title: The importance of protein kinase A in prostate cancer: relationship to patient outcome in Radiation Therapy Oncology Group trial 92-02.
abstract: OBJECTIVE
  We previously reported that protein kinase A type I (PKA(RIalpha)) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy (RT) +/- short-term androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKA(RIalpha) overexpression.
  
  
  METHODS
  There were 313 cases in the RTOG 92-02 study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKA(RIalpha) staining intensity was quantified manually and by image analysis. Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models.
  
  
  RESULTS
  The expression levels of PKA(RIalpha), determined by manual and image analysis, were strongly correlated (P < 0.0001). In the multivariate analyses, manual-quantified and image analysis-quantified PKA(RIalpha) staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P <or= 0.01). Furthermore, the benefit of long-term AD over STAD was much less when PKA(RIalpha) expression was high.
  
  
  CONCLUSIONS
  PKA(RIalpha) overexpression has been shown in two RTOG trials to be associated with an increased risk of failure after AD + RT. In this series of contemporary high-risk patients, PKA(RIalpha) overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKA(RIalpha) knockdown strategy.
authors.affiliation: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. apollack@med.miami.edu
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
authors.forename: Kyounghwa
authors.initials: K
authors.lastname: Bae
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Khor
authors.forename: Tahseen
authors.initials: T
authors.lastname: Al-Saleem
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Hammond
authors.forename: Varagur
authors.initials: V
authors.lastname: Venkatesan
authors.forename: Roger W
authors.initials: RW
authors.lastname: Byhardt
authors.forename: Sucha O
authors.initials: SO
authors.lastname: Asbell
authors.forename: William U
authors.initials: WU
authors.lastname: Shipley
authors.forename: Howard M
authors.initials: HM
authors.lastname: Sandler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy*; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D054743:Cyclic AMP-Dependent Protein Kinase Type I
references.citation: Cancer. 2005 Sep 1;104(5):962-7
references.pmid: 16007688
references.citation: Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):25-30
references.pmid: 16814949
references.citation: Oncogene. 2004 Nov 18;23(54):8847-56
references.pmid: 15480415
references.citation: Br J Cancer. 1994 Apr;69(4):738-42
references.pmid: 8142263
references.citation: Eur J Cancer. 1993;29A(7):989-91
references.pmid: 8388698
references.citation: J Biol Chem. 1999 Mar 19;274(12):7777-83
references.pmid: 10075669
references.citation: Cancer Res. 2008 May 1;68(9):3225-31
references.pmid: 18451148
references.citation: J Clin Oncol. 2008 May 20;26(15):2497-504
references.pmid: 18413638
references.citation: J Biol Chem. 2005 Mar 25;280(12):11583-9
references.pmid: 15653681
references.citation: Int J Radiat Oncol Biol Phys. 2008 Aug 1;71(5):1309-15
references.pmid: 18455330
references.citation: Lancet Oncol. 2008 Apr;9(4):342-51
references.pmid: 18343725
references.citation: Prostate. 2004 Aug 1;60(3):257-71
references.pmid: 15176055
references.citation: Cancer Res. 1990 Nov 15;50(22):7093-100
references.pmid: 2224844
references.citation: J Biol Chem. 1996 Aug 16;271(33):19900-7
references.pmid: 8702703