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High Ki-67 expression is significantly associated with poor prognosis of ovarian cancer patients: evidence from a meta-analysis

  • Dongmei Qiu
  • Wanqiu Cai
  • Zhiqiao ZhangEmail author
  • Hongyan Li
  • Dongmei Zhou
Gynecologic Oncology

Abstract

Objective

The prognostic significance of Ki-67 expression in patients with ovarian cancer was controversial in various studies. Therefore, we carried out a meta-analysis to determine the prognostic significance of Ki-67 in ovarian cancer patients.

Methods

We searched PubMed, Cochrane Library, EMBASE, Web of Knowledge, China National Knowledge Infrastructure database and WanFang digital database for eligible studies from January 1, 1990 to June 1, 2017. The pooled hazard ratios and 95% confidence intervals were calculated to assess the prognostic significance of Ki-67 expression for overall survival in ovarian cancer patients.

Results

Finally, 38 eligible studies and 5004 ovarian cancer patients were included in the current study. The pooled hazard ratio was 1.35 (95% confidence interval 1.24–1.46, P = 0.001) for overall survival in ovarian cancer patients. The funnel plot bias was obviously asymmetrical and Egger’s test also detected significant publication bias (P = 0.001). The Contour-enhanced funnel plot with trim-and-fill method supplemented 11 dummy studies to balance the funnel plot and nine new supplementary studies were in area with statistical significance. Sensitivity analysis and cumulative meta-analysis further demonstrated that the association between high Ki-67 expression and poor overall survival of ovarian cancer patients was stable and reliable.

Conclusions

High Ki-67 expression is significantly related to poor overall survival and may serve as a prognostic biomarker for ovarian cancer patients.

Keywords

Ovarian cancer ki-67 Meta-analysis Prognostic value 

Notes

Author contributions

Conceptualization: ZZ, DQ, WC. Data curation: ZZ, WC. Formal analysis: ZZ, WC. Funding acquisition: ZZ. Investigation: ZZ, WC, DQ. Methodology: ZZ, WC, DQ. Project administration: ZZ, DZ. Resources: ZZ, HL. Software: ZZ, DZ, HL. Supervision: ZZ, WC. Validation: ZZ, DQ,WC. Visualization: ZZ, HL. Writing - original draft: ZZ, WC. Writing- review& editing: ZZ, WC.

Funding

This study was funded in part by Health Department and Finance Department of Guangdong Province. The Grant Numbers were No: B2018237 (Grant Recipient: Zhiqiao Zhang) and No: A2016450 (Grant Recipient: Zhiqiao Zhang).The total funding account was RMB 5000. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The URLs of Health Department of Guangdong Province was https://www.gdwst.gov.cn/.

Compliance with ethical standards

Conflict of interest

The authors have declared that they had no conflict of interests in relation to the work described. The authors have declared that they have had full control of all primary data and that they agreed to allow the Journal to review their data if requested.

Ethical approval

The present study is a meta-analysis and ethical approval is not needed for meta-analysis.

Supplementary material

404_2019_5082_MOESM1_ESM.doc (69 kb)
Supplementary file1 (DOC 69 kb)
404_2019_5082_MOESM2_ESM.dta (6 kb)
Supplementary file2 (DTA 7 kb)

