p53 status and prognosis of locally advanced prostatic adenocarcinoma: A study based on RTOG 8610

David Grignon, Richard Caplan, Fazlul H. Sarkar, Colleen A. Lawton, Elizabeth H. Hammond, Miljenko V. Pilepich, Jeffrey D. Forman, John Mesic, Karen K. Fu, Ross A. Abrams, Thomas F. Pajak, William U. Shipley, James D. Cox

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

Background: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease. Purpose: We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy. Methods: The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 ('a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy'). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20% or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided. Results: One hundred twenty-nine (27%) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91). Conclusions: Determination of p53 protein expression status yields significant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy. Implications: The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations.

Original languageEnglish (US)
Pages (from-to)158-165
Number of pages8
JournalJournal of the National Cancer Institute
Volume89
Issue number2
StatePublished - Jan 15 1997
Externally publishedYes

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Adenocarcinoma
Radiotherapy
Proteins
Neoplasm Metastasis
Neoplasms
Disease-Free Survival
Prostatic Neoplasms
Hormones
Survival
Goserelin
Flutamide
Mutation
Radiation Oncology
Neoplasm Grading
Incidence
Needle Biopsy
Therapeutics
Tumor Suppressor Genes
Cell Nucleus
Proportional Hazards Models

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Grignon, D., Caplan, R., Sarkar, F. H., Lawton, C. A., Hammond, E. H., Pilepich, M. V., ... Cox, J. D. (1997). p53 status and prognosis of locally advanced prostatic adenocarcinoma: A study based on RTOG 8610. Journal of the National Cancer Institute, 89(2), 158-165.

p53 status and prognosis of locally advanced prostatic adenocarcinoma : A study based on RTOG 8610. / Grignon, David; Caplan, Richard; Sarkar, Fazlul H.; Lawton, Colleen A.; Hammond, Elizabeth H.; Pilepich, Miljenko V.; Forman, Jeffrey D.; Mesic, John; Fu, Karen K.; Abrams, Ross A.; Pajak, Thomas F.; Shipley, William U.; Cox, James D.

In: Journal of the National Cancer Institute, Vol. 89, No. 2, 15.01.1997, p. 158-165.

Research output: Contribution to journalArticle

Grignon, D, Caplan, R, Sarkar, FH, Lawton, CA, Hammond, EH, Pilepich, MV, Forman, JD, Mesic, J, Fu, KK, Abrams, RA, Pajak, TF, Shipley, WU & Cox, JD 1997, 'p53 status and prognosis of locally advanced prostatic adenocarcinoma: A study based on RTOG 8610', Journal of the National Cancer Institute, vol. 89, no. 2, pp. 158-165.
Grignon, David ; Caplan, Richard ; Sarkar, Fazlul H. ; Lawton, Colleen A. ; Hammond, Elizabeth H. ; Pilepich, Miljenko V. ; Forman, Jeffrey D. ; Mesic, John ; Fu, Karen K. ; Abrams, Ross A. ; Pajak, Thomas F. ; Shipley, William U. ; Cox, James D. / p53 status and prognosis of locally advanced prostatic adenocarcinoma : A study based on RTOG 8610. In: Journal of the National Cancer Institute. 1997 ; Vol. 89, No. 2. pp. 158-165.
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title = "p53 status and prognosis of locally advanced prostatic adenocarcinoma: A study based on RTOG 8610",
abstract = "Background: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease. Purpose: We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy. Methods: The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 ('a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy'). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20{\%} or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided. Results: One hundred twenty-nine (27{\%}) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18{\%}) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91). Conclusions: Determination of p53 protein expression status yields significant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy. Implications: The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations.",
author = "David Grignon and Richard Caplan and Sarkar, {Fazlul H.} and Lawton, {Colleen A.} and Hammond, {Elizabeth H.} and Pilepich, {Miljenko V.} and Forman, {Jeffrey D.} and John Mesic and Fu, {Karen K.} and Abrams, {Ross A.} and Pajak, {Thomas F.} and Shipley, {William U.} and Cox, {James D.}",
year = "1997",
month = "1",
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TY - JOUR

T1 - p53 status and prognosis of locally advanced prostatic adenocarcinoma

T2 - A study based on RTOG 8610

AU - Grignon, David

AU - Caplan, Richard

AU - Sarkar, Fazlul H.

AU - Lawton, Colleen A.

AU - Hammond, Elizabeth H.

AU - Pilepich, Miljenko V.

AU - Forman, Jeffrey D.

AU - Mesic, John

AU - Fu, Karen K.

AU - Abrams, Ross A.

AU - Pajak, Thomas F.

AU - Shipley, William U.

AU - Cox, James D.

PY - 1997/1/15

Y1 - 1997/1/15

N2 - Background: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease. Purpose: We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy. Methods: The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 ('a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy'). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20% or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided. Results: One hundred twenty-nine (27%) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91). Conclusions: Determination of p53 protein expression status yields significant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy. Implications: The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations.

AB - Background: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease. Purpose: We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy. Methods: The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 ('a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy'). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20% or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided. Results: One hundred twenty-nine (27%) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91). Conclusions: Determination of p53 protein expression status yields significant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy. Implications: The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations.

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