol Markers 2002;17:201–214.PubMedGoogle Scholar
  7. 7.
    Amadori D, Nanni O, Marangolo M, et al. Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate and fluorouracil in patients with node-negative rapidly proliferating breast cancer: a randomized multicenter study. J Clin Oncol 2000;18:3125–3134.PubMedGoogle Scholar
  8. 8.
    Paradiso A, Schittulli F, Cellamare G, et al. Randomized clinical trial of adjuvant fluorouracil, epirubicin, and cyclophosphamide chemotherapy for patients with fast-proliferating, node-negative breast cancer. J Clin Oncol 2001;19:3929–3937.PubMedGoogle Scholar
  9. 9.
    Silvestrini R. Cell kinetics: prognostic and therapeutic implications in human tumors. Cell Prolif 1994;27:579–596.Google Scholar
  10. 10.
    van Diest PJ, Brugal G, Baak JP A. Proliferation markers in tumours: interpretation and clinical value. J Clin Pathol 1998;51:716–724.PubMedGoogle Scholar
  11. 11.
    Quinn CM, Wright NA. The clinical assessment of proliferation and growth in human tumours: evaluation of methods and applications as prognostic variables. J Pathol 1990;160:93–102.PubMedCrossRefGoogle Scholar
  12. 12.
    van Diest PJ, Baak JP, Matze-Cok P, et al. Reproducibility of mitosis counting in 2,469 breast cancer specimens: results from the Multi-Center Morphometric Mammary Carcinoma Project. Hum Pathol 1992;23:603–607.PubMedCrossRefGoogle Scholar
  13. 13.
    Meyer JS, Connor RE. In vitro labeling of solid tissues with tritiated thymidine for autoradiographic detection of S-phase nuclei. Stain Technol 1977;52:185–195.PubMedGoogle Scholar
  14. 14.
    Hedley DW. Flow cytometry using paraffin-embedded tissue: five years on. Cytometry 1989;10:229–241.PubMedCrossRefGoogle Scholar
  15. 15.
    Bagwell CB, Clark GM, Spyratos F, et al. Optimizing flow cytometric DNA ploidy and S-phase fraction as independent prognostic markers for node-negative breast cancer specimens. Cytometry 2001;46:121–135.PubMedCrossRefGoogle Scholar
  16. 16.
    Cattoretti G, Becker MHG, Key G, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 1992;168:357–363.PubMedCrossRefGoogle Scholar
  17. 17.
    Galand P, Degraef C. Cyclin/PCNA immunostaining as an alternative to tritiated thymidine pulse labeling for marking S phase cells in paraffin sections from animal and human tissues. Cell Tissue Kinet 1989;22:383–392.PubMedGoogle Scholar
  18. 18.
    Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000;182:311–322.PubMedCrossRefGoogle Scholar
  19. 19.
    Rudolph P, Alm P, Heidebrecht HJ, et al. Immunologic proliferation marker Ki-S2 as prognostic indicator for lymph node-negative breast cancer. J Natl Cancer Inst 1999;91:271–278.PubMedCrossRefGoogle Scholar
  20. 20.
    Howell WM. Selective staining of nucleolar organizer regions (NORs) In: Bush H, Tothblum L, eds. The Cell Nucleus. Academic Press, New York, 1982:89–142.Google Scholar
  21. 21.
    He W, Meyer JS, Scrivner DL, Koehm S, Hughes J. Assessment of proliferating cell nuclear antigen (PCNA) in breast cancer using anti-PCNA and 19A2: correlation with 5-bromo-2′-deoxyuridine or tritiated thymidine labeling and flow cytometric analysis. Biotechn Histochem 1994;69:203–212.CrossRefGoogle Scholar
  22. 22.
    Silvestrini R and the SICCAB Group for Quality Control of Cell Kinetic Determination. Feasibility and reproducibility of the 3H-dT labeling index in breast cancer. Cell Prolif 1991;24:437–445.PubMedGoogle Scholar
  23. 23.
