The importance of protein kinase A in prostate cancer: Relationship to patient outcome in Radiation Therapy Oncology Group trial 92-02

Purpose: Wepreviously reported that protein kinase A type I (PKA _RIα) 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 _RIα overexpression. Experimental Design: 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 _RIα staining intensity was quantified manually and by image analysis. Multivariate analyseswere done for overallmortality 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 _RIα, determined bymanual and image analysis, were strongly correlated (P < 0.0001). In the multivariate analyses, manual-quantified and image analysis-quantified PKA _RIα staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P ≤ 0.01). Furthermore, the benefit of long-term AD over STAD was much less when PKA _RIα expression was high. Conclusions: PKA _RIα 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 _RIα overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKA _RIα knockdown strategy.