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
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References
Bonadonna G, Veronesi U, Brambilla C, Ferrari L, Luini A, Greco M, Bartoli C, Coopmans de Yoldi,, Zucali R, Rilke F, Andreola S, Silvestrini R, Di Fronzo G and Valagussa P (1990) Primary chemotherapy to avoid mastectomy in tumours with diameters of three centimeters or more. J Natl Cancer Inst 82: 1539–1545
Bonadonna G, Valagussa P, Brambilla C, Ferrari L, Molinterni A, Terenziani M and Zambetti M (1998) Primary chemotherapy in operable breast cancer: eight-years experience at the Milan Cancer Institute. J Clin Oncol 16: 93–100
Bonetti A, Zaninelli M, Rodella S, Molino A, Sperotto L, Piubello Q, Bonetti F, Nortilli R, Turazza M and Cetto GL (1996) Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma. Breast Cancer Res Treat 38: 289–297
Bottini A, Berruti A, Bersiga A, Brizzi MP, Brunelli A, Gorzegno G, DiMarco B, Aguggini S, Bolsi G, Cirillo F, Filippini L, Betri E, Bertoli G, Alquati P and Dogliotti L (2000) p53 but not bcl2 immunostaining is predictive of poor clinical complete response to primary chemotherapy in breast cancer patients. Clin Cancer Res 6: 2751–2758
Chang J, Powles TJ, Allred DC, Ashley SE, Clark GM, Makris A, Assersohn L, Gregory RK, Osborne CK and Dowsett M (1999) Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol 17: 3058–3063
Clarke RB, Laidlaw IJ, Jones LJ, Howell A and Anderson E (1993) Effect of tamoxifen in Ki67 labeling index in human breast tumors and its relationship to oestrogen and progesterone receptor status. Br J Cancer 67: 606–611
Daidone MG, Silvestrini R, Valentinis B, Ferrari L and Bartoli C (1991) Changes in cell kinetics induced by primary chemotherapy in breast cancer. Int J Cancer 47: 380–383
Dickson RB and Lippman ME (1996) Oncogenes and suppressor genes. In: Harris JR, Lippman ME, Morrow M, Hellman S (eds): Diseases of the Breast, Philadelphia, Lippincott-Raven, pp 221–234
Elledge RM, Green S, Howes L, Clark GM, Berardo M, Allred DC, Pugh R, Ciocca D, Ravdin P, O'sallivan J, Rivkin S, Martino S and Osborne CK (1997) Bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. J Clin Oncol 15: 1916–1922
Elston CW and 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: 403–410
Fisher B and Mamounas EP (1995) Preoperative chemotherapy: a model for studying the biology and therapy of primary breast cancer. J Clin Oncol 13: 537–540
Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr., Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW and Dimitrov NV (1997) The effect of preoperative therapy on local-regional disease in women with operable breast cancer: Findings from NSABP B-18. J Clin Oncol 15: 2483–2493
Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr., Hoehn JL, Lees AW, Dimitrov NV and Bear HD (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16: 2672–2685
Frassoldati A, Adami F, Banzi C, Criscuolo M, Piccinini L and Silingardi V (1997) Changes of biological features in breast cancer cells determined by primary chemotherapy. Breast Cancer Res Treat 44(3): 185–192
Gardin G, Alama A, Rosso R, Rosso R, Campora E, Repetto L, Pronzato P, Merlini L, Naso C, Camoriano A, Meazza R, Barbieri F, Baldini E, Giannessi PG and Conte PF (1994) 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 32: 311–318
Hamilton A and Piccart M (2000) 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 11(6)647–663
Makris A, Powels TJ, Ashley SE, Chang J, Hickish T, Tidy VA, Nash AG and Ford HT (1998) A reduction in the requirement for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol 9: 1179–1184
Mauriac L, Durand M, Avril A and Dihuydy JM (1991) Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumours larger than 3 cm. Ann Oncol 2: 347–354
McCarty KS Jr., Miller LS, Cox EB, Konrath J and McCarty KS Sr. (1985) Estrogen receptor analyses. Arch Pathol Lab Med 109: 716–721
Osborne CK, Boldt DH, Clark GM and Trent JM (1983) Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res 43(8)3583–3585
Pegram MD, Pauletti G and Slamon DJ (1998) Her-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 52: 65–77
Powles TJ, Hickish TF, Makris A, Ashley SE, O’Brien ME, Tidy VA, Casey S, Nash AG, Sacks N and Cosgrove D (1995) Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13: 547–552
Robertson JFR, Ellis IO, Elston CV and Blamey RW (1992) Mastectomy or tamoxifen as initial therapy for operable breast cancer: 5-years follow-up. Eur J Cancer 28: 908–910
Silvestrini R, Benini E, Daidone MG, Veneroni S, Boracchi P, Cappelletti V, Di Fronzo G and Veronesi U (1993) p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Natl Cancer Inst 85: 965–970
Silvestrini R, Daidone MG, Luisi A, Boracchi P, Mezzetti M, Di Fronzo G, Andreola S, Salvadori B and Veronesi U (1995) Biologic and clinicopathologic factors as indicators of specific relapse types in node-negative breast cancer. J Clin Oncol 13: 697–704
Statsoft Inc. (1995) Statistica for Windows, Rel. 5.0. 2325 East 13th Street, Tulsa OK 74104
Tetu B and Brisson J (1994) Prognostic significance of HER-2/neu oncoprotein expression in node-positive breast cancer. The influence of the pattern of immunostaining and adjuvant therapy. Cancer 73: 2359–2365
World Health Organization (1978) WHO handbook for reporting results of cancer treatment. WHO offset publication, Geneva, Switzerland, UICC
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Bottini, A., Berruti, A., Bersiga, A. et al. Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer. Br J Cancer 85, 1106–1112 (2001). https://doi.org/10.1054/bjoc.2001.2048
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DOI: https://doi.org/10.1054/bjoc.2001.2048
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