    Collan YU, Kuopio T, Baak JP, et al. Standardized mitotic counts in breast cancer. Evaluation of the method. Pathol Res Pract 1996;192:931–941.PubMedGoogle Scholar
  24. 24.
    Baldetorp B, Bendahl PO, Ferno M, et al. Reproducibility in DNA flow cytometric analysis of breast cancer: comparison of 12 laboratories’ results for 67 sample homogenates. Cytometry 1995;22:115–127.PubMedCrossRefGoogle Scholar
  25. 25.
    Mengel M, von Wasielewski R, Wiese B, Rudiger T, Muller-Hermelin HK, Kreipe H. Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multicentre trial. J Pathol 2002;198:292–299.PubMedCrossRefGoogle Scholar
  26. 26.
    Silvestrini R, Daidone MG, Del Bino G, et al. Prognostic significance of proliferative activity and ploidy in node-negative breast cancers. Ann Oncol 1993;4:213–219.PubMedGoogle Scholar
  27. 27.
    Rudas M, Gnant MFX, Mittlböck M, et al. Thymidine labeling index and Ki-67 growth fraction in breast cancer: comparison and correlation with prognosis. Breast Cancer Res Treat 1994;32:165–175.PubMedCrossRefGoogle Scholar
  28. 28.
    Gaglia P, Bernardi A, Venesio T, et al. Cell proliferation of breast cancer evaluated by anti-BrdU and anti-Ki-67 antibodies: its prognostic value on short-term recurrences. Eur J Cancer 1993;29A:1509–1513.PubMedCrossRefGoogle Scholar
  29. 29.
    Thor AD, Liu S, Moore IIDH, Edgerton SM. Comparison of mitotic index, in vitro bromodeoxyuridine labeling, and MIB-1 assay s to quantitate proliferation in breast cancer. J Clin Oncol 1999;17:470–477.PubMedGoogle Scholar
  30. 30.
    Meyer JS, Province MA. S-phase fraction and nuclear size in long-term prognosis of patients with breast cancer. Cancer 1994;74:2287–2299.PubMedCrossRefGoogle Scholar
  31. 31.
    Peirò G, Lerma E, Climent MA, Seguf MA, Alonso MC, Prat J. Prognostic value of S-phase fraction in lymph-node-negative breast cancer by image and flow cytometric analysis. Mod Pathol 1997;10:216–222.PubMedGoogle Scholar
  32. 32.
    Winchester DJ, Duda RB, August CZ, et al. The importance of DNA flow cytometry in node-negative breast cancer. Arch Surg 1990;125:886–889.PubMedGoogle Scholar
  33. 33.
    Simpson JF, Gray R, Dressler LG, et al. Prognostic value of histological grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 2000;18:2059–2069.PubMedGoogle Scholar
  34. 34.
    Hatschek T, Gröntoft O, Fagerberg G, et al. Cytometric and histopathological features of tumors detected in a randomized mammography screening program: correlation and relative prognostic influence. Breast Cancer Res Treat 1990;15:149–160.PubMedCrossRefGoogle Scholar
  35. 35.
    Eskelinen M, Lipponen P, Papinaho S, et al. DNA flow cytometry, nuclear morphometry, mitotic indices and steroid receptors as independent prognostic factors in female breast cancer. Int J Cancer 1992;51:555–561.PubMedCrossRefGoogle Scholar
  36. 36.
    Lipponen P, Papinaho S, Eskelinen M, et al. DNA ploidy, S-phase fraction and mitotic indices as prognostic predictors of female breast cancer. Anticancer Res 1992;12:1533–1538.PubMedGoogle Scholar
  37. 37.
    Joensuu H, Toikkanen S, Klemi PJ. DNA index and S-phase fraction and their combination as prognostic factors in operable ductal breast carcinoma. Cancer 1990;66:331–340.PubMedCrossRefGoogle Scholar
  38. 38.
    Keshgegian AA, Cnaan A. Proliferation markers in breast carcinoma. Mitotic figure count, S-phase fraction, proliferation cell nuclear antigen, Ki-67 and MIB-1. Anat Pathol 1995;104:42–49.Google Scholar
  39. 39.
