Prospective validation of diagnostic tumor biomarkers in men treated with radiotherapy for prostate cancer

Alan Pollack, Deukwoo Kwon, Gail Walker, Li Yan Khor, Eric M. Horwitz, Mark K. Buyyounouski, Radka Stoyanova

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial. Methods: Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n=231), MDM2 (n=209), p16 (n=195), Cox-2 (n=126), p53 (n=206), bcl2 (n=223), bax (n=210), and PKA (n=160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided. Results: Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2&bax (HR=2.19, 95% CI=1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR=2.26, 95% CI=1.12 to 4.58, P = .02; bcl2&bax: HR=2.14, 95% CI=1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2%, while for the base model was only 46.2%; Ki-67 was the most statistically significant when tested without bcl2&bax. Conclusions: In this prospective multiple biomarker analysis in men with prostate cancer treated with RT6ADT, both Ki-67 and bcl2&bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume109
Issue number2
DOIs
StatePublished - 2017

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Tumor Biomarkers
Prostatic Neoplasms
Radiotherapy
Biomarkers
Confidence Intervals
Androgens
Prostate
Retrospective Studies
Regression Analysis
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Prospective validation of diagnostic tumor biomarkers in men treated with radiotherapy for prostate cancer. / Pollack, Alan; Kwon, Deukwoo; Walker, Gail; Khor, Li Yan; Horwitz, Eric M.; Buyyounouski, Mark K.; Stoyanova, Radka.

In: Journal of the National Cancer Institute, Vol. 109, No. 2, 2017.

Research output: Contribution to journalArticle

Pollack, Alan ; Kwon, Deukwoo ; Walker, Gail ; Khor, Li Yan ; Horwitz, Eric M. ; Buyyounouski, Mark K. ; Stoyanova, Radka. / Prospective validation of diagnostic tumor biomarkers in men treated with radiotherapy for prostate cancer. In: Journal of the National Cancer Institute. 2017 ; Vol. 109, No. 2.
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abstract = "Background: In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial. Methods: Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n=231), MDM2 (n=209), p16 (n=195), Cox-2 (n=126), p53 (n=206), bcl2 (n=223), bax (n=210), and PKA (n=160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided. Results: Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95{\%} confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2&bax (HR=2.19, 95{\%} CI=1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR=2.26, 95{\%} CI=1.12 to 4.58, P = .02; bcl2&bax: HR=2.14, 95{\%} CI=1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2{\%}, while for the base model was only 46.2{\%}; Ki-67 was the most statistically significant when tested without bcl2&bax. Conclusions: In this prospective multiple biomarker analysis in men with prostate cancer treated with RT6ADT, both Ki-67 and bcl2&bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.",
author = "Alan Pollack and Deukwoo Kwon and Gail Walker and Khor, {Li Yan} and Horwitz, {Eric M.} and Buyyounouski, {Mark K.} and Radka Stoyanova",
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T1 - Prospective validation of diagnostic tumor biomarkers in men treated with radiotherapy for prostate cancer

AU - Pollack, Alan

AU - Kwon, Deukwoo

AU - Walker, Gail

AU - Khor, Li Yan

AU - Horwitz, Eric M.

AU - Buyyounouski, Mark K.

AU - Stoyanova, Radka

PY - 2017

Y1 - 2017

N2 - Background: In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial. Methods: Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n=231), MDM2 (n=209), p16 (n=195), Cox-2 (n=126), p53 (n=206), bcl2 (n=223), bax (n=210), and PKA (n=160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided. Results: Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2&bax (HR=2.19, 95% CI=1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR=2.26, 95% CI=1.12 to 4.58, P = .02; bcl2&bax: HR=2.14, 95% CI=1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2%, while for the base model was only 46.2%; Ki-67 was the most statistically significant when tested without bcl2&bax. Conclusions: In this prospective multiple biomarker analysis in men with prostate cancer treated with RT6ADT, both Ki-67 and bcl2&bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.

AB - Background: In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial. Methods: Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n=231), MDM2 (n=209), p16 (n=195), Cox-2 (n=126), p53 (n=206), bcl2 (n=223), bax (n=210), and PKA (n=160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided. Results: Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2&bax (HR=2.19, 95% CI=1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR=2.26, 95% CI=1.12 to 4.58, P = .02; bcl2&bax: HR=2.14, 95% CI=1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2%, while for the base model was only 46.2%; Ki-67 was the most statistically significant when tested without bcl2&bax. Conclusions: In this prospective multiple biomarker analysis in men with prostate cancer treated with RT6ADT, both Ki-67 and bcl2&bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.

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