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30CrossRefGoogle Scholar
  2. 2.
    Bast RC Jr, Hennessy B, Mills GB (2009) The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 9:415–428CrossRefGoogle Scholar
  3. 3.
    Schluter C, Duchrow M, Wohlenberg C, Becker MH, Key G, Flad HD et al (1993) The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biol 123:513–522CrossRefGoogle Scholar
  4. 4.
    Cattoretti G, Becker MH, Key G, Duchrow M, Schluter C, Galle J et al (1992) Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 168:357–363CrossRefGoogle Scholar
  5. 5.
    Felix AS, Sherman ME, Hewitt SM, Gunja MZ, Yang HP, Cora RL et al (2015) Cell-cycle protein expression in a population-based study of ovarian and endometrial cancers. Front Oncol 5:25CrossRefGoogle Scholar
  6. 6.
    Hua M, Yan S, Deng Y, Xi Q, Liu R, Yang S et al (2015) CAP1 is overexpressed in human epithelial ovarian cancer and promotes cell proliferation. Int J Mol Med 35:941–949CrossRefGoogle Scholar
  7. 7.
    Deng Y, Chen C, Hua M, Xi Q, Liu R, Yang S et al (2015) Annexin A2 plays a critical role in epithelial ovarian cancer. Arch Gynecol Obstet 292:175–182CrossRefGoogle Scholar
  8. 8.
    Battista MJ, Mantai N, Sicking I, Cotarelo C, Weyer V, Lebrecht A et al (2014) Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: results of an explorative, retrospective study. Oncol Rep 31:2213–2219CrossRefGoogle Scholar
  9. 9.
    Vallen MJ, Massuger LF, Ten DG, Bulten JV, Kuppevelt TH (2012) Highly sulfated chondroitin sulfates, a novel class of prognostic biomarkers in ovarian cancer tissue. Gynecol Oncol 127:202–209CrossRefGoogle Scholar
  10. 10.
    Kim H, Kim K, No JH, Jeon YT, Jeon HW, Kim YB (2012) Prognostic value of biomarkers related to drug resistance in patients with advanced epithelial ovarian cancer. Anticancer Res 32:589–594CrossRefGoogle Scholar
  11. 11.
    Lu M, Xiang J, Xu F, Wang Y, Yin Y, Chen D (2012) The expression and significance of pThr32-FOXO3a in human ovarian cancer. Med Oncol 29:1258–1264CrossRefGoogle Scholar
  12. 12.
    Lee JS, Choi YD, Choi C, Lee MC, Park CS, Min KW (2005) Expression of PTEN in ovarian epithelial tumors and its relation to tumor behavior and growth. Anal Quant Cytol Histol 27:202–210Google Scholar
  13. 13.
    Khalifeh I, Munkarah AR, Schimp V, Morris R, Lawrence WD, Ali-Fehmi R (2005) The impact of c-kit and ki-67 expression on patients prognosis in advanced ovarian serous carcinoma. Int J Gynecol Pathol 24:228–234CrossRefGoogle Scholar
  14. 14.
    Ali-Fehmi R, Morris RT, Bandyopadhyay S, Che M, Schimp V, Malone JM et al (2005) Expression of cyclooxygenase-2 in advanced stage ovarian serous carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, and survival. Am J Obstet Gynecol 192:819–825CrossRefGoogle Scholar
  15. 15.
    Nakayama K, Takebayashi Y, Hata K, Fujiwaki R, Iida K, Fukumoto M et al (2004) Allelic loss at 19q12 and Xq11-12 predict an adverse clinical outcome in patients with mucinous ovarian tumours of low malignant potential. Br J Cancer 90:1204–1210CrossRefGoogle Scholar
  16. 16.
    Layfield LJ, Saria EA, Berchuck A, Dodge RK, Thompson JK, Conlon DH et al (1997) Prognostic value of MIB-1 in advanced ovarian carcinoma as determined using automated immunohistochemistry and quantitative image analysis. J Surg Oncol 66:230–237CrossRefGoogle Scholar
  17. 17.
    Wang K, Li D, Sun L (2016) High levels of EGFR expression in tumor stroma are associated with aggressive clinical features in epithelial ovarian cancer. Onco Targets Ther 9:377–386CrossRefGoogle Scholar
  18. 18.
    Masoumi-Moghaddam S, Amini A, Wei AQ, Robertson G, Morris DL (2015) Sprouty 1 predicts prognosis in human epithelial ovarian cancer. Am J Cancer Res 5:1531–1541Google Scholar
