title: Expression of Bcl-2, p53, and MDM2 in localized prostate cancer with respect to the outcome of radical radiotherapy dose escalation.
abstract: OBJECTIVE
  Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation.
  
  
  METHODS
  Between 1995 and 2001, 308 patients with localized prostate cancer received neoadjuvant androgen deprivation and radical radiotherapy at our institution in one of two dose-escalation trials. The biopsy specimens in 201 cases were used to make a biopsy tissue microarray. We evaluated tumor expression of Bcl-2, p53, and MDM2 by immunohistochemistry with respect to outcome.
  
  
  RESULTS
  Median follow-up was 7 years, and 5-year freedom from biochemical failure (FFBF) was 70.4% (95% CI, 63.5-76.3%). On univariate analysis, expression of Bcl-2 (p < 0.001) and p53 (p = 0.017), but not MDM2 (p = 0.224), was significantly associated with FFBF. Expression of Bcl-2 remained significantly associated with FFBF (p = 0.001) on multivariate analysis, independently of T stage, Gleason score, initial prostate-specific antigen level, and radiotherapy dose. Seven-year biochemical control was 61% vs. 41% (p = 0.0122) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-positive tumors and 87% vs. 81% (p = 0.423) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-negative tumors. There was no statistically significant interaction between dose and Bcl-2 expression.
  
  
  CONCLUSIONS
  Bcl-2 expression was a significant, independent determinant of biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for prostate cancer. These data generate the hypothesis that Bcl-2 expression could be used to inform the choice of radiotherapy dose in individual patients.
authors.affiliation: Academic Urology Unit, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Surrey, UK.
authors.forename: Roy
authors.initials: R
authors.lastname: Vergis
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Corbishley
authors.forename: Karen
authors.initials: K
authors.lastname: Thomas
authors.forename: Alan
authors.initials: A
authors.lastname: Horwich
authors.forename: Robert
authors.initials: R
authors.lastname: Huddart
authors.forename: Vincent
authors.initials: V
authors.lastname: Khoo
authors.forename: Ros
authors.initials: R
authors.lastname: Eeles
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
authors.forename: Colin S
authors.initials: CS
authors.lastname: Cooper
authors.forename: David
authors.initials: D
authors.lastname: Dearnaley
authors.forename: Chris
authors.initials: C
authors.lastname: Parker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011879:Radiotherapy Dosage; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D017430:Prostate-Specific Antigen