MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02

Li Yan Khor, Kyounghwa Bae, Rebecca Paulus, Tahseen Al-Saleem, M. Elizabeth Hammond, David J. Grignon, Mingxin Che, Varagur Venkatesan, Roger W. Byhardt, Marvin Rotman, Gerald E. Hanks, Howard M. Sandler, Alan Pollack

Research output: Contribution to journalArticle

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Abstract

Purpose: MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. Patients and Methods: Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results: In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). Conclusion: Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.

Original languageEnglish
Pages (from-to)3177-3184
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number19
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

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Androgens
Prostatic Neoplasms
Radiotherapy
Neoplasm Metastasis
Mortality
Cell Cycle Checkpoints
Proportional Hazards Models
Multivariate Analysis
Biomarkers
Immunohistochemistry
Clinical Trials
Apoptosis
Staining and Labeling
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer : RTOG 92-02. / Khor, Li Yan; Bae, Kyounghwa; Paulus, Rebecca; Al-Saleem, Tahseen; Elizabeth Hammond, M.; Grignon, David J.; Che, Mingxin; Venkatesan, Varagur; Byhardt, Roger W.; Rotman, Marvin; Hanks, Gerald E.; Sandler, Howard M.; Pollack, Alan.

In: Journal of Clinical Oncology, Vol. 27, No. 19, 01.07.2009, p. 3177-3184.

Research output: Contribution to journalArticle

Khor, LY, Bae, K, Paulus, R, Al-Saleem, T, Elizabeth Hammond, M, Grignon, DJ, Che, M, Venkatesan, V, Byhardt, RW, Rotman, M, Hanks, GE, Sandler, HM & Pollack, A 2009, 'MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02', Journal of Clinical Oncology, vol. 27, no. 19, pp. 3177-3184. https://doi.org/10.1200/JCO.2008.19.8267
Khor, Li Yan ; Bae, Kyounghwa ; Paulus, Rebecca ; Al-Saleem, Tahseen ; Elizabeth Hammond, M. ; Grignon, David J. ; Che, Mingxin ; Venkatesan, Varagur ; Byhardt, Roger W. ; Rotman, Marvin ; Hanks, Gerald E. ; Sandler, Howard M. ; Pollack, Alan. / MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer : RTOG 92-02. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 19. pp. 3177-3184.
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abstract = "Purpose: MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. Patients and Methods: Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results: In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). Conclusion: Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.",
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T1 - MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer

T2 - RTOG 92-02

AU - Khor, Li Yan

AU - Bae, Kyounghwa

AU - Paulus, Rebecca

AU - Al-Saleem, Tahseen

AU - Elizabeth Hammond, M.

AU - Grignon, David J.

AU - Che, Mingxin

AU - Venkatesan, Varagur

AU - Byhardt, Roger W.

AU - Rotman, Marvin

AU - Hanks, Gerald E.

AU - Sandler, Howard M.

AU - Pollack, Alan

PY - 2009/7/1

Y1 - 2009/7/1

N2 - Purpose: MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. Patients and Methods: Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results: In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). Conclusion: Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.

AB - Purpose: MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. Patients and Methods: Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results: In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). Conclusion: Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.

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