title: Prospective Validation of Diagnostic Tumor Biomarkers in Men Treated With Radiotherapy for Prostate Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  In this prospective multiple biomarker analysis in men with prostate cancer treated with RT±ADT, 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.
authors.affiliation: Departments of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
authors.affiliation: Biostatistics and Bioinformatics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Deukwoo
authors.initials: D
authors.lastname: Kwon
authors.affiliation: Biostatistics and Bioinformatics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Walker
authors.affiliation: Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Li Yan
authors.initials: LY
authors.lastname: Khor
authors.affiliation: Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Horwitz
authors.affiliation: Radiation Oncology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Buyyounouski
authors.affiliation: Departments of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Radka
authors.initials: R
authors.lastname: Stoyanova
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D003131:Combined Modality Therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000032:analysis; D019583:Dose Fractionation, Radiation; D005500:Follow-Up Studies; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000737:chemistry* / Q000188:drug therapy / Q000532:radiotherapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis; D012372:ROC Curve; D017211:Treatment Failure; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C494826:BAX protein, human; C000595707:BCL2 protein, human; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051546:Cyclooxygenase 2; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017430:Prostate-Specific Antigen