Expression of Bcl-2, p53, and MDM2 in localized prostate cancer with respect to the outcome of radical radiotherapy dose escalation.
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.
Vergis
Roy
R
Academic Urology Unit, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Surrey, UK.
Corbishley
Catherine M
CM
Thomas
Karen
K
Horwich
Alan
A
Huddart
Robert
R
Khoo
Vincent
V
Eeles
Ros
R
Sydes
Matthew R
MR
Cooper
Colin S
CS
Dearnaley
David
D
Parker
Chris
C
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*
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