Clinical Investigation
Prognostic Value of Abnormal p53 Expression in Locally Advanced Prostate Cancer Treated With Androgen Deprivation and Radiotherapy: A Study Based on RTOG 9202

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Purpose

The goal of this study was to verify the significance of p53 as a prognostic factor in Radiation Therapy Oncology Group 9202, which compared short-term androgen deprivation (STAD) with radiation therapy (RT) to long-term androgen deprivation + RT in men with locally advanced prostate cancer (Pca).

Methods and Materials

Tumor tissue was sufficient for p53 analysis in 777 cases. p53 status was determined by immunohistochemistry. Abnormal p53 expression was defined as 20% or more tumor cells with positive nuclei. Univariate and multivariate Cox proportional hazards models were used to evaluate the relationships of p53 status to patient outcomes.

Results

Abnormal p53 was detected in 168 of 777 (21.6%) cases, and was significantly associated with cause-specific mortality (adjusted hazard ratio [HR] = 1.89; 95% confidence interval (CI) 1.14 – 3.14; p = 0.014) and distant metastasis (adjusted HR = 1.72; 95% CI 1.13–2.62; p = 0.013). When patients were divided into subgroups according to assigned treatment, only the subgroup of patients who underwent STAD + RT showed significant correlation between p53 status and cause-specific mortality (adjusted HR = 2.43; 95% CI = 1.32–4.49; p = 0.0044). When patients were divided into subgroups according to p53 status, only the subgroup of patients with abnormal p53 showed significant association between assigned treatment and cause-specific mortality (adjusted HR = 3.81; 95% CI 1.40–10.37; p = 0.0087).

Conclusions

Abnormal p53 is a significant prognostic factor for patients with prostate cancer who undergo short-term androgen deprivation and radiotherapy. Long-term androgen deprivation may significantly improve the cause-specific survival for those with abnormal p53.

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).

Section snippets

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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