Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Oct;85(8):1106–1112. doi: 10.1054/bjoc.2001.2048

Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer

A Bottini 1, A Berruti 3, A Bersiga 2, M P Brizzi 3, P Bruzzi 4, S Aguggini 1, A Brunelli 1, G Bolsi 2, G Allevi 1, D Generali 1, E Betri 2, G Bertoli 2, P Alquati 1, L Dogliotti 3
PMCID: PMC2375158  PMID: 11710821

Abstract

The association between tumour shrinkage and reduction in kinetic cell activity after primary chemotherapy in human breast cancer is still a matter of investigation. 157 patients with T2-4, N0-1, M0 breast cancer received primary chemotherapy consisting of either the CMF regimen + tamoxifen (the first consecutive 76 cases) or the single agent epirubicin (the subsequent 81). Ki67, p53, bcl2, c-erbB2 and steroid hormone receptors were evaluated immunohistochemically in tumour specimens obtained before chemotherapy and at surgery. Tumour shrinkage of >50% occurred in 72.4% of patients. Ki67 expression significantly decreased after chemotherapy; the reduction correlated with tumour response in both univariate (P < 0.005) and multivariate analysis (P = 0.02). p53, bcl-2, steroid hormone receptor and c-erbB2 immunostaining were scarcely affected. Baseline bcl2 (P = 0.04) and c-erbB2 (P = 0.02) were directly and inversely associated with the reduction in Ki67 immunostaining, respectively. Baseline p53 expression (P < 0.01) was directly related with Ki67 expression at residual tumour, whereas oestrogen receptor expression (P < 0.001) was inversely related. Ki67 at residual tumour was a better predictor for relapse-free survival (RFS) than baseline Ki67. Clinical response (P < 0.03), but not reduction in Ki67, was a significant independent predictor for disease recurrence. Chemotherapy was found to induce tumour shrinkage and to reduce the number of cells in the cell cycle, but its effect on tumour biology/aggressiveness was minimal. Reduction in Ki67 immunostaining correlated with clinical response but failed to be related to RFS. Ki67 expression at surgery rather than at baseline appears to be a better predictor for disease relapse. © 2001 Cancer Research Campaign  http://www.bjcancer.com

