title: Prognostic value of Ki67 in localized prostate carcinoma: a multi-institutional study of >1000 prostatectomies.
abstract: Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes.
  
  
  
  After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up).
  
  
  
  In 1004 PCs (∼4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as ⩾5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03).
  
  
  
  In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Tretiakova
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Boyer
authors.affiliation: University of Washington, Seattle, WA, USA.|Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Newcomb
authors.affiliation: Canary Foundation, Redwood City, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hawley
authors.affiliation: Canary Foundation, Redwood City, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Auman
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Vakar-Lopez
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: McKenney
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Fazli
authors.affiliation: University of California at San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Simko
authors.affiliation: Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Troyer
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Hurtado-Coll
authors.affiliation: University of Texas Health Sciences Center at San Antonio, TX, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Thompson
authors.affiliation: University of California at San Francisco, CA, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Carroll
authors.affiliation: University of Washington, Seattle, WA, USA.|Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Ellis
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: M E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: University of Washington, Seattle, WA, USA.|Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: University of Washington, Seattle, WA, USA.|Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Lin
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: True
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Stanford University, Stanford, CA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Brooks
mesh_terms: D049109:Cell Proliferation; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D012008:Recurrence; D046888:Tissue Array Analysis
chemical_list: D019394:Ki-67 Antigen; D017430:Prostate-Specific Antigen