Introduction:

Prostate cancer (PCa) remains the most common non-cutaneous malignancy in men in the United States. With the incorporation of multiparametric MRI (mpMRI) into the pre-biopsy algorithm for adjudicating elevated PSA, men are more appropriately selected for prostate biopsy. However, many patients with elevated PSA are still subjected to unnecessary biopsy, with final pathology returning benign or clinically insignificant PCa (Gleason 3+3). The use of biomarkers, such as PHI testing, has been explored to better select men for prostate biopsy. Prostate-derived extracellular vesicles (ProstEVs) are microscopic particles released naturally in biofluids by prostate cancer cells. Since ProstEVs inherit genomic and proteomic patterns from the cell of origin, they are promising liquid biomarkers for prostate cancer. Our group sought to evaluate the utility of novel blood-based ProstEV assays prior to prostate biopsy to better determine the risk of clinically-significant prostate cancer (csPCa; grade group >2) compared to mpMRI alone.

Methods:

Following IRB approval, men presenting with elevated PSA were prospectively identified and enrolled. Inclusion criteria were adult males (>18 years), PSA ≥ 2 ng/ml, with or without previous biopsy, or on active surveillance, and able to provide a blood draw. Exclusion criteria included PSA <2 or ≥20 and previous treatment for prostate cancer. Blood concentrations of ProstEVs (PSMA⁺, STEAP1⁺) were determined by flow cytometry using the prostate cancer markers PSMA and STEAP1. Patients then underwent mpMRI, followed by systematic and targeted transperineal, ultrasound-guided MRI fusion biopsy. Primary endpoint was predictive ability of ProstEVs, mpMRI alone or in combination to detect csPCa prior to prostate biopsy. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, and receiver operator characteristic (ROC) curves were created. Results analyzed for patients presenting with any biopsy status (naive, prior negative, prior positive on active surveillance).

Results:

A total of 179 men were enrolled. Of those enrolled, 102 (57%) were biopsy-naïve, 39 (22%) had a prior negative biopsy, and 38 (21%) were on active surveillance. Median age was 65 (IQR 60-71) and median pre-biopsy PSA was 6.35 (IQR 5.0-0.3). Figure 1 demonstrates ROC curves comparing the available testing. Table 1 presents the testing characteristics for PSA, mpMRI (PIRADS >3), STEAP1-EV and combinations. When considering all patients, mpMRI alone had an AUC of 0.76 while combination of mpMRI + STEAP1-EV had an AUC of 0.81. Addition of STEAP1-EV test reduced the false positive rate by 19% while missing 6.3% of csPCa compared to mpMRI alone.

Conclusion:

Extracellular vesicles represent a promising biomarker to reduce the false positive rate of mpMRI in men with elevated PSA, potentially avoiding unnecessary biopsy and the associated morbidity. Our work will serve as scientific justification for validation studies and investigation of other EV-based biomarkers in an effort to further improve the ability to detect csPCa prior to biopsy.

Funding: N/a