Multi-institutional validation of the prognostic value of Ki-67 labeling index in patients treated with radical prostatectomy
Original Article
First Online:
Received:
Accepted:
- 196 Downloads
- 10 Citations
Abstract
Objective
Several smaller single-center studies have reported a prognostic role for Ki-67 labeling index in prostate cancer. Our aim was to test whether Ki-67 is an independent prognostic marker of biochemical recurrence (BCR) in a large international cohort of patients treated with radical prostatectomy (RP).
Methods
Ki-67 immunohistochemical staining on prostatectomy specimens from 3,123 patients who underwent RP for prostate cancer was retrospectively performed. Univariable and multivariable Cox regression models were used to assess the association of Ki-67 status with BCR.
Results
Ki-67 positive status was observed in 762 (24.4 %) patients and was associated with lymph node involvement (LNI) (p = 0.039). Six hundred and twenty-one (19.9 %) patients experienced BCR. The estimated 3-year biochemical-free survivals were 85 % for patients with negative Ki-67 status and 82.1 % for patients with positive Ki-67 status (log-rank test, p = 0.014). In multivariable analysis that adjusted for the effects of age, preoperative PSA, RP Gleason sum, seminal vesicle invasion, extracapsular extension, positive surgical margins, lymphovascular invasion, and LNI, Ki-67 was significantly associated with BCR (HR = 1.19; p = 0.019). Subgroup analysis revealed that Ki-67 is associated with BCR in patients without LNI (p = 0.004), those with RP Gleason sum 7 (p = 0.015), and those with negative surgical margins (p = 0.047).
Conclusion
We confirmed Ki-67 as an independent predictor of BCR after RP. Ki-67 could be particularly informative in patients with favorable pathologic characteristics to help in the clinical decision-making regarding adjuvant therapy and optimized follow-up scheduling.
Keywords
Prostate cancer Radical prostatectomy Ki-67 Prognosis Disease recurrenceNotes
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical standard
This study has been approved by the appropriate ethics committee.
References
- 1.Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T et al (2014) EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol 65(1):124–137PubMedCrossRefGoogle Scholar
- 2.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):1710–1715PubMedGoogle Scholar
- 3.Kristiansen G (2012) Diagnostic and prognostic molecular biomarkers for prostate cancer. Histopathology 60(1):125–141PubMedCrossRefGoogle Scholar
- 4.Shariat SF, Canto EI, Kattan MW, Slawin KM (2004) Beyond prostate-specific antigen: new serologic biomarkers for improved diagnosis and management of prostate cancer. Rev Urol 6(2):58–72PubMedCentralPubMedGoogle Scholar
- 5.Shariat SF, Karam JA, Margulis V, Karakiewicz PI (2008) New blood-based biomarkers for the diagnosis, staging and prognosis of prostate cancer. BJU Int 101(6):675–683PubMedCrossRefGoogle Scholar
- 6.Wheeler TM, Lebovitz RM (1994) Fresh tissue harvest for research from prostatectomy specimens. Prostate 25(5):274–279PubMedCrossRefGoogle Scholar
- 7.Gallee MP, Visser-de Jong E, ten Kate FJ, Schroeder FH, Van der Kwast TH (1989) Monoclonal antibody Ki-67 defined growth fraction in benign prostatic hyperplasia and prostatic cancer. J Urol 142(5):1342–1346PubMedGoogle Scholar
- 8.Bubendorf L, Sauter G, Moch H, Schmid HP, Gasser TC, Jordan P et al (1996) Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. J Pathol 178(4):437–441PubMedCrossRefGoogle Scholar
- 9.Bettencourt MC, Bauer JJ, Sesterhenn IA, Mostofi FK, McLeod DG, Moul JW (1996) Ki-67 expression is a prognostic marker of prostate cancer recurrence after radical prostatectomy. J Urol 156(3):1064–1068PubMedCrossRefGoogle Scholar
- 10.Cheng L, Pisansky TM, Sebo TJ, Leibovich BC, Ramnani DM, Weaver AL et al (1999) Cell proliferation in prostate cancer patients with lymph node metastasis: a marker for progression. Clin Cancer Res 5(10):2820–2823PubMedGoogle Scholar
- 11.Vis AN, Noordzij MA, Fitoz K, Wildhagen MF, Schroder FH, van der Kwast TH (2000) Prognostic value of cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44 s in surgically treated patients with prostate cancer. J Urol 164(6):2156–2161PubMedCrossRefGoogle Scholar
- 12.Halvorsen OJ, Haukaas S, Hoisaeter PA, Akslen LA (2001) Maximum Ki-67 staining in prostate cancer provides independent prognostic information after radical prostatectomy. Anticancer Res 21(6A):4071–4076PubMedGoogle Scholar
