title: Pro-prostate-specific antigen measurements in serum and tissue are associated with treatment necessity among men enrolled in expectant management for prostate cancer.
abstract: OBJECTIVE
  We assessed the association of quantitative clinical and pathologic information, including serum and tissue pro-prostate-specific antigen (proPSA) measurements, with outcomes among men with prostate cancer in an expectant management (active surveillance) program.
  
  
  METHODS
  We identified 71 men enrolled in expectant management with frozen serum and tissue available from diagnosis: 39 subsequently developed unfavorable biopsies (Gleason score > or =7, > or =3 cores positive for cancer, >50% of any core involved with cancer), whereas 32 maintained favorable biopsies (median follow-up, 3.93 years). Serum total PSA, free PSA (fPSA), and [-2]proPSA were measured by the Beckman Coulter immunoassay. [-5/-7]proPSA was evaluated in cancer and benign-adjacent areas (BAA) by quantitative immunohistochemistry. Cox proportional hazards and Kaplan-Meier analyses were used to identify significant associations with unfavorable biopsy conversion.
  
  
  RESULTS
  The ratio [-2]proPSA/% fPSA in serum was significantly higher at diagnosis (0.87 +/- 0.44 versus 0.65 +/- 0.36 pg/mL; P = 0.02) in men developing unfavorable biopsies. [-5/-7]proPSA tissue staining was more intense (4104.09 +/- 3033.50 versus 2418.06 +/- 1606.04; P = 0.03) and comprised a greater fractional area (11.58 +/- 7.08% versus 6.88 +/- 5.20%; P = 0.01) in BAA of these men. Serum [-2]proPSA/% fPSA [hazard ratio, 2.53 (1.18-5.41); P = 0.02], BAA [-5/-7]proPSA % area [hazard ratio, 1.06 (1.01-1.12); P = 0.02] and BAA [-5/-7]proPSA stain intensity [hazard ratio, 1.000213 (1.000071-1.000354); P = 0.003] were significantly associated with unfavorable biopsy in Kaplan-Meier and Cox analyses. Serum [-2]proPSA/% fPSA significantly correlated with BAA [-5/-7]proPSA % area (rho = 0.40; P = 0.002) and BAA [-5/-7]proPSA stain intensity (rho = 0.33; P = 0.016).
  
  
  CONCLUSIONS
  In a prospective cohort of men enrolled into expectant management for prostate cancer, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment. The increase in serum proPSA/% fPSA might be driven by increased proPSA production from "premalignant" cells in the prostate BAA.
authors.affiliation: Robert Wood Johnson Clinical Scholars Program, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Danil V
authors.initials: DV
authors.lastname: Makarov
authors.forename: Sumit
authors.initials: S
authors.lastname: Isharwal
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Sokoll
authors.forename: Patricia
authors.initials: P
authors.lastname: Landis
authors.forename: Cameron
authors.initials: C
authors.lastname: Marlow
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.forename: H Ballentine
authors.initials: HB
authors.lastname: Carter
authors.forename: Robert W
authors.initials: RW
authors.lastname: Veltri
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D001706:Biopsy; D006801:Humans; D008297:Male; D008495:Medical Oncology / Q000379:methods; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000097:blood* / Q000378:metabolism* / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen