Personalized Medicine and Imaging A Tissue Biomarker–Based Model That Identifies Patients with a High Risk of Distant Metastasis and Differential Survival by Length of AndrogenDeprivation Therapy in RTOG Protocol 92-02

Purpose: To examine the relationship between the expression of 7 promising apoptotic/cell proliferation proteins (Ki-67, p53, MDM2, bcl-2, bax, p16, and Cox-2) and risk of distant metastasis. Experimental Design: RTOG 92-02 compared external beam radiotherapy (EBRT) to approximately 70 Gy þ short-term androgen deprivation therapy (STADT) with EBRT þ long-term ADT (LTADT). Immunohistochemical analysis was available for 4 biomarkers in 616 of 1,521 assessable cases. Biomarkers were evaluated individually and jointly via multivariable modeling of distant metastasis using competing risks hazards regression, adjusting for age, prostate-specific antigen, Gleason score, T stage, and treatment. Results:Modeling identified four biomarkers (Ki-67,MDM2,p16 andCox-2) thatwere jointly associated with distant metastasis. The c-index was 0.77 for the full model and 0.70 for the model without the biomarkers; a relative improvement of about 10% (likelihood ratio P < 0.001). Subdivision of the patients into quartiles based on predicted distant metastasis risk identified a high-risk group with 10-year distant metastasis risk of 52.5% after EBRT þ STADT and 31% with EBRT þ LTADT; associated 10-year prostate cancer–specific mortality (PCSM) risks were 45.9% and 14.5% with STADT and LTADT. Conclusion: Four biomarkers were found to contribute significantly to a model that predicted distant metastasis and identified a subgroup of patients at a particularly high risk of both distant metastasis and PCSM when EBRT þ STADT was used. LTADT resulted in significant reductions in distant metastasis and improvements in PCSM, and there was a suggestion of greater importance in the very high risk subgroup. Clin Cancer Res; 20(24); 6379–88. 2014 AACR.