Cross-Comparison Individual Patient Level Analysis of Three Gene Expression Signatures in Localized Prostate in over 50,000 Men

Abstract

Risk stratification guides the management of localized prostate cancer. Multiple commercial gene expression biomarkers have been developed to improve estimates of prognosis, however the 22-gene Decipher genomic classifier (22-GC) is the only test with level 1 evidence supporting its use per NCCN guidelines. It is unknown whether other commercial signatures, Oncotype (GPS) or Prolaris (CCP), are sufficiently correlated to negate the differences in evidence supporting these commercial tests. Herein, we aim to perform a cross-comparison of these signatures in a large cohort of patients diagnosed with localized prostate cancer. Patients diagnosed with localized prostate cancer who underwent whole transcriptome gene expression microarray analysis on their primary tumor biopsy specimen were included. The 22-GC score was calculated by Veracyte using a commercially locked model. Individual genes in each of the GPS and CCP gene signatures were identified, and the gene weights in each signature were retrained for prediction of metastasis in a multi-institutional cohort of 1,574 men with long-term outcome data. This was performed to improve correlation performance of GPS and CCP given only the 22-GC was trained for prediction of metastasis. For each of the three signatures, both continuous and categorical scores were calculated. Linear regression and spearman correlations were calculated both on univariable and multivariable analyses adjusting for age, grade group, PSA, and T-stage. A total of 50,881 patients were included (15,379 (30.2%) NCCN low-risk, 14,773 (29.0%) favorable intermediate-risk, 15,544 (30.5%) unfavorable intermediate-risk, and 5,185 (10.2%) high/very high-risk) with a median age of 68 years, and a median PSA of 6.2 ng/mL. On linear regression, the GPS model had poor goodness-of-fit to the 22-GC with an R2 of 0.36, as did the CCP model to the 22-GC with an R2 of 0.32. For CCP, the linear sum of the 31-genes was also tested but had inferior performance (R2 0.28) compared to the reoptimized CCP model. Results were similar on multivariable analysis adjusting for age, PSA, clinical stage and grade group. Spearman correlation between the continuous GPS model scores and the 22-GC was moderate at 0.59, as was the correlation between CCP model and the 22-GC of 0.54. CCP is a measure of proliferation, but in 22-GC high-risk patients, the majority (64.1%) of patients had low-average proliferation and only 35.9% had high proliferation, potentially explaining the lack of strong correlation. There is minimal to moderate correlation between the 22-GC and GPS or CCP gene expression signatures tested. Therefore, these tests should not be viewed as interchangeable, and utilization should be based on the level of evidence supporting each gene expression biomarker.