    Dettmar P, Harbeck N, Thomssen C, et al. Prognostic impact of proliferation-associated factors MIB (Ki-67) and S-phase in node-negative breast cancer. Br J Cancer 1997;75:1525–1533.PubMedGoogle Scholar
  40. 40.
    Harbeck N, Dettmar P, Thomssen C, et al. Prognostic impact of tumor biological factors on survival in node-negative breast cancer. Anticancer Res 1998;18:2187–2197.PubMedGoogle Scholar
  41. 41.
    Railo M, Lundin J, Haglund C, von Smitten K, von Boguslawsky K, Nordling S. Ki-67, p53, Er-receptors, ploidy and S-phase as prognostic factors in T1 node negative breast cancer. Acta Oncol 1997;36:369–374.PubMedGoogle Scholar
  42. 42.
    Brown WR, Allred DC, Clark GM, Osborne CK, Hilsenbeck SG. Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res 1996;2:585–592.PubMedGoogle Scholar
  43. 43.
    Wiesener B, Hauser-Kronberger CE, Zipperer E, Dietze O, Menzel C, Hacker GW. p34cdc2 in invasive breast cancer: relationship to DNA content, Ki67 index and c-erbB-2 expression. Histopathology 1998;33:522–530.PubMedCrossRefGoogle Scholar
  44. 44.
    Gasparini G, Boracchi P, Verderio P, Bevilacqua P. Cell kinetics in human breast cancer: comparison between the prognostic value of the cytofluorimetric S-phase fraction and that of the antibodies to Ki-67 and PCNA antigens detected by immunocytochemistry. Int J Cancer 1994;57:822–829.PubMedCrossRefGoogle Scholar
  45. 45.
    Jansen RL, Hupperets PS, Arends JW, et al. MIB-1 labelling index is an independent prognostic marker in primary breast cancer. Br J Cancer 1998;78:460–465.PubMedGoogle Scholar
  46. 46.
    Leong AC, Hanby AM, Potts HW, et al. Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast. Int J Cancer 2000;89:26–31.PubMedCrossRefGoogle Scholar
  47. 47.
    Clahsen PC, van de Velde CY, Duval C, 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. Eur J Surg Oncol 1999;25:356–363.PubMedCrossRefGoogle Scholar
  48. 48.
    Jacquemier JD, Penault-Llorca FM, Bertucci F, et al. Angiogenesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapy: a multi-parametric and immunohistochemical analysis. J Pathol 1998;184:130–135.PubMedCrossRefGoogle Scholar
  49. 49.
    Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM, Syrjanen K. The important prognostic value of Ki-67 expression as determined by image analysis in breast cancer. J Cancer Res Clin Oncol 1996;122:687–692.PubMedCrossRefGoogle Scholar
  50. 50.
    Hayes DF, Trock B, Harris AL. Assessing the clinical impact of prognostic factors: when is “statistically significant” clinically useful? Breast Cancer Res Treat 1998;52:305–319.PubMedCrossRefGoogle Scholar
  51. 51.
    Medri L, Nanni O, Volpi A, et al. Tumor microvessel density and prognosis in node-negative breast cancer. Int J Cancer 2000;89:74–80.PubMedCrossRefGoogle Scholar
  52. 52.
    Paradiso A, Mangia A, Barletta A, et al. Heterogeneity of intratumour proliferative activity in primary breast cancer: biological and clinical aspects. Eur J Cancer 1995;31A:911–916.PubMedCrossRefGoogle Scholar
  53. 53.
    Silvestrini R, Daidone MG, Di Fronzo G, Morabito A, Valagussa P, Bonadonna G. Prognostic implication of labelling index versus estrogen receptors and tumor size in node-negative breast cancer. Breast Cancer Res Treat 1986;7:161–169.PubMedCrossRefGoogle Scholar
  54. 54.
    Courdi A, Hery M, Dahan E, et al. Factors affecting relapse in node-negative breast cancer. A multivariate analysis including the labeling index. Eur J Cancer Clin Oncol 1989;25:351–356.PubMedCrossRefGoogle Scholar
  55. 55.
