TMPRSS2:ERG gene fusion predicts subsequent detection of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia

Abstract

Purpose: High-grade prostatic intraepithelial neoplasia (HGPIN) is considered a precursor lesion of prostate cancer (PCa). The predictive value of ERG gene fusion in HGPIN for PCa was interrogated as a post hoc analysis in the context of a randomized clinical trial.

Patients and methods: The GTx Protocol G300104 randomly assigned 1,590 men with biopsy-diagnosed HGPIN to receive toremifene or placebo for 3 years or until a diagnosis of PCa was made on prostate biopsy. As part of this phase III clinical trial, a central pathologist evaluated biopsies of patients with isolated HGPIN at baseline and 12, 24, and 36 months of follow-up. ERG immunohistochemistry was performed on biopsies from 461 patients and evaluated for protein overexpression.

Results: ERG expression was detected in 11.1% of patients (51 of 461 patients) with isolated HGPIN. In the first year and during the 3-year clinical trial, 14.7% and 36.9% of 461 patients were diagnosed with PCa, respectively. Patients with ERG expression were more likely to develop PCa, with 27 (53%) of 51 ERG-positive and 143 (35%) of 410 ERG-negative patients experiencing progression to PCa (P = .014, Fisher's exact test). ERG expression was not associated with age, baseline PSA, Gleason score, or tumor volume.

Conclusion: This study underscores the necessity of more stringent follow-up for men with HGPIN that is also positive for ERG overexpression. Clinicians should consider molecular characterization of HGPIN as a means to improve risk stratification.

Fig 1.

CONSORT diagram illustrating study participants, ERG status in high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate cancer incidence. PSA, prostate-specific antigen.

Fig 2.

ERG immunohistochemistry on prostate needle biopsies with isolated high-grade prostatic intraepithelial neoplasia (HGPIN). (A to F) Representative photomicrographs of strong and diffuse ERG expression in HGPINs of various morphology (×20 magnification). (G and H) ERG-negative HGPINs with ERG-positive endothelial cells and lymphocytes (×20 magnification).

Fig 3.

By Kaplan-Meier estimate, prostate cancer–free survival was significantly worse among patients who expressed ERG than patients who did not.

Fig A1.

ERG expression defines molecular tumorigenesis in precancerous prostate glands. (A to C) Heterogeneous ERG expression between and within high-grade prostatic intraepithelial neoplasias (HGPINs) implies beginning of malignant molecular alteration and confirms that HGPIN is the precursor lesion of prostate cancer (×20 magnification). (D to F) Clear demarcation between ERG-positive and ERG-negative cells is noted within the same gland (×40 magnification). (G and H) Glands that might not meet the histologic criteria for HGPIN demonstrate ERG expression, adjacent to ERG-negative HGPINs (×40 magnification).