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Published in: Breast Cancer 4/2010

01-10-2010 | Original Article

Clinical significance of Ki-67 in neoadjuvant chemotherapy for primary breast cancer as a predictor for chemosensitivity and for prognosis

Authors: Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, Mitsuhiro Hayashi, Nobuyuki Arima

Published in: Breast Cancer | Issue 4/2010

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Abstract

Background

Neoadjuvant chemotherapy (NAC) is one of the main strategies for patients with locally advanced breast cancer. In recent years several biological markers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2 were discovered to be predictive factors for the effectiveness of NAC to help individualize treatment. In this retrospective study, we focused on Ki-67 as a biological marker and examined the correlation between Ki-67 and chemosensitivity, and the prognosis after the start of treatment.

Patients and methods

Between July 1996 and March 2008, 148 patients with tumors ≥3 cm in diameter or lymph node metastases received NAC and surgery. The items investigated were ER/PgR and Ki-67 from core needle biopsy. The treatment regimens were EC in 36 cases, ET in 51 cases, and FEC-DOC in 61 cases. The patients with FEC-DOC regimen had smaller tumors and higher Ki-67 values than the others.

Results

Clinical response (cCR + cPR) was 79.7%, and the pathological complete response (pCR) was 14.2%. Multivariate analysis revealed that Ki-67 was significantly related to pCR. Moreover, there was no pathological responder in cases with Ki-67 < 25%. The Ki-67 values significantly decreased after NAC (median from 45.0 to 17.5%). Patients with cCR had significantly lower Ki-67 values after NAC than those with cPR, cSD, and cPD. There was a significant difference in the Ki-67 value in terms of the presence and the absence of recurrence (median 26.0% with recurrence vs. 12% without recurrence). The disease-free survival (DFS) rate after the start of treatment was significantly higher in the patients with Ki-67 < 12% after NAC than those with Ki-67 ≥ 12%.