    Silvestrini R, Daidone MG, Luisi A, et al. Biologic and clinico-pathological factors as indicators of specific relapse types in node-negative breast cancer. J Clin Oncol 1995;13:697–704.PubMedGoogle Scholar
  56. 56.
    Cooke TG, Stanton PD, Winstanley J, et al. Long term prognostic significance of thymidine labeling index in primary breast cancer. Eur J Cancer 1992;28:424–426.PubMedCrossRefGoogle Scholar
  57. 57.
    Tubiana M, Pejovic MH, Koscielny S, Chavaudra N, Malaise E. Growth rate, kinetics of tumor cell proliferation and long-term outcome in human breast cancer. Int J Cancer 1989;44:17–22.PubMedCrossRefGoogle Scholar
  58. 58.
    Aubele M, Auer G, Falkmer U, et al. Identification of a low-risk group of stage I breast cancer patients by cytometrically assessed DNA and nuclear texture parameters. J Pathol 1995;177:377–384.PubMedCrossRefGoogle Scholar
  59. 59.
    Sigurdsson H, Baldetorp B, Borg A, et al. Indicators of prognosis in node-negative breast cancer. N Engl J Med 1990;322:1045–1049.PubMedCrossRefGoogle Scholar
  60. 60.
    O’Reilly SM, Camplejohn RS, Barnes DM, Millis RR, Rubens RD, Richards MA. Node-negative breast cancer: prognostic subgroups defined by tumor size and flow cytometry. J Clin Oncol 1990;8:2040–2045.PubMedGoogle Scholar
  61. 61.
    Harbeck N, Dettmar P, Thomssen C, et al. Risk-group discrimination in node-negative breast cancer using invasion and proliferation markers: 6-year median follow-up. Br J Cancer 1999;80:419–426.PubMedCrossRefGoogle Scholar
  62. 62.
    Merkel DE, Winchester DJ, Goldschmidt RA, August CZ, Wruck DM, Rademaker AW. DNA flow cytometry and pathological grading as prognostic guides in axillary lymph node-negative breast cancer. Cancer 1993;72:1926–1932.PubMedCrossRefGoogle Scholar
  63. 63.
    Balslev I, Christensen IJ, Bruun Rasmussen B, et al. Flow cytometric DNA ploidy defines patients with poor prognosis in node-negative breast cancer. Int J Cancer 1994;56:16–25.PubMedGoogle Scholar
  64. 64.
    Stal O, Dufmats M, Hatscheck T, et al. S-phase is a prognostic factor in stage I breast carcinoma. J Clin Oncol 1993;11:1717–1722.PubMedGoogle Scholar
  65. 65.
    Isola J, Visakorpi T, Holli K, Kallioniemi OP. Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst 1992;84:1109–1114.PubMedCrossRefGoogle Scholar
  66. 66.
    Bosari S, Lee AK, Tahan SR, et al. DNA flow cytometric analysis and prognosis of axillary lymph node-negative breast carcinoma. Cancer 1992;70:1943–1950.PubMedCrossRefGoogle Scholar
  67. 67.
    Johnson H Jr, Masood S, Belluco C, et al. Prognostic factors in node-negative breast cancer. Arch Surg 1992;127:1386–1391.PubMedGoogle Scholar
  68. 68.
    Witzig TE, Ingle JN, Cha SS, et al. DNA ploidy and the percentage of cells in S-phase as prognostic factors for women with lymph node-negative breast cancer. Cancer 1994;74:1752–1761.PubMedCrossRefGoogle Scholar
  69. 69.
    Joensuu H, Toikkanem S. Identification of subgroups with favorable prognosis in breast cancer. Acta Oncol 1992;31:293–301.PubMedCrossRefGoogle Scholar
  70. 70.
    Klintenberg C, Stal O, Nordenskjold B, Wallgren A, Arvidsson S, Skoog L. Proliferative index, cytosol estrogen receptor and axillary node status as prognostic predictors in human mammary carcinoma. Breast Cancer Res Treat 1986;7:S99–106.PubMedGoogle Scholar
  71. 71.