  19. 19.
    Khandakar B, Mathur SR, Kumar L, Kumar S, Datta Gupta S, Iyer VK et al (2014) Tissue biomarkers in prognostication of serous ovarian cancer following neoadjuvant chemotherapy. Biomed Res Int 401245Google Scholar
  20. 20.
    Bachmayr-Heyda A, Aust S, Heinze G, Polterauer S, Grimm C, Braicu EI et al (2013) Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients–a study of the OVCAD consortium. BMC Cancer 13:422CrossRefGoogle Scholar
  21. 21.
    Heeran MC, Hogdall CK, Kjaer SK, Christensen L, Jensen A, Blaakaer J et al (2013) Prognostic value of tissue protein expression levels of MIB-1 (Ki-67) in Danish ovarian cancer patients. From the ‘MALOVA’ ovarian cancer study. APMIS 121:1177–1186CrossRefGoogle Scholar
  22. 22.
    Liu P, Sun YL, Du J, Hou XS, Meng H (2012) CD105/Ki67 coexpression correlates with tumor progression and poor prognosis in epithelial ovarian cancer. Int J Gynecol Cancer 22:586–592CrossRefGoogle Scholar
  23. 23.
    Katagiri A, Nakayama K, Rahman MT, Rahman M, Katagiri H, Nakayama N et al (2012) Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma. Mod Pathol 25:282–288CrossRefGoogle Scholar
  24. 24.
    Aune G, Stunes AK, Tingulstad S, Salvesen O, Syversen U, Torp SH (2011) The proliferation markers Ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas. Int J Clin Exp Pathol 4:444–453Google Scholar
  25. 25.
    Kondoh E, Mori S, Yamaguchi K, Baba T, Matsumura NC, Barnett J et al (2010) Targeting slow-proliferating ovarian cancer cells. Int J Cancer 126:2448–2456Google Scholar
  26. 26.
    Adams SF, Levine DA, Cadungog MG, Hammond R, Facciabene A, Olvera N et al (2009) Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer. Cancer 115:2891–2902CrossRefGoogle Scholar
  27. 27.
    Kobel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C et al (2008) Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med V5:e232CrossRefGoogle Scholar
  28. 28.
    Garcia-Velasco A, Mendiola C, Sanchez-Munoz A, Ballestin C, Colomer R, Cortes-Funes H (2008) Prognostic value of hormonal receptors, p53, ki67 and HER2/neu expression in epithelial ovarian carcinoma. Clin Transl Oncol 10:367–371CrossRefGoogle Scholar
  29. 29.
    Tetu B, Popa I, Bairati I, L'Esperance S, Bachvarova M, Plante M et al (2008) Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas. Mod Pathol 21:1002–1010CrossRefGoogle Scholar
  30. 30.
    Khouja MH, Baekelandt M, Nesland JM, Holm R (2007) The clinical importance of Ki-67, p16, p14, and p57 expression in patients with advanced ovarian carcinoma. Int J Gynecol Pathol 26:418–425CrossRefGoogle Scholar
  31. 31.
    Yamamoto S, Tsuda H, Kita T, Maekawa K, Fujii K, Kudoh K et al (2007) Clinicopathological significance of WT1 expression in ovarian cancer: a possible accelerator of tumor progression in serous adenocarcinoma. Virchows Arch 451:27–35CrossRefGoogle Scholar
  32. 32.
    Yamamoto S, Tsuda H, Yoshikawa T, Kudoh K, Kita T, Furuya K et al (2007) Clear cell adenocarcinoma associated with clear cell adenofibromatous components: a subgroup of ovarian clear cell adenocarcinoma with distinct clinicopathologic characteristics. Am J Surg Pathol 31:999–1006CrossRefGoogle Scholar
  33. 33.
    Green JA, Berns EM, Coens C, Luijk I, Thompson-Hehir JV, Diest P et al (2006) Alterations in the p53 pathway and prognosis in advanced ovarian cancer: a multi-factorial analysis of the EORTC Gynaecological Cancer group (study 55865). Eur J Cancer 42:2539–2548CrossRefGoogle Scholar
  34. 34.
