The Importance of Protein Kinase A in Prostate Cancer: Relationship to Patient Outcome in Radiation Therapy Oncology Group Trial 92-02

Purpose: We previously 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 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 Gray9s regression models. Results: The expression levels of PKA RIα , determined by manual and image analysis, were strongly correlated ( P RIα staining intensities were independent predictors of distant metastasis ( P P 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. (Clin Cancer Res 2009;15(17):5478–84)