The importance of protein kinase A in prostate cancer: relationship to patient outcome in Radiation Therapy Oncology Group trial 92-02.
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.
Pollack
Alan
A
Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. apollack@med.miami.edu
Bae
Kyounghwa
K
Khor
Li-Yan
LY
Al-Saleem
Tahseen
T
Hammond
M Elizabeth
ME
Venkatesan
Varagur
V
Byhardt
Roger W
RW
Asbell
Sucha O
SO
Shipley
William U
WU
Sandler
Howard M
HM
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
D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D054743:Cyclic AMP-Dependent Protein Kinase Type I
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