Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

Area of Science:

• Urology
• Oncology
• Biomarker Discovery

Background:

• Prostate-specific antigen (PSA) screening for prostate cancer (PCa) has limitations, including poor specificity leading to unnecessary biopsies and overdetection of indolent cancers.
• Accurate identification of high-grade PCa (Grade Group [GG] 2 or greater) is crucial for effective patient management and avoiding overtreatment.

Purpose of the Study:

• To develop and externally validate a multiplex urinary biomarker panel for the accurate detection of high-grade PCa.
• To compare the performance of the new urinary test against existing guideline-endorsed biomarkers.

Main Methods:

• RNA sequencing identified 54 PCa markers, with 17 specific to high-grade PCa.
• Gene expression and clinical data were used to develop the MyProstateScore 2.0 (MPS2) and MPS2+ urinary tests.
• Blinded external validation was performed in a prospective National Cancer Institute trial cohort.

Main Results:

• The MPS2 and MPS2+ models demonstrated superior diagnostic accuracy (AUC 0.81-0.82) compared to PSA alone (AUC 0.60), risk calculators (AUC 0.66), and Prostate Health Index (PHI) (AUC 0.77).
• At 95% sensitivity for GG2+ PCa, MPS2 significantly reduced unnecessary biopsies in both initial (35-42%) and repeat (46-51%) biopsy populations.
• MPS2 models achieved high negative predictive values (95-99% for GG2+ PCa, 99% for GG3+ PCa).

Conclusions:

• The 18-gene MPS2 test offers higher diagnostic accuracy for high-grade PCa than current biomarker tests.
• Clinical implementation of MPS2 can reduce unnecessary biopsies while maintaining high sensitivity for detecting aggressive PCa.
• This novel biomarker test supports improved prostate cancer screening by minimizing harms and preserving benefits for patients with elevated PSA levels.