title: Prognostic value of p16 in locally advanced prostate cancer: a study based on Radiation Therapy Oncology Group Protocol 9202.
abstract: OBJECTIVE
  Deregulation of the retinoblastoma (RB) pathway is commonly found in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected member of this pathway. In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on Radiation Therapy Oncology Group protocol 9202.
  
  
  METHODS
  RTOG 9202 was a phase III randomized study comparing long-term (LT) versus short-term (ST) androgen-deprivation therapy (AD). Of the 1,514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Expression levels of p16 were determined by immunohistochemistry (IHC). IHC staining was scored quantitatively using an image analysis system.
  
  
  RESULTS
  On multivariate analysis, intact p16 expression was significantly associated with decreased rate of distant metastases (P = .0332) when both STAD and LTAD treatment arms were considered together. For patients with intact (high levels of immunostaining) p16 (mean p16 index > 81.3%), LTAD plus radiotherapy (RT) significantly improved prostate cancer survival (PCS) compared with STAD plus RT (P = .0008) and reduced the frequency of distant metastasis (P = .0069) compared with STAD plus RT. In contrast, for patients with tumors demonstrating p16 loss (low levels of immunostaining, mean p16 index < or = 81.3%), LTAD plus RT significantly improved biochemical no evidence of disease survival over STAD (P < .0001) primarily by decreasing the frequency of local progression (P = .02), as opposed to distant metastasis, which was the case in the high-p16 cohort.
  
  
  CONCLUSIONS
  Low levels of p16 on image analysis appear to be associated with a significantly higher risk of distant metastases among all study patients. p16 expression levels also appear to identify patients with locally advanced prostate cancer with distinct patterns of failure after LTAD.
authors.affiliation: Massachusetts General Hospital/Harvard Medical School, Department of Radiation Oncology, Boston, MA 02114, USA. achakravarti@partners.org
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Michelle
authors.initials: M
authors.lastname: DeSilvio
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Grignon
authors.forename: Seth
authors.initials: S
authors.lastname: Rosenthal
authors.forename: Sucha O
authors.initials: SO
authors.lastname: Asbell
authors.forename: Gerald
authors.initials: G
authors.lastname: Hanks
authors.forename: Howard M
authors.initials: HM
authors.lastname: Sandler
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Khor
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
authors.forename: William
authors.initials: W
authors.lastname: Shipley
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001707:Biopsy, Needle; D003131:Combined Modality Therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D020266:Radiotherapy, Conformal / Q000379:methods*; D012016:Reference Values; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017430:Prostate-Specific Antigen