    Arnerlov C, Emdin SO, Lundgren B, et al. Mammographic growth rate, DNA ploidy, and S-phase fraction analysis in breast carcinoma. Cancer 1992;70:1935–1942.PubMedCrossRefGoogle Scholar
  72. 72.
    Stanton PD, Cooke TG, Oakes SJ, et al. Lack of prognostic significance of DNA ploidy and S phase fraction in breast cancer. Br J Cancer 1992;66:925–929.PubMedGoogle Scholar
  73. 73.
    Fisher B, Gunduz N, Costantino J, et al. DNA flow cytometric analysis of primary operable breast cancer. Cancer 1991;68:1465–1469.PubMedCrossRefGoogle Scholar
  74. 74.
    Toikkanen S, Joensuu H, Klemi P. The prognostic significance of nuclear DNA content in invasive breast cancer—a study with long-term-follow-up. Br J Cancer 1989;60:693–700.PubMedGoogle Scholar
  75. 75.
    Laderkarl M, Jensen V. Quantitative histopathology in lymph node-negative breast cancer. Prognostic significance of mitotic count. Virchows Arch 1995;427;265–270.Google Scholar
  76. 76.
    Kato T, Kimura T, Miyakawa R, et al. Clinicopathological study associated with long-term survival in Japanese patients with node-negative breast cancer. Br J Cancer 2000;82:404–411.PubMedCrossRefGoogle Scholar
  77. 77.
    Aaltomaa S, Lipponen P, Eskelinen M, et al. Prognostic scores combining clinical, histological and morphometric variables in assessment of the disease outcome in female breast cancer. Int J Cancer 1991;49:886–892.PubMedCrossRefGoogle Scholar
  78. 78.
    Clayton F. Pathologic correlates of survival in 378 lymph node-negative infiltrating ductal breast carcinomas. Mitotic count is the best single predictor. Cancer 1991;68:1309–1317.PubMedCrossRefGoogle Scholar
  79. 79.
    Iacopetta B, Grieu F, Powell B, Soong R, McCaul K, Seshadri R. Analysis of p53 gene mutation by polymerase chain reaction-single strand conformational polymorphism provides independent prognostic information in node-negative breast cancer. Clin Cancer Res 1998;4:1597–1602.PubMedGoogle Scholar
  80. 80.
    Pinder SE, Wencyk P, Sibbering DM, et al. Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: associations with other prognostic factors and survival. Br J Cancer 1995;71:146–149.PubMedGoogle Scholar
  81. 81.
    Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998;90:1601–1608.PubMedCrossRefGoogle Scholar
  82. 82.
    Hutchins L, Green S, Ravdin P, Lew D, Martino S, Abeloff M. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of Intergroup trial INT 0102. In: Proceedings of the 34th Annual Meeting of the American Association of Cancer Research, 1998; Abstr 2.Google Scholar
  83. 83.
    Sulkes A, Livingstone RB, Murphy WK. Tritiated thymidine labeling index and response in human breast cancer. J Natl Cancer Inst 1979;62:513–515.PubMedGoogle Scholar
  84. 84.
    Amadori D, Volpi A, Maltoni R, et al. Cell proliferation as a predictor of response to chemotherapy in metastatic breast cancer: a prospective study. Breast Cancer Res Treat 1997;43:7–14.PubMedCrossRefGoogle Scholar
  85. 85.
    Remvikos Y, Beuzeboc P, Zajdela A, Voillemot N, Magdelenat H, Pouillart P. Correlation of pretreatment proliferative activity of breast cancer with the response to cytotoxic chemotherapy. J Natl Cancer Inst 1989;81:1383–1387.PubMedCrossRefGoogle Scholar
  86. 86.
    Hietanen P, Blomqvist C, Wasenius VM, Niskanen E, Franssila K, Nordling S. Do DNA ploidy and S-phase fraction in primary tumor predict the response to chemotherapy in metastatic breast cancer? Br J Cancer 1995;71:1029–1032.PubMedGoogle Scholar
  87. 87.
