Originally published as JCO Early Release 10.1200/JCO.2008.19.8267 on May 26 2009
Journal of Clinical Oncology, Vol 27, No 19 (July 1), 2009: pp. 3177-3184
© 2009 American Society of Clinical Oncology.
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
From the Department of Pathology, Drexel University College of Medicine; Department of Statistics, Radiation Therapy Oncology Group, American College of Radiology; and Departments of Pathology and of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA; Department of Pathology, LDS Hospital, Intermountain Health Care, Salt Lake City, UT; Department of Pathology, Indiana University, Indianapolis, IN; Department of Anatomic Pathology, Quest Diagnostics Incorporated, Schaumberg, IL; Radiation Oncology, University of Western Ontario, London, Ontario, Canada; Department of Radiation Therapy, Medical College of Wisconsin, Milwaukee, WI; Department of Radiation Oncology, State University of New York, Brooklyn, NY; Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI; and Department of Radiation Oncology, University of Miami, Miami, FL.
Corresponding author: Alan Pollack, MD, PhD, Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center, 1475 NW 12th Ave, Suite 1501, Miami, FL 33130; e-mail: apollack{at}med.miami.edu.
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.
Supported in part by Grants No. CA-006927, CA-101984-01, CA-21661, and CA-32115 from the National Cancer Institute and by grants from Varian Medical Systems, Palo Alto, CA and the Pennsylvania Department of Health. The contents are solely the responsibility of the authors and do not necessarily represent the official views of these organizations.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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