Abstract
A proliferative marker, expressed as the percentage of cells in a cell cycle, has been developed and used as a discriminant of more aggressive malignant phenotypes in early breast cancer (BC). The marker is usually expressed by the immunohistochemical staining of the cell cycle antigen Ki-67. It has not, however, yet been definitely evaluated, due to methodological concerns, which specific Ki-67 cut-off provide the strongest prognostic information in resected BC. We conducted a meta-analysis to explore the prognostic value of different cut-off levels of Ki-67 in terms of overall survival (OS) and disease-free survival (DFS) in early BC. The databases of PubMed, the ISI Web of Science, EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials, and CINHAL were used to identify the relevant literature. Data from studies reporting a hazard ratio (HR) and a 95 % confidence interval (CI) calculated as a multivariate analysis were pooled in a meta-analysis, with metaregression used to test for trends in predefined subgroups. All the statistical tests were 2-sided. Forty-one studies encompassing 64,196 BC patients were included in the analysis. Overall, n = 25 studies were available for the OS analysis. The pooled HR for high versus low Ki-67 was 1.57 (95 % CI 1.33–1.87, P < 0.00001). Twenty-nine studies were available for the DFS analysis. The pooled HR for high versus low Ki-67 was 1.50 (95 % CI 1.34–1.69, P < 0.00001). When a cut-off of Ki-67 staining ≥ 25 % was used, the pooled HR for OS was 2.05 (95 % CI 1.66–2.53, P < 0.00001), which was significantly different to studies where the cut-offs chosen were <25 %. In ER+ tumors, the HR for high versus low Ki-67 was similar and significant (HR = 1.51, 95 % CI 1.25–1.81, P < 0.0001). We conclude that Ki-67 has an independent prognostic value in terms of OS in BC patients. The Ki-67 threshold with the greatest prognostic significance is as yet unknown, but a cut-off >25 % is associated with a greater risk of death compared with lower expression rates.
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References
Page DL (1991) Prognosis and breast cancer. Recognition of lethal and favourable prognostic types. Am J Surg Pathol 15:334–349
Koscielny S, Tubiana M, Lê MG et al (1984) Breast cancer: relationship between the size of the primary tumour and the probability of metastatic dissemination. Br J Cancer 49:709–715
Rosen PP, Groshen S, Saigo PE et al (1989) Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol 7:1239–1251
Carter CL, Allen C, Henson DE (1989) Relation of tumour size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 63:181–187
Elston CW, 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
Galea MH, Blamey RW, Elston CE et al (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22:207–219
de Azambuja E, Cardoso F, de Castro Jr G et al (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
Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6:e1000100
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177e88
Aleskandarany MA, Green AR, Benhasouna AA et al (2012) Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer. Breast Cancer Res 14(1):R3
Viale G, Giobbie-Hurder A, Regan MM et al (2008) 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 26(34):5569–5575
Bago-Horvath Z, Rudas M, Dubsky P et al (2011) Adjuvant sequencing of tamoxifen and anastrozole is superior to tamoxifen alone in postmenopausal women with low proliferating breast cancer. Clin Cancer Res 17(24):7828–7834
Boström P, Söderström M, Vahlberg T et al (2011) MMP-1 expression has an independent prognostic value in breast cancer. BMC Cancer 11(11):348
Brennan DJ, Rexhepaj E, O’Brien SL et al (2008) Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer. Clin Cancer Res 14(9):2681–2689
Brown RW, Allred CD, Clark GM et al (1996) Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res 2(3):585–592
Cancello G, Maisonneuve P, Rotmensz N et al (2013) Progesterone receptor loss identifies Luminal B breast cancer subgroups at higher risk of relapse. Ann Oncol 24(3):661–668
De Cicco C, Gilardi L, Botteri E et al (2013) Is [18F] fluorodeoxyglucose uptake by the primary tumor a prognostic factor in breast cancer? Breast 22(1):39–43
