Genomic Validation of Three-Tiered Sub-Classification of High-Risk Prostate Cancer

Abstract

Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score >= 8, or prostate-specific antigen [PSA] > 20 ng/mL) is a heterogeneous group in terms of long-term patient outcomes. We sought to determine whether sub-classification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. We identified 2,983 patients with NCCN unfavorable intermediate-risk (n=1,778) or high-risk (n=1,205) prostate cancer. We defined the following sub-classification of high-risk prostate cancer based on previously published data: favorable high-risk (cT1c, Gleason 6, and PSA > 20 ng/mL or cT1c, Gleason 4+4=8, PSA < 10 ng/mL); very high-risk (cT3b-T4 or primary Gleason pattern 5); and standard high-risk (all others with cT3a, Gleason score >=8, or PSA > 20 ng/mL). We used a set of 39 previously published genomic classifiers, including the 22-gene Decipher assay, to determine whether high-risk genomic features correlated with the clinical sub-classification of high-risk prostate cancer. Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 51.1%, 64.7%, and 81.5% had a high-risk Decipher score, respectively (p < 0.001). Among 38 other high-risk genomic signatures, 34 had a similar increasing trend across the three sub-classes of high-risk (p < 0.05 after Benjamini-Hochberg correction for multiple hypothesis testing). Patients in the three sub-classes of high-risk disease were positive for a median number of 6, 8, and 15 high-risk signatures. Under a novel clinical-genomic risk group classification (Spratt et al., 2017), 27.0%, 19.1%, and 7.0% of patients with favorable, standard, or very high-risk disease would be re-classified as intermediate-risk, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.9% had a high-risk Decipher score (and would be re-classified as Spratt high-risk) and the median number of high-risk signatures was 4. Genomic markers of risk correlate with the clinical sub-classification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, validating the prognostic utility of this stratification.