Conclusion

The Ki-67 value before NAC was a significant predictive factor for the effectiveness of NAC. The Ki-67 values after NAC significantly decreased and correlated with clinical response and DFS. Therefore, higher Ki-67 values (≥25%) before NAC as well as lower values (<12%) after NAC might be clinically significant for treating patients.
Literature
1.
go back to reference Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–85.PubMed Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–85.PubMed
2.
go back to reference Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, et al. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A:645–52.CrossRefPubMed Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, et al. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A:645–52.CrossRefPubMed
3.
go back to reference Burcombe RJ, Makris A, Richman PI, Daley FM, Noble S, Pittam M, et al. Evaluation of ER, PgR, HER2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer. Br J Cancer. 2005;92:147–55.CrossRefPubMed Burcombe RJ, Makris A, Richman PI, Daley FM, Noble S, Pittam M, et al. Evaluation of ER, PgR, HER2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer. Br J Cancer. 2005;92:147–55.CrossRefPubMed
4.
go back to reference Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, et al. Comparative value of tumour grade, hormonal receptors, Ki-67, HER2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer. 2004;40:205–11.CrossRefPubMed Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, et al. Comparative value of tumour grade, hormonal receptors, Ki-67, HER2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer. 2004;40:205–11.CrossRefPubMed
5.
go back to reference Abrial SC, Penault-Llorca F, Delva R, Bougnoux P, Leduc B, Mouret-Reynier MA, et al. High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer. Breast Cancer Res Treat. 2005;94:255–63.CrossRefPubMed Abrial SC, Penault-Llorca F, Delva R, Bougnoux P, Leduc B, Mouret-Reynier MA, et al. High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer. Breast Cancer Res Treat. 2005;94:255–63.CrossRefPubMed
6.
go back to reference von Minckwitz G, Sinn HP, Raab G, Loibl S, Blohmer JU, Eidtmann H, et al. Clinical response after two cycles compared to HER2, Ki-67, p53, and bcl-2 in independently predicting a pathological complete response after preoperative chemotherapy in patients with operable carcinoma of the breast. Breast Cancer Res. 2008;10:R30. doi:10.1186/bcr1989.CrossRef von Minckwitz G, Sinn HP, Raab G, Loibl S, Blohmer JU, Eidtmann H, et al. Clinical response after two cycles compared to HER2, Ki-67, p53, and bcl-2 in independently predicting a pathological complete response after preoperative chemotherapy in patients with operable carcinoma of the breast. Breast Cancer Res. 2008;10:R30. doi:10.​1186/​bcr1989.CrossRef
7.
go back to reference Pritchard KI, Messersmith H, Elavathil L, Trudeau M, O’Malley F, Dhesy-Thind B. HER-2 and topoisomerase II as predictors of response to chemotherapy. J Clin Oncol. 2008;26:736–44.CrossRefPubMed Pritchard KI, Messersmith H, Elavathil L, Trudeau M, O’Malley F, Dhesy-Thind B. HER-2 and topoisomerase II as predictors of response to chemotherapy. J Clin Oncol. 2008;26:736–44.CrossRefPubMed
8.
go back to reference Andre F, Broglio K, Roche H, Martin M, Mackey JR, Penault-Llorca F, et al. Estrogen receptor expression and efficacy of docetaxel-containing adjuvant chemotherapy in patients with node-positive breast cancer: results from a pooled analysis. J Clin Oncol. 2008;26:2636–43.CrossRefPubMed Andre F, Broglio K, Roche H, Martin M, Mackey JR, Penault-Llorca F, et al. Estrogen receptor expression and efficacy of docetaxel-containing adjuvant chemotherapy in patients with node-positive breast cancer: results from a pooled analysis. J Clin Oncol. 2008;26:2636–43.CrossRefPubMed
9.
go back to reference Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol. 2009;27:1168–76.CrossRefPubMed Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol. 2009;27:1168–76.CrossRefPubMed
10.
go back to reference Berns EM, Foekens JA, Vossen R, Look MP, Devilee P, Henzen-Logmans SC, et al. Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. Cancer Res. 2000;60:2155–62.PubMed Berns EM, Foekens JA, Vossen R, Look MP, Devilee P, Henzen-Logmans SC, et al. Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. Cancer Res. 2000;60:2155–62.PubMed
11.
go back to reference Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124:966–78.PubMed Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124:966–78.PubMed
12.
go back to reference Di Leo A, Tanner M, Desmedt C, Paesmans M, Cardoso F, Durbecq V, et al. p-53 gene mutations as a predictive marker in a population of advanced breast cancer patients randomly treated with doxorubicin or docetaxel in the context of a phase III clinical trial. Ann Oncol. 2007;18:997–1003.CrossRefPubMed Di Leo A, Tanner M, Desmedt C, Paesmans M, Cardoso F, Durbecq V, et al. p-53 gene mutations as a predictive marker in a population of advanced breast cancer patients randomly treated with doxorubicin or docetaxel in the context of a phase III clinical trial. Ann Oncol. 2007;18:997–1003.CrossRefPubMed
