Abstract
The research question of this investigation is whether the reduction rate of Ki-67 after neoadjuvant chemotherapy (NAC) could indicate a survival in patients with non-pCR. A total of 455 patients had received NAC, and subsequent surgery was analyzed retrospectively. Patients with non-pCR were divided into three subgroups according to Ki-67 change: High-reduction (the absolute value of Ki-67 was reduced by >80 % compared with that prior to NAC), Low-reduction (the absolute value of Ki-67 was reduced by 0–80 % compared with that prior to NAC), and Increase group (the absolute value of Ki-67 was increased compared with that prior to NAC). The relapse-free survival (RFS) rates were compared among subgroups. pCR was achieved in 93 patients (20.4 %). In patients with non-pCR, the median reduction rate of Ki-67 was 60 %. A total of 15 % of patients were in the High-reduction, 63 % in the Low-reduction, and 22 % in the Increase group. The median follow-up period was 64.5 months. The 5-year RFS rates among the three groups were significantly different (p < 0.0001), and the differences were also observed in the HER2 (p = 0.033), triple-negative (p = 0.034), and luminal-like subtypes (p = 0.001). Patients in the High-reduction group showed comparable RFS to that of patients with pCR (p = 0.363). In patients with non-pCR, the reduction rate of Ki-67 after NAC significantly predicted RFS regardless of cancer subtypes. Therefore, patients who are non-pCR but who achieve a high reduction of Ki-67 can be expected to have a favorable prognosis similar to that of patients with pCR.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aebi S, Davidson T, Gruber G, Cardoso F (2011) Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 22(Suppl 6):vi12–vi24. doi:10.1093/annonc/mdr371
Kaufmann M, von Minckwitz G, Bear HD, Buzdar A, McGale P, Bonnefoi H, Colleoni M, Denkert C, Eiermann W, Jackesz R, Makris A, Miller W, Pierga JY, Semiglazov V, Schneeweiss A, Souchon R, Stearns V, Untch M, Loibl S (2007) Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Oncol 18(12):1927–1934. doi:10.1093/annonc/mdm201
Bonadonna G, Valagussa P, Brambilla C, Ferrari L, Moliterni A, Terenziani M, Zambetti M (1998) Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 16(1):93–100
Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B (2001) Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Nat Cancer Inst Monogr 30:96–102
Chollet P, Amat S, Cure H, de Latour M, Le Bouedec G, Mouret-Reynier MA, Ferriere JP, Achard JL, Dauplat J, Penault-Llorca F (2002) Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer. Br J Cancer 86(7):1041–1046. doi:10.1038/sj.bjc.6600210
Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N (2008) Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26(5):778–785. doi:10.1200/JCO.2007.15.0235
Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, Ah-See AK, Eremin O, Walker LG, Sarkar TK, Eggleton SP, Ogston KN (2002) Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20(6):1456–1466
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133(4):1710–1715
Gerdes J, Li L, Schlueter C, Duchrow M, Wohlenberg C, Gerlach C, Stahmer I, Kloth S, Brandt E, Flad HD (1991) Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol 138(4):867–873
de Azambuja E, Cardoso F, De Castro G Jr, Colozza M, Mano MS, Durbecq V, Sotiriou C, Larsimont D, Piccart-Gebhart MJ, Paesmans M (2007) Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer 96(10):1504–1513. doi:10.1038/sj.bjc.6603756
Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ (2005) Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol 16(11):1723–1739. doi:10.1093/annonc/mdi352
Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24(9):2206–2223. doi:10.1093/annonc/mdt303
Archer CD, Parton M, Smith IE, Ellis PA, Salter J, Ashley S, Gui G, Sacks N, Ebbs SR, Allum W, Nasiri N, Dowsett M (2003) Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer. Br J Cancer 89(6):1035–1041. doi:10.1038/sj.bjc.6601173
Assersohn L, Salter J, Powles TJ, A’Hern R, Makris A, Gregory RK, Chang J, Dowsett M (2003) Studies of the potential utility of Ki67 as a predictive molecular marker of clinical response in primary breast cancer. Breast Cancer Res Treat 82(2):113–123. doi:10.1023/B:BREA.0000003968.45511.3f
Jones RL, Salter J, A’Hern R, Nerurkar A, Parton M, Reis-Filho JS, Smith IE, Dowsett M (2009) The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 116(1):53–68. doi:10.1007/s10549-008-0081-7
Takada M, Kataoka A, Toi M, Bando H, Toyama K, Horiguchi S, Ueno T, Linder S, Saji S, Hayashi Y, Funata N, Kinoshita J, Murakami S, Ohono S (2004) A close association between alteration in growth kinetics by neoadjuvant chemotherapy and survival outcome in primary breast cancer. Int J Oncol 25(2):397–405
Billgren AM, Rutqvist LE, Tani E, Wilking N, Fornander T, Skoog L (1999) Proliferating fraction during neoadjuvant chemotherapy of primary breast cancer in relation to objective local response and relapse-free survival. Acta Oncol 38(5):597–601
Matsubara N, Mukai H, Fujii S, Wada N (2013) Different prognostic significance of Ki-67 change between pre- and post-neoadjuvant chemotherapy in various subtypes of breast cancer. Breast Cancer Res Treat 137(1):203–212. doi:10.1007/s10549-012-2344-6
Lee J, Im YH, Lee SH, Cho EY, Choi YL, Ko YH, Kim JH, Nam SJ, Kim HJ, Ahn JS, Park YS, Lim HY, Han BK, Yang JH (2008) Evaluation of ER and Ki-67 proliferation index as prognostic factors for survival following neoadjuvant chemotherapy with doxorubicin/docetaxel for locally advanced breast cancer. Cancer Chemother Pharmacol 61(4):569–577. doi:10.1007/s00280-007-0506-8
Burcombe R, Wilson GD, Dowsett M, Khan I, Richman PI, Daley F, Detre S, Makris A (2006) Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer. Breast Cancer Res: BCR 8(3):R31. doi:10.1186/bcr1508
Carey LA, Metzger R, Dees EC, Collichio F, Sartor CI, Ollila DW, Klauber-DeMore N, Halle J, Sawyer L, Moore DT, Graham ML (2005) American Joint Committee on Cancer tumor–node–metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst 97(15):1137–1142. doi:10.1093/jnci/dji206
Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD (2003) A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12(5):320–327
Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T, McShane L, Paik S, Penault-Llorca F, Prudkin L, Regan M, Salter J, Sotiriou C, Smith IE, Viale G, Zujewski JA, Hayes DF (2011) Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 103(22):1656–1664. doi:10.1093/jnci/djr393
Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25(28):4414–4422. doi:10.1200/JCO.2007.10.6823
Acknowledgments
This investigation has no sources of financial and material support. This investigation was presented as a part of The 2013 ASCO annual meeting, May 31–June 4, 2013, Chicago, IL, USA.
Ethical standards
The study was carried out in accordance with the Declaration of Helsinki and Japanese ethical guidelines for epidemiological research.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Matsubara, N., Mukai, H., Masumoto, M. et al. Survival outcome and reduction rate of Ki-67 between pre- and post-neoadjuvant chemotherapy in breast cancer patients with non-pCR. Breast Cancer Res Treat 147, 95–102 (2014). https://doi.org/10.1007/s10549-014-3084-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-014-3084-6