Validation of Cyclic Adenosine Monophosphate Phosphodiesterase-4D7 for its Independent Contribution to Risk Stratification in a Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

Background: The clinical metrics used to date to assess the progression risk of newly diagnosed prostate cancer patients only partly represent the true biological aggressiveness of the underlying disease. Objective: Validation of the prognostic biomarker phosphodiesterase-4D7 (PDE4D7) in predicting longitudinal biological outcomes in a historical surgery cohort to improve postsurgical risk stratification. Design, patients, and methods: RNA was extracted from biopsy punches of resected tumors from 550 patients. PDE4D7 was quantified using one-step quantitative reverse transcription-polymerase chain reaction. PDE4D7 scores were calculated by normalization of PDE4D7 to reference genes. Multivariate analyses were adjusted for clinical prognostic variables. Outcomes tested were: prostate-specific antigen relapse, start of salvage treatment, progression to metastases, overall mortality, and prostate cancer-specific mortality. The PDE4D7 score was combined with the clinical risk model Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) using multivariate regression modeling; the combined score was tested in post-treatment progression free survival prediction. Outcome measurements and statistical analysis: Correlations with outcomes were analyzed using multivariate Cox regression and logistic regression statistics. Results and limitations: The PDE4D7 score was significantly associated with time-to-prostate specific antigen failure after prostatectomy (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.41-0.67 for each unit increase, p. <. 0.0001). After adjustment for postsurgical prognostic variables the HR was 0.56 (95% CI: 0.43-0.73, p. <. 0.0001). The PDE4D7 score remained significant after adjusting the multi-variate analysis for the CAPRA-S model categories (HR = 0.54, 95% CI = 0.42-0.69, p. <. 0.0001). Combination of the PDE4D7 score with the CAPRA-S demonstrated a significant incremental value of 4-6% in 2-yr (p = 0.004) or 5-yr (p = 0.003) prediction of progression free survival after surgery. The combined model of PDE4D7 and CAPRA-S improves patient selection with very high risk of fast disease relapse after primary intervention. Conclusions: The PDE4D7 score has the potential to provide independent risk information and to restratify patients with clinical intermediate- to high-risk characteristics to a very low-risk profile. Patient summary: In this report, we studied the potential of a novel biomarker to predict outcomes of a cohort of prostate cancer patients who underwent surgery more than 10 yr ago. We found that a gene called phosphodiesterase-4D7 added extra information to the available clinical data. We conclude that the measurement of this gene in tumor tissue may contribute to more effective treatment decisions. We validated the added value of the prostate cancer biomarker phosphodiesterase-4D7 to predict the outcomes of prostate cancer patients in a historic patient cohort. We concluded that phosphodiesterase-4D7 provides extra information on patient risk next to the standard clinical prognosticators.

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