- 13.Sebo TJ, Cheville JC, Riehle DL, Lohse CM, Pankratz VS, Myers RP et al (2002) Perineural invasion and MIB-1 positivity in addition to Gleason score are significant preoperative predictors of progression after radical retropubic prostatectomy for prostate cancer. Am J Surg Pathol 26(4):431–439PubMedCrossRefGoogle Scholar
- 14.Rubin MA, Dunn R, Strawderman M, Pienta KJ (2002) Tissue microarray sampling strategy for prostate cancer biomarker analysis. Am J Surg Pathol 26(3):312–319PubMedCrossRefGoogle Scholar
- 15.Revelos K, Petraki C, Gregorakis A, Scorilas A, Papanastasiou P, Tenta R et al (2005) p27(kip1) and Ki-67 (MIB1) immunohistochemical expression in radical prostatectomy specimens of patients with clinically localized prostate cancer. In Vivo 19(5):911–920PubMedGoogle Scholar
- 16.Inoue T, Segawa T, Shiraishi T, Yoshida T, Toda Y, Yamada T et al (2005) Androgen receptor, Ki67, and p53 expression in radical prostatectomy specimens predict treatment failure in Japanese population. Urology 66(2):332–337PubMedCrossRefGoogle Scholar
- 17.Rubio J, Ramos D, Lopez-Guerrero JA, Iborra I, Collado A, Solsona E et al (2005) Immunohistochemical expression of Ki-67 antigen, cox-2 and Bax/Bcl-2 in prostate cancer; prognostic value in biopsies and radical prostatectomy specimens. Eur Urol 48(5):745–751PubMedCrossRefGoogle Scholar
- 18.Shimizu Y, Segawa T, Inoue T, Shiraishi T, Yoshida T, Toda Y et al (2007) Increased Akt and phosphorylated Akt expression are associated with malignant biological features of prostate cancer in Japanese men. BJU Int 100(3):685–690PubMedCrossRefGoogle Scholar
- 19.Laitinen S, Martikainen PM, Tolonen T, Isola J, Tammela TL, Visakorpi T (2008) EZH2, Ki-67 and MCM7 are prognostic markers in prostatectomy treated patients. Int J Cancer 122(3):595–602PubMedCrossRefGoogle Scholar
- 20.Goto T, Nguyen BP, Nakano M, Ehara H, Yamamoto N, Deguchi T (2008) Utility of Bcl-2, P53, Ki-67, and caveolin-1 immunostaining in the prediction of biochemical failure after radical prostatectomy in a Japanese population. Urology 72(1):167–171PubMedCrossRefGoogle Scholar
- 21.Gunia S, Albrecht K, Koch S, Herrmann T, Ecke T, Loy V et al (2008) Ki67 staining index and neuroendocrine differentiation aggravate adverse prognostic parameters in prostate cancer and are characterized by negligible inter-observer variability. World J Urol 26(3):243–250PubMedCrossRefGoogle Scholar
- 22.Miyake H, Muramaki M, Kurahashi T, Takenaka A, Fujisawa M (2010) Expression of potential molecular markers in prostate cancer: correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. Urol Oncol 28(2):145–151PubMedCrossRefGoogle Scholar
- 23.Antonarakis ES, Keizman D, Zhang Z, Gurel B, Lotan TL, Hicks JL et al (2012) An immunohistochemical signature comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy. Cancer 118(24):6063–6071PubMedCentralPubMedCrossRefGoogle Scholar
- 24.Kachroo N, Gnanapragasam VJ (2013) The role of treatment modality on the utility of predictive tissue biomarkers in clinical prostate cancer: a systematic review. J Cancer Res Clin Oncol 139(1):1–24PubMedCrossRefGoogle Scholar
- 25.Zellweger T, Gunther S, Zlobec I, Savic S, Sauter G, Moch H et al (2009) Tumour growth fraction measured by immunohistochemical staining of Ki67 is an independent prognostic factor in preoperative prostate biopsies with small-volume or low-grade prostate cancer. Int J Cancer 124(9):2116–2123PubMedCrossRefGoogle Scholar
- 26.Shariat SF (2014) Incorporating biomarker research in a real-world setting: challenges of a prophecy. Urol Oncol 32(3):219–221PubMedCrossRefGoogle Scholar
- 27.D’Amico AV, Whittington R, Malkowicz SB, Cote K, Loffredo M, Schultz D et al (2002) Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer 95(2):281–286PubMedCrossRefGoogle Scholar
- 28.Verze P, Scuzzarella S, Martina GR, Giummelli P, Cantoni F, Mirone V (2013) Long-term oncological and functional results of extraperitoneal laparoscopic radical prostatectomy: one surgical team’s experience on 1,600 consecutive cases. World J Urol 31(3):529–534PubMedCrossRefGoogle Scholar
- 29.Bolton DM, Ta A, Bagnato M, Muller D, Lawrentschuk NL, Severi G et al (2014) Interval to biochemical recurrence following radical prostatectomy does not affect survival in men with low-risk prostate cancer. World J Urol 32(2):431–435PubMedCrossRefGoogle Scholar
- 30.Bensalah K, Montorsi F, Shariat SF (2007) Challenges of cancer biomarker profiling. Eur Urol 52(6):1601–1609PubMedCrossRefGoogle Scholar
Copyright information
© Springer-Verlag Berlin Heidelberg 2014