title: Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG) 94-08.
abstract: OBJECTIVE
  The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08.
  
  
  METHODS
  468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria.
  
  
  RESULTS
  In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation.
  
  
  CONCLUSIONS
  High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
authors.forename: Bret
authors.initials: B
authors.lastname: Verhoven
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Mark
authors.initials: M
authors.lastname: Ritter
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Khor
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hammond
authors.forename: Christopher
authors.initials: C
authors.lastname: Jones
authors.forename: Mahul
authors.initials: M
authors.lastname: Amin
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bahary
authors.forename: Kenneth
authors.initials: K
authors.lastname: Zeitzer
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D049109:Cell Proliferation; D005485:Flutamide / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008297:Male; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D019394:Ki-67 Antigen; D005485:Flutamide; D017430:Prostate-Specific Antigen