Dolled-Filhart M, McCabe A, Giltnane J et al (2006) Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res 66(10):5487–5494
Dumontet C, Krajewska M, Treilleux I et al (2010) BCIRG 001 molecular analysis: prognostic factors in node-positive breast cancer patients receiving adjuvant chemotherapy. Clin Cancer Res 16(15):3988–3997
Ermiah E, Buhmeida A, Abdalla F et al (2012) Prognostic value of proliferation markers: immunohistochemical ki-67 expression and cytometric s-phase fraction of women with breast cancer in Libya. J Cancer 3:421–431
Gamucci T, Vaccaro A, Ciancola F et al (2013) Recurrence risk in small, node-negative, early breast cancer: a multicenter retrospective analysis. J Cancer Res Clin Oncol 139(5):853–860
Gluz O, Nitz UA, Harbeck N et al (2008) Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial. Ann Oncol 19(5):861–870
Inwald EC, Klinkhammer-Schalke M, Hofstädter F et al (2013) Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat 139(2):539–552
Jacquemier J, Boher JM, Roche H et al (2011) Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC-PACS 01 randomized trial. Breast Cancer Res 13(6):R109
Jacquemier J, Charafe-Jauffret E, Monville F et al (2009) Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer. Breast Cancer Res 11(2):R23
Jung SY, Jeong J, Shin SH et al (2010) The invasive lobular carcinoma as a prototype luminal A breast cancer: a retrospective cohort study. BMC Cancer 3(10):664
Jung SY, Kim HY, Nam BH et al (2010) Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer. Breast Cancer Res Treat 120(3):627–637
Kim RG, Kim EK, Kim HA et al (2011) Prognostic significance of molecular subtype in T1N0M0 breast cancer: Korean experience. Eur J Surg Oncol 37(7):629–634
Kwon JH, Kim YJ, Lee KW et al (2010) Triple negativity and young age as prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm or less. BMC Cancer 15(10):557
Lee JA, Kim KI, Bae JW et al (2010) Triple negative breast cancer in Korea-distinct biology with different impact of prognostic factors on survival. Breast Cancer Res Treat 123(1):177–187
Lee KH, Im SA, Oh DY et al (2007) Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy. BMC Cancer 12(7):63
Li FY, Wu SG, Zhou J et al (2014) Prognostic value of Ki-67 in breast cancer patients with positive axillary lymph nodes: a retrospective cohort study. PLoS ONE 9(2):e87264
Lin CH, Lu YS, Huang CS et al (2011) Prognostic molecular markers in women aged 35 years or younger with breast cancer: is there a difference from the older patients? J Clin Pathol 64(9):781–787
Loussouarn D, Campion L, Leclair F et al (2009) Validation of UBE2C protein as a prognostic marker in node-positive breast cancer. Br J Cancer 101(1):166–173
Meattini I, Desideri I, Saieva C et al (2014) Impact of sentinel node tumor burden on outcome of invasive breast cancer patients. Eur J Surg Oncol 40(10):1195–1202
Michalides R, van Tinteren H, Balkenende A et al (2002) Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment. Br J Cancer 86(3):402–408
Naoi Y, Kishi K, Tanei T et al (2011) Development of 95-gene classifier as a powerful predictor of recurrences in node-negative and ER-positive breast cancer patients. Breast Cancer Res Treat 128(3):633–641
Niikura N, Masuda S, Kumaki N et al (2014) Prognostic significance of the Ki67 scoring categories in breast cancer subgroups. Clin Breast Cancer. 14(5):323–329.e3
Nishimura R, Osako T, Okumura Y et al (2010) Ki-67 as a prognostic marker according to breast cancer subtype and a predictor of recurrence time in primary breast cancer. Exp Ther Med 1(5):747–754
Rocca A, Bravaccini S, Scarpi E et al. Benefit from anthracyclines in relation to biological profiles in early breast cancer. Breast Cancer Res Treat. 2014; 144(2):307–318. Erratum in: Breast Cancer Res Treat. 2014; 144(2):319
Sundara Rajan S, Hanby AM, Horgan K et al (2014) The potential utility of geminin as a predictive biomarker in breast cancer. Breast Cancer Res Treat 143(1):91–8
Synnestvedt M, Borgen E, Russnes HG et al (2013) Combined analysis of vascular invasion, grade, HER2 and Ki67 expression identifies early breast cancer patients with questionable benefit of systemic adjuvant therapy. Acta Oncol 52(1):91–101