    Stål O, Skoog L, Rutqvist LE, et al. S-phase fraction and survival benefit from adjuvant chemotherapy or radiotherapy of breast cancer. Br J Cancer 1994;70:1258–1272.PubMedGoogle Scholar
  88. 88.
    O’Reilly SM, Camplejohn RS, Millis RR, Rubens RD, Richards MA. Proliferative activity, histological grade and benefit from adjuvant chemotherapy in node-positive breast cancer. Eur J Cancer 1990;26:1035–1038.PubMedCrossRefGoogle Scholar
  89. 89.
    Dressler LG, Eudey L, Gray R, et al. Prognostic potential of DNA flow cytometry measurements in node-negative breast cancer patients: preliminary analysis of an Intergroup study (INT 0076). J Natl Cancer Inst Monogr 1992;11:167–172.PubMedGoogle Scholar
  90. 90.
    Zambetti M, Valagussa P, Bonadonna G. Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Updated results. Ann Oncol 1996;7:481–485.PubMedGoogle Scholar
  91. 91.
    Silvestrini R, Luisi A, Zambetti M, et al. Cell proliferation and outcome following doxorubicin plus CMF regimens in node-positive breast cancer. Int J Cancer 2000;87:405–411.PubMedCrossRefGoogle Scholar
  92. 92.
    Daidone MG, Veneroni S, Benini E, et al. Biological markers and changes induced in their profiles following primary chemotherapy: relevance for short-and long-term clinical outcome. In: Howell A and Dowsett M, eds. ESO Scientific Updates, Vol. 4. Elsevier, Philadelphia, 1999:53–72.Google Scholar
  93. 93.
    Baldini E, Giannessi PG, Collecchi P, et al. Effects of primary chemotherapy on proliferative activity, IGF-1R and bcl2 expression in locally advanced breast cancer (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1996;15:Abstr 139.Google Scholar
  94. 94.
    Briffod M, Tubiana-Hulin M, Spyratos F, et al. Fine-needle cytopunctures for early prediction of tumor response to preoperative chemotherapy in 94 operable breast carcinomas. Proc Annu Meet Am Soc Clin Oncol 1995;14:Abstr 261.Google Scholar
  95. 95.
    Chevillard S, Pouillart P, Beldjord C, et al. Sequential assessment of multidrug resistance phenotype and measurement of S-phase fraction as predictive markers of breast cancer response to neoadjuvant chemotherapy. Cancer 1996;77:292–300.PubMedCrossRefGoogle Scholar
  96. 96.
    Collecchi P, Baldini E, Giannessi P, et al. Primary chemotherapy in locally advanced breast cancer (LABC): effects on tumour proliferative activity, bcl-2 expression and the relationship between tumour regression and biological markers. Eur J Cancer 1998;34:1701–1704.PubMedCrossRefGoogle Scholar
  97. 97.
    Daidone MG, Silvestrini R, Luisi A, et al. Changes in biological markers after primary chemotherapy for breast cancers. Int J Cancer 1995;61:301–305.PubMedCrossRefGoogle Scholar
  98. 98.
    Pierga JY, Lainé-Bidron C, Beuzeboc P, De Crémoux P, Pouillart P, Magdelénat H. Plasminogen activator inhibitor-1 (PAI-1) is not related to response to neoadjuvant chemotherapy in breast cancer. Br J Cancer 1997;76:537–540.PubMedGoogle Scholar
  99. 99.
    Rozan S, Vincent-Salomon A, Zafrani B, et al. No significant predictive value of c-erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer. Int J Cancer (Pred Oncol) 1998;79:27–33.CrossRefGoogle Scholar
  100. 100.
    Remvikos Y, Mosseri V, Asselain B, et al. S-phase fractions of breast cancer predict overall and post-relapse survival. Eur J Cancer 1997;33:581–586.PubMedCrossRefGoogle Scholar
  101. 101.
    Dowsett M. Preoperative models to evaluate endocrine strategies for breast cancer. Clin Cancer Res 2003;9:502S–510S.PubMedGoogle Scholar
  102. 102.
    Decensi A, Robertson C, Viale G, et al. A randomized trial of low dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 2003;95:779–790.PubMedCrossRefGoogle Scholar
  103. 103.
