(S028) Patient-Level DNA Damage and Repair Pathway Profiles Are Prognostic After Prostatectomy for High-Risk Prostate Cancer

Joseph R. Evans, MD, PhD, Shuang Zhao, MSE, Scott A. Tomlins, MD, PhD, Karen E. Knudsen, PhD, Eric A. Klein, MD, Robert B. Den, MD, R. Jeffrey Karnes, MD, Elai Davivioni, PhD, Felix Y. Feng, MD; University of Michigan; Thomas Jefferson University; Cleveland Clinic; Mayo Clinic; GenomeDx Biosciences Inc.

PURPOSE/OBJECTIVES: A substantial number of patients who are diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients who are at the highest risk so that therapy can be intensified. 

MATERIALS AND METHODS: We developed a novel patient-level DNA damage and repair (DDR) pathway profiling approach in a cohort of 1,090 patients undergoing prostatectomy for high-risk prostate cancer who had long follow-up (mean, 7–13 yr). High-density microarray gene expression data from prostatectomy samples were analyzed for DDR pathway enrichment with the gene set enrichment analysis algorithm and clustered hierarchically. The prognostic performance of pathway-based biomarkers for metastatic progression and overall survival (OS) was analyzed with univariate and multivariate logistic regression models. 

RESULTS: We found that there were distinct clusters of DDR pathway patterns within the cohort. DDR pathway enrichment correlated only weakly with the clinical variables age, Gleason score, and PSA (Spearman’s rho ≤ 0.20) and correlated much more strongly with AR pathway enrichment (Spearman’s rho up to 0.82). Many of the individual pathways were significantly associated with increased metastatic progression risk (odds ratio [OR] = 1.28–1.78) and worse OS (OR = 1.51–2.23) on univariate and multivariate analysis, and a composite DDR pathway biomarker showed improved prognostic performance for metastatic progression risk (OR = 2.09 [1.33, 3.28]). Interestingly, this prognostic significance was restricted to patients aged < 70 years. 

CONCLUSIONS: Patient-level DDR pathway profiling revealed distinct clusters. Individual DDR pathways and a composite biomarker showed strong prognostic performance with the long-term outcomes of metastatic progression and OS, which may be useful for risk stratification of high-risk prostate cancer patients aged < 70 years.

Proceedings of the 97th Annual Meeting of the American Radium Society- americanradiumsociety.org