title: A tissue biomarker-based model that identifies patients with a high risk of distant metastasis and differential survival by length of androgen deprivation therapy in RTOG protocol 92-02.
abstract: OBJECTIVE
  To examine the relationship between the expression of 7 promising apoptotic/cell proliferation proteins (Ki-67, p53, MDM2, bcl-2, bax, p16, and Cox-2) and risk of distant metastasis.
  
  
  METHODS
  RTOG 92-02 compared external beam radiotherapy (EBRT) to approximately 70 Gy + short-term androgen deprivation therapy (STADT) with EBRT + long-term ADT (LTADT). Immunohistochemical analysis was available for ≥4 biomarkers in 616 of 1,521 assessable cases. Biomarkers were evaluated individually and jointly via multivariable modeling of distant metastasis using competing risks hazards regression, adjusting for age, prostate-specific antigen, Gleason score, T stage, and treatment.
  
  
  RESULTS
  Modeling identified four biomarkers (Ki-67, MDM2, p16 and Cox-2) that were jointly associated with distant metastasis. The c-index was 0.77 for the full model and 0.70 for the model without the biomarkers; a relative improvement of about 10% (likelihood ratio P < 0.001). Subdivision of the patients into quartiles based on predicted distant metastasis risk identified a high-risk group with 10-year distant metastasis risk of 52.5% after EBRT + STADT and 31% with EBRT + LTADT; associated 10-year prostate cancer-specific mortality (PCSM) risks were 45.9% and 14.5% with STADT and LTADT.
  
  
  CONCLUSIONS
  Four biomarkers were found to contribute significantly to a model that predicted distant metastasis and identified a subgroup of patients at a particularly high risk of both distant metastasis and PCSM when EBRT + STADT was used. LTADT resulted in significant reductions in distant metastasis and improvements in PCSM, and there was a suggestion of greater importance in the very high risk subgroup.
authors.affiliation: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida. APollack@med.miami.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
authors.affiliation: Department of Public Health Sciences, University of Chicago, Chicago, Illinois; and NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
authors.forename: James J
authors.initials: JJ
authors.lastname: Dignam
authors.affiliation: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Dayssy A
authors.initials: DA
authors.lastname: Diaz
authors.affiliation: Department of Public Health Sciences, University of Chicago, Chicago, Illinois; and NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Radka
authors.initials: R
authors.lastname: Stoyanova
authors.affiliation: Early Clinical Biostatistics, Novartis Pharmaceuticals, East Hanover, New Jersey.
authors.forename: Kyounghwa
authors.initials: K
authors.lastname: Bae
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Howard
authors.initials: H
authors.lastname: Sandler
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Hanks
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D061766:Proton Therapy; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor