Introduction: Prostate cancer (PCa) is diagnosed in over 1.2 million men worldwide annually. Most men have indolent PCa and can safely defer treatment with active surveillance. However, many men are commonly treated with surgery or radiation therapy which are associated with reduced quality of life. Clinicians are increasingly using molecular information to further understand a patient’s risk of aggressive PCa, and while these signatures have shown promise, there remains a significant opportunity for improving prognostic capacity. Methods: Expression of a novel six-gene signature was measured by RT-qPCR in prostate samples from an Irish cohort of men diagnosed with PCa and treated with radical prostatectomy (RP) (PCRC, n=426). Cross-validated logistic regression identified a six-gene molecular risk score (MRS) with strong prognostic performance to predict aggressive PCa. The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score to create a molecular plus clinical risk score (MCRS). The MRS and MCRS were clinically validated in an independent Swedish cohort of men diagnosed with PCa and treated by RP (UPCA, n=203 RP and n=100 biopsy samples). Results: We identified a six-gene signature, four prognostic and two reference genes, with improved prognostic value over clinical features. In the clinical biopsy validation study, the AUC of the signature for AP was 0.72 (MRS) and 0.82 (MCRS) versus 0.72 (EAU) and 0.82 (CAPRA), and for high primary Gleason was 0.75 (MRS) and 0.85 (MCRS) versus 0.77 (EAU) and 0.83 (CAPRA). The C index for BCR was 0.62 (MRS) and 0.74 (MCRS) versus 0.65 (EAU) and 0.73 (CAPRA). In bivariable analysis, the six-gene signature added statistically significant (p < 0.001) prognostic value to EAU and CAPRA. In the RP clinical validation study, the C index for BCR was 0.74 (MRS) and 0.83 (MCRS) versus 0.69 (EAU) and 0.77 (CAPRA). In bivariable analysis, the six-gene signature added statistically significant (p < 0.0001) prognostic value to EAU and CAPRA. Conclusions: The six-gene molecular prognostic signature has strong performance for AP, high primary Gleason and BCR in independent clinical validation studies when tested on prostate biopsy or RP tissue. MCRS provides improved prognostic stratification and can inform optimal patient management post-diagnosis and post-treatment. SOURCE OF Funding: Support is acknowledged from the Swedish Cancer Society, the Swedish Scientific Council and Government Funding of Clinical Research within the Swedish National Health Service (ALF), the Irish Cancer Society, and OncoAssure Ltd.
