ERG Status at the Margin Is Associated With Biochemical Recurrence After Radical Prostatectomy With Positive Surgical Margins

Abstract

Positive surgical margins at radical prostatectomy are associated with an increased risk of biochemical recurrence (BCR). However, there is considerable variability in outcomes, suggesting that molecular biomarkers-when assessed specifically at the margin tumor tissue-may be useful to stratify prognosis in this group. We used a case-cohort design for the outcome of BCR, selecting 215 patients from a cohort of 813 patients undergoing prostatectomy treated at the Johns Hopkins from 2008 to 2017 with positive margins and available clinical data. Tissue microarrays were created from the tumor adjacent to the positive margin and stained for PTEN, ERG, and Ki-67. Cases were scored dichotomously (PTEN and ERG) or by the Ki-67 staining index using previously validated protocols. The analysis used Cox proportional hazards models weighted for the case-cohort design. Overall, 20% (37/185) of evaluable cases had PTEN loss and 38% (71/185) had ERG expression, and the median Ki-67 expression was 0.42%. In multivariable analysis adjusting for the CAPRA-S score, adjuvant radiation, and grade group at the positive margin, ERG-positive tumors were associated with a higher risk of BCR compared to those that were ERGnegative (hazard ratio [HR], 2.4; 95% CI, 1.2-4.9; P = .012) regardless of PTEN status at the margin, and adding ERG to clinicopathologic variables increased the concordance index from 0.827 to 0.847. PTEN loss was associated with an increased risk of BCR on univariable analysis (HR, 3.19; 95% CI, 1.72-5.92; P = .0002), but this association did not remain after adjusting for clinicopathologic variables (HR, 1.06; 95% CI, 0.49-2.29; P = .890). Thus, in the setting of prostate tumors with positive surgical margins after prostatectomy, ERG-positive tumors with or without PTEN loss at the positive margin are associated with a significantly higher risk of BCR after adjusting for clinicopathologic variables. If validated, ERG status may be helpful in decision-making surrounding adjuvant therapy after prostatectomy.

Keywords: ERG; Ki-67; PTEN; positive surgical margins; prostate cancer; radical prostatectomy.