title: MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02.
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.
authors.affiliation: Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center, 1475 NW 12th Ave, Suite 1501, Miami, FL 33130, USA. apollack@med.miami.edu
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Khor
authors.forename: Kyounghwa
authors.initials: K
authors.lastname: Bae
authors.forename: Rebecca
authors.initials: R
authors.lastname: Paulus
authors.forename: Tahseen
authors.initials: T
authors.lastname: Al-Saleem
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Hammond
authors.forename: David J
authors.initials: DJ
authors.lastname: Grignon
authors.forename: Mingxin
authors.initials: M
authors.lastname: Che
authors.forename: Varagur
authors.initials: V
authors.lastname: Venkatesan
authors.forename: Roger W
authors.initials: RW
authors.lastname: Byhardt
authors.forename: Marvin
authors.initials: M
authors.lastname: Rotman
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Hanks
authors.forename: Howard M
authors.initials: HM
authors.lastname: Sandler
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D003131:Combined Modality Therapy; D015870:Gene Expression; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011878:Radiotherapy; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2