13.
go back to reference Di Leo A, Biganzoli L, Claudino W, Licitra S, Pestrin M, Larsimont D. Topoisomerase II alpha as a marker predicting anthracyclines’ activity in early breast cancer patients: ready for the primetime? Eur J Cancer. 2008;44:2791–8.CrossRefPubMed Di Leo A, Biganzoli L, Claudino W, Licitra S, Pestrin M, Larsimont D. Topoisomerase II alpha as a marker predicting anthracyclines’ activity in early breast cancer patients: ready for the primetime? Eur J Cancer. 2008;44:2791–8.CrossRefPubMed
14.
go back to reference Durbecq V, Desmed C, Paesmans M, Cardoso F, Di Leo A, Mano M, et al. Correlation between topoisomerase-II alpha gene amplification and protein expression in HER-2 amplified breast cancer. Int J Oncol. 2004;25:1473–9.PubMed Durbecq V, Desmed C, Paesmans M, Cardoso F, Di Leo A, Mano M, et al. Correlation between topoisomerase-II alpha gene amplification and protein expression in HER-2 amplified breast cancer. Int J Oncol. 2004;25:1473–9.PubMed
15.
go back to reference Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710–5.PubMed Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710–5.PubMed
16.
go back to reference Nishimura R, Nagao K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, et al. An evaluation of predictive factors involved in clinical or pathological response to primary chemotherapy in advanced breast cancer. Breast Cancer. 2002;9:145–52.CrossRefPubMed Nishimura R, Nagao K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, et al. An evaluation of predictive factors involved in clinical or pathological response to primary chemotherapy in advanced breast cancer. Breast Cancer. 2002;9:145–52.CrossRefPubMed
17.
go back to reference Viale Giuseppe, Giobbie-Hurder Anita, Regan MM, Coates AS, Mastropasqua MG, Dell’Orto P, et al. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1–98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol. 2008;26:5569–75.CrossRefPubMed Viale Giuseppe, Giobbie-Hurder Anita, Regan MM, Coates AS, Mastropasqua MG, Dell’Orto P, et al. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1–98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol. 2008;26:5569–75.CrossRefPubMed
18.
go back to reference Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, A’Hern R, et al. Prognostic value of Ki-67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99:167–70.CrossRefPubMed Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, A’Hern R, et al. Prognostic value of Ki-67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99:167–70.CrossRefPubMed
19.
go back to reference Kai K, Nishimura R, Arima N, Miyayama H, Iwase H. p53 Expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: a cohort study. Int J Clin Oncol. 2006;11:426–33.CrossRefPubMed Kai K, Nishimura R, Arima N, Miyayama H, Iwase H. p53 Expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: a cohort study. Int J Clin Oncol. 2006;11:426–33.CrossRefPubMed
20.
go back to reference Japan Breast Cancer Society. General rules for clinical and pathological recording of breast cancer, 16th edn (in Japanese). Tokyo: Kanehara Publications; 2008. Japan Breast Cancer Society. General rules for clinical and pathological recording of breast cancer, 16th edn (in Japanese). Tokyo: Kanehara Publications; 2008.
21.
go back to reference Kuroi K, Toi M, Tsuda H, Kurosumi M, Akiyama F. Issues in the assessment of the pathologic effect of primary systemic therapy for breast cancer. Breast Cancer. 2006;13:38–48.CrossRefPubMed Kuroi K, Toi M, Tsuda H, Kurosumi M, Akiyama F. Issues in the assessment of the pathologic effect of primary systemic therapy for breast cancer. Breast Cancer. 2006;13:38–48.CrossRefPubMed
22.
go back to reference Kurosumi M, Akashi-Tanaka S, Akiyama F, Komoike Y, Mukai H, Nakamura S, et al. Histopathological criteria for assessment of therapeutic response in breast cancer (2007 version). Breast Cancer. 2008;15:5–7.CrossRefPubMed Kurosumi M, Akashi-Tanaka S, Akiyama F, Komoike Y, Mukai H, Nakamura S, et al. Histopathological criteria for assessment of therapeutic response in breast cancer (2007 version). Breast Cancer. 2008;15:5–7.CrossRefPubMed
23.
go back to reference von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, et al. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008;100:542–51.CrossRef von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, et al. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008;100:542–51.CrossRef
24.
go back to reference Tashima R, Nishimura R. Changes in biological markers, particularly hormone receptors, due to pre-operative chemotherapy (epirubicin/docetaxel) in operable breast cancer. Oncol Rev. 2008;2:229–34.CrossRef Tashima R, Nishimura R. Changes in biological markers, particularly hormone receptors, due to pre-operative chemotherapy (epirubicin/docetaxel) in operable breast cancer. Oncol Rev. 2008;2:229–34.CrossRef
