Molecular markers of outcome after radiotherapy in patients with prostate carcinoma: Ki-67, bcl-2, bax, and bcl-x

Alan Pollack, Didier Cowen, Patricia Troncoso, Gunar K. Zagars, Andrew C. Von Eschenbach, Marvin L. Meistrich, Timothy McDonnell

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

BACKGROUND. Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki-67, bcl-2, bax, and bcl-x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone. METHODS. Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1-T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki-67 (MIB-1 staining; n = 106 patients), bcl-2 (n = 77 patients), bax (n = 70 patients), and bcl-x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki-67 labeling index (Ki67-LI) was available for all patients and was derived from the percentage of Ki-67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow-up. The median follow-up was 62 months. RESULTS. High Ki67-LI (> 3.5%) expression was observed in 33% of patients, overexpression of bcl-2 was observed in 16% of patients, altered bax expression was observed in 23% of patients, and altered bcl-x expression was observed in 53% of patients. There was no correlation found between the biomarkers. Kaplan-Meier survival estimates of freedom from biochemical failure (bNED) and the log-rank test revealed significantly lower rates in association with high Ki67-LI, positive bcl-2, and altered bax staining. No correlation was observed between bcl-x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl-2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67-LI in predicting bNED. CONCLUSIONS. Abnormalities in the expression levels of bcl-2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki-67 staining and conventional clinical prognostic factors.

Original languageEnglish
Pages (from-to)1630-1638
Number of pages9
JournalCancer
Volume97
Issue number7
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Fingerprint

Prostate
Radiotherapy
Carcinoma
Staining and Labeling
Biomarkers
Biopsy
Neoplasm Grading
Kaplan-Meier Estimate
Prostate-Specific Antigen
Neoplasms
Multivariate Analysis

Keywords

  • Bax
  • Bcl-2
  • Bcl-x
  • MIB-1
  • Prostate carcinoma
  • Prostate specific antigen
  • Radiotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pollack, A., Cowen, D., Troncoso, P., Zagars, G. K., Von Eschenbach, A. C., Meistrich, M. L., & McDonnell, T. (2003). Molecular markers of outcome after radiotherapy in patients with prostate carcinoma: Ki-67, bcl-2, bax, and bcl-x. Cancer, 97(7), 1630-1638. https://doi.org/10.1002/cncr.11230

Molecular markers of outcome after radiotherapy in patients with prostate carcinoma : Ki-67, bcl-2, bax, and bcl-x. / Pollack, Alan; Cowen, Didier; Troncoso, Patricia; Zagars, Gunar K.; Von Eschenbach, Andrew C.; Meistrich, Marvin L.; McDonnell, Timothy.

In: Cancer, Vol. 97, No. 7, 01.04.2003, p. 1630-1638.

Research output: Contribution to journalArticle

Pollack, A, Cowen, D, Troncoso, P, Zagars, GK, Von Eschenbach, AC, Meistrich, ML & McDonnell, T 2003, 'Molecular markers of outcome after radiotherapy in patients with prostate carcinoma: Ki-67, bcl-2, bax, and bcl-x', Cancer, vol. 97, no. 7, pp. 1630-1638. https://doi.org/10.1002/cncr.11230
Pollack, Alan ; Cowen, Didier ; Troncoso, Patricia ; Zagars, Gunar K. ; Von Eschenbach, Andrew C. ; Meistrich, Marvin L. ; McDonnell, Timothy. / Molecular markers of outcome after radiotherapy in patients with prostate carcinoma : Ki-67, bcl-2, bax, and bcl-x. In: Cancer. 2003 ; Vol. 97, No. 7. pp. 1630-1638.
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abstract = "BACKGROUND. Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki-67, bcl-2, bax, and bcl-x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone. METHODS. Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1-T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki-67 (MIB-1 staining; n = 106 patients), bcl-2 (n = 77 patients), bax (n = 70 patients), and bcl-x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki-67 labeling index (Ki67-LI) was available for all patients and was derived from the percentage of Ki-67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow-up. The median follow-up was 62 months. RESULTS. High Ki67-LI (> 3.5{\%}) expression was observed in 33{\%} of patients, overexpression of bcl-2 was observed in 16{\%} of patients, altered bax expression was observed in 23{\%} of patients, and altered bcl-x expression was observed in 53{\%} of patients. There was no correlation found between the biomarkers. Kaplan-Meier survival estimates of freedom from biochemical failure (bNED) and the log-rank test revealed significantly lower rates in association with high Ki67-LI, positive bcl-2, and altered bax staining. No correlation was observed between bcl-x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl-2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67-LI in predicting bNED. CONCLUSIONS. Abnormalities in the expression levels of bcl-2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki-67 staining and conventional clinical prognostic factors.",
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AU - Pollack, Alan

AU - Cowen, Didier

AU - Troncoso, Patricia

AU - Zagars, Gunar K.

AU - Von Eschenbach, Andrew C.

AU - Meistrich, Marvin L.

AU - McDonnell, Timothy

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N2 - BACKGROUND. Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki-67, bcl-2, bax, and bcl-x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone. METHODS. Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1-T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki-67 (MIB-1 staining; n = 106 patients), bcl-2 (n = 77 patients), bax (n = 70 patients), and bcl-x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki-67 labeling index (Ki67-LI) was available for all patients and was derived from the percentage of Ki-67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow-up. The median follow-up was 62 months. RESULTS. High Ki67-LI (> 3.5%) expression was observed in 33% of patients, overexpression of bcl-2 was observed in 16% of patients, altered bax expression was observed in 23% of patients, and altered bcl-x expression was observed in 53% of patients. There was no correlation found between the biomarkers. Kaplan-Meier survival estimates of freedom from biochemical failure (bNED) and the log-rank test revealed significantly lower rates in association with high Ki67-LI, positive bcl-2, and altered bax staining. No correlation was observed between bcl-x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl-2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67-LI in predicting bNED. CONCLUSIONS. Abnormalities in the expression levels of bcl-2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki-67 staining and conventional clinical prognostic factors.

AB - BACKGROUND. Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki-67, bcl-2, bax, and bcl-x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone. METHODS. Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1-T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki-67 (MIB-1 staining; n = 106 patients), bcl-2 (n = 77 patients), bax (n = 70 patients), and bcl-x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki-67 labeling index (Ki67-LI) was available for all patients and was derived from the percentage of Ki-67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow-up. The median follow-up was 62 months. RESULTS. High Ki67-LI (> 3.5%) expression was observed in 33% of patients, overexpression of bcl-2 was observed in 16% of patients, altered bax expression was observed in 23% of patients, and altered bcl-x expression was observed in 53% of patients. There was no correlation found between the biomarkers. Kaplan-Meier survival estimates of freedom from biochemical failure (bNED) and the log-rank test revealed significantly lower rates in association with high Ki67-LI, positive bcl-2, and altered bax staining. No correlation was observed between bcl-x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl-2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67-LI in predicting bNED. CONCLUSIONS. Abnormalities in the expression levels of bcl-2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki-67 staining and conventional clinical prognostic factors.

KW - Bax

KW - Bcl-2

KW - Bcl-x

KW - MIB-1

KW - Prostate carcinoma

KW - Prostate specific antigen

KW - Radiotherapy

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