    Surowiak P, Materna V, Kaplenko I, Spaczynski M, Dietel M, Lage H et al (2006) Topoisomerase 1A, HER/2neu and Ki67 expression in paired primary and relapse ovarian cancer tissue samples. Histol Histopathol 21:713–720Google Scholar
  35. 35.
    Kritpracha K, Hanprasertpong J, Chandeying V, Dechsukhum C, Geater A (2005) Survival analysis in advanced epithelial ovarian carcinoma in relation to proliferative index of MIB-1 immunostaining. J Obstet Gynaecol Res 31:268–276CrossRefGoogle Scholar
  36. 36.
    Elie C, Geay JF, Morcos M, Tourneau A, Girre V, Broet P et al (2004) Lack of relationship between EGFR-1 immunohistochemical expression and prognosis in a multicentre clinical trial of 93 patients with advanced primary ovarian epithelial cancer (GINECO group). Br J Cancer 91:470–475CrossRefGoogle Scholar
  37. 37.
    Camilleri-Broet S, Hardy-Bessard AC, Le Tourneau A, Paraiso D, Levrel O, Leduc B et al (2004) HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. Ann Oncol 15:104–112CrossRefGoogle Scholar
  38. 38.
    Itamochi H, Kigawa J, Sugiyama T, Kikuchi Y, Suzuki M, Terakawa N (2002) Low proliferation activity may be associated with chemoresistance in clear cell carcinoma of the ovary. Obstet Gynecol 100:281–287Google Scholar
  39. 39.
    Sengupta PS, McGown AT, Bajaj V, Blackhall F, Swindell R, Bromley M et al (2000) P53 and related proteins in epithelial ovarian cancer. Eur J Cancer 36:2317–2328CrossRefGoogle Scholar
  40. 40.
    Costa MJ, Hansen CL, Walls JE, Scudder SA (1999) Immunohistochemical markers of cell cycle control applied to ovarian and primary peritoneal surface epithelial neoplasms: p21(WAF1/CIP1) predicts survival and good response to platinin-based chemotherapy. Hum Pathol 30:640–647CrossRefGoogle Scholar
  41. 41.
    Anttila M, Kosma VM, Ji H, Wei-Ling X, Puolakka J, Juhola M et al (1998) Clinical significance of alpha-catenin, collagen IV, and Ki-67 expression in epithelial ovarian cancer. J Clin Oncol 16:2591–2600CrossRefGoogle Scholar
  42. 42.
    Viale G, Maisonneuve P, Bonoldi E, Bacco A, Bevilacqua P, Panizzoni GA et al (1997) The combined evaluation of p53 accumulation and of Ki-67 (MIB1) labelling index provides independent information on overall survival of ovarian carcinoma patients. Ann Oncol V8:469–476CrossRefGoogle Scholar
  43. 43.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al (2000) Meta analysis of observational studies in epidemiology: a proposal for reporting. Meta analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012CrossRefGoogle Scholar
  44. 44.
    Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2008) Contour-enhanced meta analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 61:991–996CrossRefGoogle Scholar
  45. 45.
    Wen S, Zhou W, Li CM, Hu J, Hu XM, Chen P et al (2015) Ki-67 as a prognostic marker in early-stage non-small cell lung cancer in Asian patients: a meta analysis of published studies involving 32 studies. BMC Cancer 15:520CrossRefGoogle Scholar
  46. 46.
    Pan D, Wei K, Ling Y, Su S, Zhu M, Chen G (2015) The prognostic role of Ki-67/MIB-1 in cervical cancer: a systematic review with meta analysis. Med Sci Monit 21:882–889CrossRefGoogle Scholar
  47. 47.
    Pyo JS, Kang G, Sohn JH (2016) Ki-67labeling index can be used as a prognostic marker in gastrointestinal stromal tumor: asystematic review and meta analysis. Int J Biol Markers 31:204–210CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyThe Affiliated Chencun Hospital of Shunde Hospital of Southern Medical UniversityShundePeople’s Republic of China
  2. 2.Department of Internal MedicineThe Affiliated Chencun Hospital of Shunde Hospital, Southern Medical UniversityShundePeople’s Republic of China

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