25.
go back to reference Mauriac L, MacGrogan G, Avril A, Durand M, Floquet A, Debled M, et al. 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. 1999;10:47–52.CrossRefPubMed Mauriac L, MacGrogan G, Avril A, Durand M, Floquet A, Debled M, et al. 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. 1999;10:47–52.CrossRefPubMed
26.
go back to reference Nishimura R, Arima N. Is triple negative a prognostic factor in breast cancer? Breast Cancer. 2008;15:303–8.CrossRefPubMed Nishimura R, Arima N. Is triple negative a prognostic factor in breast cancer? Breast Cancer. 2008;15:303–8.CrossRefPubMed
27.
go back to reference Nishimura R, Okumura Y, Arima N. Trastuzumab: monotherapy versus combination therapy for treating recurrent breast cancer—time to progression and survival. Breast Cancer. 2008;15:57–64.CrossRefPubMed Nishimura R, Okumura Y, Arima N. Trastuzumab: monotherapy versus combination therapy for treating recurrent breast cancer—time to progression and survival. Breast Cancer. 2008;15:57–64.CrossRefPubMed
28.
go back to reference Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst. 2008;100:14–20.CrossRefPubMed Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst. 2008;100:14–20.CrossRefPubMed
29.
go back to reference Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.CrossRefPubMed Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.CrossRefPubMed
30.
go back to reference Sánchez-Muñoz A, García-Tapiador AM, Martínez-Ortega E, Dueñas-García R, Jaén-Morago A, Ortega-Granados AL, et al. Tumour molecular subtyping according to hormone receptors and HER2 status defines different pathological complete response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Clin Transl Oncol. 2008;10:646–53.CrossRefPubMed Sánchez-Muñoz A, García-Tapiador AM, Martínez-Ortega E, Dueñas-García R, Jaén-Morago A, Ortega-Granados AL, et al. Tumour molecular subtyping according to hormone receptors and HER2 status defines different pathological complete response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Clin Transl Oncol. 2008;10:646–53.CrossRefPubMed
31.
go back to reference Peintinger F, Buzdar AU, Kuerer HM, Mejia JA, Hatzis C, Gonzalez-Angulo AM, et al. Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. Ann Oncol. 2008;19:2020–5.CrossRefPubMed Peintinger F, Buzdar AU, Kuerer HM, Mejia JA, Hatzis C, Gonzalez-Angulo AM, et al. Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. Ann Oncol. 2008;19:2020–5.CrossRefPubMed
32.
go back to reference Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H. Adjuvant/neoadjuvant trastuzumab therapy in women with HER2/neu-overexpressing breast cancer: a systematic review. Cancer Treat Rev. 2008;34:539–57.CrossRefPubMed Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H. Adjuvant/neoadjuvant trastuzumab therapy in women with HER2/neu-overexpressing breast cancer: a systematic review. Cancer Treat Rev. 2008;34:539–57.CrossRefPubMed
33.
go back to reference Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol. 2005;23:7212–20.CrossRefPubMed Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol. 2005;23:7212–20.CrossRefPubMed
34.
go back to reference de Azambuja E, Cardoso F, de Castro G Jr, Colozza M, Mano MS, Durbecq V. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12, 155 patients. Br J Cancer. 2007;96:1504–13.CrossRefPubMed de Azambuja E, Cardoso F, de Castro G Jr, Colozza M, Mano MS, Durbecq V. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12, 155 patients. Br J Cancer. 2007;96:1504–13.CrossRefPubMed
35.
go back to reference Nishimura R, Matsuda M, Miyayama H, Baba K, Matsuoka Y. Proliferative activity evaluated by MIB-1 predicts the time and type of recurrence in breast cancer. Breast Cancer Res Treat. 2003;82(Suppl 1):S165. Nishimura R, Matsuda M, Miyayama H, Baba K, Matsuoka Y. Proliferative activity evaluated by MIB-1 predicts the time and type of recurrence in breast cancer. Breast Cancer Res Treat. 2003;82(Suppl 1):S165.
36.
go back to reference Guarneri V, Piacentini F, Ficarra G, Frassoldati A, D’Amico R, Giovannelli S. A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy. Ann Oncol. 2009. doi:10.1093/annonc/mdn761. Guarneri V, Piacentini F, Ficarra G, Frassoldati A, D’Amico R, Giovannelli S. A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy. Ann Oncol. 2009. doi:10.​1093/​annonc/​mdn761.
Metadata
Title
Clinical significance of Ki-67 in neoadjuvant chemotherapy for primary breast cancer as a predictor for chemosensitivity and for prognosis
Authors
Reiki Nishimura
Tomofumi Osako
Yasuhiro Okumura
Mitsuhiro Hayashi
Nobuyuki Arima
Publication date
01-10-2010
Publisher
Springer Japan
Published in
Breast Cancer / Issue 4/2010
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI
https://doi.org/10.1007/s12282-009-0161-5

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