International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationPrognostic Value of Abnormal p53 Expression in Locally Advanced Prostate Cancer Treated With Androgen Deprivation and Radiotherapy: A Study Based on RTOG 9202
Introduction
It is well known that p53 protein plays a central role in modulating cellular responses to cytotoxic stresses by contributing to cell-cycle arrest, programmed cell death, and double-strand DNA repair. p53 gene mutations, which are typically associated with nuclear accumulation of p53 protein 1, 2, occur in approximately half of all human malignancies (3). It has been shown that p53 gene mutation and nuclear accumulation of p53 protein are associated with aggressive phenotypes in several human cancers, including breast cancer 4, 5, lung cancer (6), and colorectal carcinoma 7, 8.
In prostate cancer (Pca), studies have described an association between p53 nuclear accumulation and poor differentiation, progression, metastasis, and androgen-independent growth 9, 10, 11, 12. Furthermore, in vitro and in vivo studies showed that restoration of p53 with adenoviral vectors could increase radiation sensitivity in prostate cancer 13, 14. In the patients with Pca who underwent radiation therapy, some studies showed that p53 nuclear accumulation was associated with biochemical failure 15, 16. An important study of the prognostic value of p53 was based on an analysis of Radiation Therapy Oncology Group (RTOG) 8610 (17).
RTOG 8610 was a phase III, randomized, clinical trial that tested the benefit of short-term androgen deprivation (STAD) begun 2 months before and continued during external beam radiation therapy (RT) for locally advanced Pca. Abnormal p53 expression, defined as ≥20% positive nuclear staining, was detected in 23 (18%) of 129 cases and independently correlated with decreased overall and progression-free survivals and increased distant metastasis.
More evidence is needed to verify the prognostic value of p53 expression in Pca and further explore the relationship between p53 status and combined androgen deprivation and RT. In this report, we analyzed p53 protein expression in diagnostic material from a large cohort of patients participating in RTOG 9202. RTOG 9202 was a phase III randomized trial that was an extension of RTOG 8610, comparing STAD + RT with long-term androgen deprivation (LTAD) given for an additional 24 months after RT (18).
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Study population
RTOG 9202 began in June 1992 and was completed in April 1995, accruing 1,514 assessable patients (18). Tumor tissue was sufficient for p53 analysis in 777 cases, with 398 (51.2%) and 379 (48.8%) from LTAD + RT and STAD + RT treatment arms, respectively. All of the cases with determined p53 status had information about pretreatment serum prostate-specific antigen (PSA) and clinical T stage. An institutional Gleason score was available in 721 (92.8%) of the cases, whereas a centrally reviewed
Clinical and pathologic characteristics of patients with determined and missing p53 data
Of the total 1,514 assessable patients who entered in RTOG 9202, 777 (51.3%) had determined p53 data. Table 1 displays the distribution of patients by baseline variables and treatment arms for those with determined and missing p53 data. There was no statistically significant difference in any of the parameters studied including age, Gleason score, pretreatment PSA, clinical stage, or assigned treatment, although a borderline significant relationship was seen with Gleason score. Of those with
Discussion
In this RTOG 9202 study, we verified the significance of p53 as a prognostic factor in Pca. The abnormal expression of p53 was related to about a 2× increased risk of death from Pca and the development of distant metastasis at 5 years. To our knowledge, this is the largest analysis of p53 ever performed in men with Pca and the first in men treated with RT + LTAD.
Although there is little doubt concerning the relationships between p53 immunoreactivity and unfavorable histology or advanced disease
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2010, Radiotherapy and OncologyCitation Excerpt :Clinical confirmation of the α/β value through ongoing prospective randomized trials remains necessary [2,27–29]. For all these reasons, we hope that personalized predictive tests with new biomarkers [11,30,31] will be able to answer most of the unresolved radiobiological questions linked to the α/β value of prostatic adenocarcinoma. No actual or perceived conflicts of interest exist.
Supported in part by the Pennsylvania Department of Health and CA101984 (from Alan Pollack, M.D., Ph.D.).
Presented in part at the 2005 Multidisciplinary Prostate Cancer Symposium, Orlando, FL, February 17–19, 2005.
Conflict of interest: none.