    Meyer JS, Lee J. Relationships of S-phase fraction of breast carcinoma in relapse to duration of remission, estrogen receptor content, therapeutic responsiveness, and duration of survival. Cancer Res 1980;40:1890–1896.PubMedGoogle Scholar
  104. 104.
    Amadori D, Bonaguri C, Nanni O, et al. Cell kinetics and hormonal features in relation to pathological stage in breast cancer. Breast Cancer Res Treat 1991;18:19–25.PubMedCrossRefGoogle Scholar
  105. 105.
    Paradiso A, Tommasi S, Mangia A, Lorusso V, Simone G, De Lena M. Tumor proliferative activity, progesterone receptor status, estrogen receptor level, and clinical outcome of estrogen receptor-positive advanced breast cancer. Cancer Res 1990;50:2958–2962.PubMedGoogle Scholar
  106. 106.
    Daidone MG, Luisi A, Martelli G, et al. Biomarkers and outcome after tamoxifen treatment in node-positive breast cancers from elderly women. Br J Cancer 2000;82:270–277.PubMedCrossRefGoogle Scholar
  107. 107.
    Wenger CR, Clark GM. S-phase fraction and breast cancer3-a decade of experience. Breast Cancer Res Treat 1998;51:255–265.PubMedCrossRefGoogle Scholar
  108. 108.
    Volpi A, De Paola F, Nanni O, et al. Prognostic significance of biologic markers in node-negative breast cancer patients: a prospective study. Breast Cancer Res Treat 2000;63:181–192.PubMedCrossRefGoogle Scholar
  109. 109.
    Ferno M, Stal O, Baldetorp B, et al. Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels. Breast Cancer Res Treat 2000;59:69–76.PubMedCrossRefGoogle Scholar
  110. 110.
    Bryant J, Fisher B, Gunduz N, Costantino JP, Emir B. S-phase fraction combined with other patient and tumor characteristics for the prognosis of node-negative, estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 1998;51:239–253.PubMedCrossRefGoogle Scholar
  111. 111.
    Jones S, Clark G, Koleszar S, et al. Low proliferative rate of invasive node-negative breast cancer predicts for a favorable outcome: a prospective evaluation of 669 patients. Clin Breast Cancer 2001;1:310–314.PubMedCrossRefGoogle Scholar
  112. 112.
    Jones S, Clark G, Koleszar S, et al. Adjuvant chemotherapy with doxorubicn and cyclophosphamide in women with rapidly proliferating node-negative breast cancer. Clin Breast Cancer 2002;3:147–152.PubMedGoogle Scholar
  113. 113.
    Baak JP, van Diest PJ, Benraadt T, et al. The Multi-Center Morphometric Mammary Carcinoma Project (MMMCP) in The Netherlands; value of morphometrically assessed proliferation and differentiation. J Cell Biochem Suppl 1993;17G:220–225.PubMedCrossRefGoogle Scholar
  114. 114.
    Sargent D, Allegra C. Issues in clinical trial design for tumor marker studies. Semin Oncol 2002;29:222–230.PubMedCrossRefGoogle Scholar
  115. 115.
    D’hautcourt JL, Spyratos F, Chassevent A. Quality control study by the French Cytometry Association on flow cytometric DNA content and S-phase fraction (S%). Assoc Francaise de Cytometrie. Cytometry 1996;26:32–39.CrossRefGoogle Scholar
  116. 116.
    Fitzgibbons PL, Page DL, Weaver D, et al. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124:966–978.PubMedGoogle Scholar
  117. 117.
    NIH-NCI consensus development conference. J Natl Cancer Inst 2001;93:979–989.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Maria Grazia Daidone
    • 1
  • Rosella Silvestrini
    • 2
  • Dino Amadori
    • 3
  1. 1.Department of Experimental OncologyNational Cancer InstituteMilanItaly
  2. 2.National Cancer InstituteMilanItaly
  3. 3.Division of Oncology and DiagnosticsPierantoni HospitalForliItaly

Personalised recommendations