Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies

OBJECTIVE: • To evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer. PATIENTS AND METHODS: • We prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high-risk features. • All men underwent repeat 12-core ultrasonography-guided biopsy. • DNA methylation of glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy. • The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI). RESULTS: • On repeat biopsy, 21/86 (24%) men had prostate cancer. • APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06-1.36), indicating APC has significantly higher NPV. • Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1. • Combining both methylation markers produced a performance similar to that of APC alone. • APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis. CONCLUSIONS: • APC methylation provided a very high NPV with a low percentage of falsenegatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy. • The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.