Keywords: Ki67, epirubicin, CMF, tamoxifen

Full Text

The Full Text of this article is available as a PDF (74.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bonadonna G., Valagussa P., Brambilla C., Ferrari L., Moliterni A., Terenziani M., Zambetti M. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol. 1998 Jan;16(1):93–100. doi: 10.1200/JCO.1998.16.1.93. [DOI] [PubMed] [Google Scholar]
  2. Bonadonna G., Veronesi U., Brambilla C., Ferrari L., Luini A., Greco M., Bartoli C., Coopmans de Yoldi G., Zucali R., Rilke F. Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst. 1990 Oct 3;82(19):1539–1545. doi: 10.1093/jnci/82.19.1539. [DOI] [PubMed] [Google Scholar]
  3. Bonetti A., Zaninelli M., Rodella S., Molino A., Sperotto L., Piubello Q., Bonetti F., Nortilli R., Turazza M., Cetto G. L. Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma. Breast Cancer Res Treat. 1996;38(3):289–297. doi: 10.1007/BF01806148. [DOI] [PubMed] [Google Scholar]
  4. Bottini A., Berruti A., Bersiga A., Brizzi M. P., Brunelli A., Gorzegno G., DiMarco B., Aguggini S., Bolsi G., Cirillo F. p53 but not bcl-2 immunostaining is predictive of poor clinical complete response to primary chemotherapy in breast cancer patients. Clin Cancer Res. 2000 Jul;6(7):2751–2758. [PubMed] [Google Scholar]
  5. Chang J., Powles T. J., Allred D. C., Ashley S. E., Clark G. M., Makris A., Assersohn L., Gregory R. K., Osborne C. K., Dowsett M. Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol. 1999 Oct;17(10):3058–3063. doi: 10.1200/JCO.1999.17.10.3058. [DOI] [PubMed] [Google Scholar]
  6. Clarke R. B., Laidlaw I. J., Jones L. J., 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. 1993 Mar;67(3):606–611. doi: 10.1038/bjc.1993.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Daidone M. G., Silvestrini R., Valentinis B., Ferrari L., Bartoli C. Changes in cell kinetics induced by primary chemotherapy in breast cancer. Int J Cancer. 1991 Feb 1;47(3):380–383. doi: 10.1002/ijc.2910470312. [DOI] [PubMed] [Google Scholar]
  8. Elledge R. M., Green S., Howes L., Clark G. M., Berardo M., Allred D. C., Pugh R., Ciocca D., Ravdin P., O'Sullivan J. bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. J Clin Oncol. 1997 May;15(5):1916–1922. doi: 10.1200/JCO.1997.15.5.1916. [DOI] [PubMed] [Google Scholar]
  9. Elston C. W., Ellis I. O. 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. 1991 Nov;19(5):403–410. doi: 10.1111/j.1365-2559.1991.tb00229.x. [DOI] [PubMed] [Google Scholar]
  10. Fisher B., Brown A., Mamounas E., Wieand S., Robidoux A., Margolese R. G., Cruz A. B., Jr, Fisher E. R., Wickerham D. L., Wolmark N. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483–2493. doi: 10.1200/JCO.1997.15.7.2483. [DOI] [PubMed] [Google Scholar]
  11. Fisher B., Bryant J., Wolmark N., Mamounas E., Brown A., Fisher E. R., Wickerham D. L., Begovic M., DeCillis A., Robidoux A. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998 Aug;16(8):2672–2685. doi: 10.1200/JCO.1998.16.8.2672. [DOI] [PubMed] [Google Scholar]
  12. Fisher B., Mamounas E. P. Preoperative chemotherapy: a model for studying the biology and therapy of primary breast cancer. J Clin Oncol. 1995 Mar;13(3):537–540. doi: 10.1200/JCO.1995.13.3.537. [DOI] [PubMed] [Google Scholar]
  13. Frassoldati A., Adami F., Banzi C., Criscuolo M., Piccinini L., Silingardi V. Changes of biological features in breast cancer cells determined by primary chemotherapy. Breast Cancer Res Treat. 1997 Jul;44(3):185–192. doi: 10.1023/a:1005875002458. [DOI] [PubMed] [Google Scholar]
  14. Gardin G., Alama A., Rosso R., Campora E., Repetto L., Pronzato P., Merlini L., Naso C., Camoriano A., Meazza R. Relationship of variations in tumor cell kinetics induced by primary chemotherapy to tumor regression and prognosis in locally advanced breast cancer. Breast Cancer Res Treat. 1994;32(3):311–318. doi: 10.1007/BF00666008. [DOI] [PubMed] [Google Scholar]
  15. Hamilton A., Piccart M. The contribution of molecular markers to the prediction of response in the treatment of breast cancer: a review of the literature on HER-2, p53 and BCL-2. Ann Oncol. 2000 Jun;11(6):647–663. doi: 10.1023/a:1008390429428. [DOI] [PubMed] [Google Scholar]
  16. Makris A., Powles T. J., Ashley S. E., Chang J., Hickish T., Tidy V. A., Nash A. G., Ford H. T. A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol. 1998 Nov;9(11):1179–1184. doi: 10.1023/a:1008400706949. [DOI] [PubMed] [Google Scholar]
  17. Mauriac L., Durand M., Avril A., Dilhuydy J. M. Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Results of a randomized trial in a single centre. Ann Oncol. 1991 May;2(5):347–354. doi: 10.1093/oxfordjournals.annonc.a057953. [DOI] [PubMed] [Google Scholar]
  18. McCarty K. S., Jr, Miller L. S., Cox E. B., Konrath J., McCarty K. S., Sr Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985 Aug;109(8):716–721. [PubMed] [Google Scholar]
  19. Osborne C. K., Boldt D. H., Clark G. M., Trent J. M. Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res. 1983 Aug;43(8):3583–3585. [PubMed] [Google Scholar]
  20. Pegram M. D., Pauletti G., Slamon D. J. HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat. 1998;52(1-3):65–77. doi: 10.1023/a:1006111117877. [DOI] [PubMed] [Google Scholar]
  21. Powles T. J., Hickish T. F., Makris A., Ashley S. E., O'Brien M. E., Tidy V. A., Casey S., Nash A. G., Sacks N., Cosgrove D. Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol. 1995 Mar;13(3):547–552. doi: 10.1200/JCO.1995.13.3.547. [DOI] [PubMed] [Google Scholar]
  22. Robertson J. F., Ellis I. O., Elston C. W., Blamey R. W. Mastectomy or tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up. Eur J Cancer. 1992;28A(4-5):908–910. doi: 10.1016/0959-8049(92)90148-u. [DOI] [PubMed] [Google Scholar]
  23. Silvestrini R., Benini E., Daidone M. G., Veneroni S., Boracchi P., Cappelletti V., Di Fronzo G., Veronesi U. p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Natl Cancer Inst. 1993 Jun 16;85(12):965–970. doi: 10.1093/jnci/85.12.965. [DOI] [PubMed] [Google Scholar]
  24. Silvestrini R., Daidone M. G., Luisi A., Boracchi P., Mezzetti M., Di Fronzo G., Andreola S., Salvadori B., Veronesi U. Biologic and clinicopathologic factors as indicators of specific relapse types in node-negative breast cancer. J Clin Oncol. 1995 Mar;13(3):697–704. doi: 10.1200/JCO.1995.13.3.697. [DOI] [PubMed] [Google Scholar]
  25. Têtu B., Brisson J. Prognostic significance of HER-2/neu oncoprotein expression in node-positive breast cancer. The influence of the pattern of immunostaining and adjuvant therapy. Cancer. 1994 May 1;73(9):2359–2365. doi: 10.1002/1097-0142(19940501)73:9<2359::aid-cncr2820730919>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES