The role of p53 in radiation therapy outcomes for favorable-to-intermediate-risk prostate cancer.
OBJECTIVE
Some prostate cancers may have molecular alterations that render them less responsive to radiation therapy; identification of these alterations before treatment might allow improved treatment optimization. This study investigated whether p53, a potential molecular determinant, could predict long-term radiation therapy outcome in a restricted group of relatively favorable-risk prostate cancer patients treated uniformly with irradiation alone.


METHODS
This study included 53 patients previously treated with radiotherapy for favorable-to-intermediate-risk prostate cancer. These patients were selected for relatively low pretreatment PSAs (< or =21 ng/mL) and Gleason scores (< or =7) to decrease the likelihood of nonlocalized disease, because disease localization was necessary to examine the efficacy of localized radiation therapy. The status of p53 was immunohistochemically assessed in paraffin-embedded pretreatment biopsy specimens, along with appropriate controls. This marker was selected based upon a usable mutation prevalence in early-stage prostate cancer and its potential linkage with radiation response via cell cycle, DNA repair, and cell death pathways. Correlation between p53 mutation and clinical outcome was analyzed in univariate and multivariate fashion and included conventional prognosticators, such as stage, grade, and PSA. Freedom from biochemical failure was determined using American Society for Therapeutic Radiology and Oncology criteria. Limitations of prior studies were potentially avoided by requiring adequate posttreatment follow-up (median follow-up in nonfailing patients of 5.1 years), as well as pretreatment PSA and Gleason scores that suggested localized disease, and uniformity of treatment.


RESULTS
The total group of 53 favorable-to-intermediate-risk patients demonstrated an actuarial biochemical failure rate of 35% at 5 years. Forty percent of all specimens had a greater than 10% labeling index for p53 mutation, and actuarial biochemical control was found to strongly and independently correlate with p53 status. Patients with higher p53 labeling indices demonstrated significantly higher PSA failure rates (p < 0.001). In contrast, p53 status did not correlate with pretreatment PSA, grade, or tumor stage. Similarly, pretreatment PSA (log-rank 0.22), Gleason score (log-rank 0.93), and T stage (log-rank 0.15) were not prognostic for outcome in this group of patients selected for their relatively favorable clinical characteristics.


CONCLUSIONS
(1) p53 status in pretreatment biopsies strongly predicted for long-term biochemical control after radiation therapy in favorable-to-intermediate-risk prostate cancer patients. (2) If validated in other independent clinical data sets, p53 status should be considered as a stratification factor in future clinical trials and could be useful in guiding treatment. Abnormal p53 status might favor surgical management, aggressive dose escalation, or p53-targeted therapy.
Ritter
Mark A
MA
Department of Human Oncology, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA. ritter@mail.humonc.wisc.edu
Gilchrist
Kennedy W
KW
Voytovich
Marta
M
Chappell
Richard J
RJ
Verhoven
Bret M
BM
D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D016159:Tumor Suppressor Protein p53; D017430:Prostate-Specific Antigen