Treré D, Ceccarelli C, Migaldi M et al (2006) Cell proliferation in breast cancer is a major determinant of clinical outcome in node-positive but not in node-negative patients. Appl Immunohistochem Mol Morphol 14(3):314–323
Tutt A, Wang A, Rowland C et al (2008) Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature. BMC Cancer 21(8):339
Wiesner FG, Magener A, Fasching PA et al (2009) Ki-67 as a prognostic molecular marker in routine clinical use in breast cancer patients. Breast 18(2):135–141
Xue C, Wang X, Peng R et al (2012) Distribution, clinicopathologic features and survival of breast cancer subtypes in Southern China. Cancer Sci 103(9):1679–1687
Yamamoto S, Ibusuki M, Yamamoto Y et al (2013) Clinical relevance of Ki67 gene expression analysis using formalin-fixed paraffin-embedded breast cancer specimens. Breast Cancer. 20(3):262–270
Zhang X, Li P, Ma W et al (2013) Risk factors of recurrence in small-sized, node negative breast cancer in young women: a retrospective study in Chinese population. Sci China Life Sci 56(4):335–340
Zong Y, Zhu L, Wu J et al (2014) Progesterone receptor status and Ki-67 index may predict early relapse in luminal B/HER2 negative breast cancer patients: a retrospective study. PLoS One 9(8):e95629
Cho U, Kim HE, Oh WJ et al (2015) The long-term prognostic performance of Ki-67 in primary operable breast cancer and evaluation of its optimal cutoff value. Appl Immunohistochem Mol Morphol. doi:10.1097/PAI.0000000000000164
Stuart-Harris R, Caldas C, Pinder SE, Pharoah P (2008) Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients. Breast 17(4):323–334
Coates AS, Winer EP, Goldhirsch A et al (2015) Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 26:1533–1546
Cheang MC, Chia SK, Voduc D et al (2009) Ki-67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750
Senkus E, Kyriakides S, Penault-Llorca F et al (2013) Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24 Suppl 6:vi7–23
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 12 April 2014
Dowsett M, Nielsen TO, A’Hern R et al (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
Polley MY, Leung SC, McShane LM et al (2013) An international Ki67 reproducibility study. J Natl Cancer Inst 105(24):1897–1906
Polley MY, Leung SC, Gao D et al (2015) An international study to increase concordance in Ki67 scoring. Mod Pathol 28(6):778–786
Penault-Llorca F, André F, Sagan C et al (2009) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27(17):2809–2815
Criscitiello C, Disalvatore D, De Laurentiis M et al (2014) High Ki-67 score is indicative of a greater benefit from adjuvant chemotherapy when added to endocrine therapy in luminal B HER2 negative and node-positive breast cancer. Breast 23(1):69–75
Sahebjam S, Aloyz R, Pilavdzic D et al (2011) Ki 67 is a major, but not the sole determinant of Oncotype Dx recurrence score. Br J Cancer 105(9):1342–1345
Acs G, Esposito NN, Kiluk J et al (2012) A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas. Mod Pathol 25(4):556–566
Aktas B, Bankfalvi A, Heubner M et al (2013) Evaluation and correlation of risk recurrence in early breast cancer assessed by Oncotype DX(®), clinicopathological markers and tumor cell dissemination in the blood and bone marrow. Mol Clin Oncol 1(6):1049–1054
Thaker NG, Hoffman KE, Stauder MC et al (2015) The 21-gene recurrence score complements IBTR! Estimates in early-stage, hormone receptor-positive, HER2-normal, lymph node-negative breast cancer. Springerplus 30(4):36
Turner BM, Skinner KA, Tang P, Jackson MC, Soukiazian N, Shayne M, Huston A, Ling M, Hicks DG (2015) Use of modified Magee equations and histologic criteria to predict the Oncotype DX recurrence score. Mod Pathol 28(7):921–931
Cuzick J, Dowsett M, Pineda S et al (2011) Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 29(32):4273–4278
Sgroi DC, Sestak I, Cuzick J et al (2013) Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 14(11):1067–1076
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Petrelli, F., Viale, G., Cabiddu, M. et al. Prognostic value of different cut-off levels of Ki-67 in breast cancer: a systematic review and meta-analysis of 64,196 patients. Breast Cancer Res Treat 153, 477–491 (2015). https://doi.org/10.1007/s10549-015-3559-0
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DOI: https://doi.org/10.1007/s10549-015-3559-0