Over 1 million transrectal ultrasonography guided (TRUS) prostate biopsies are performed annually in the US and Europe [22]. Although clinical information such as age, race, family history, or a suspicious DRE are triggers, most TRUS biopsies are driven by PSA screening. Biopsies are often associated with pain, bleeding, sepsis and, of significant concern, an increasing rate of antibiotic resistant infection [22,23]. A significant number (approximately 70% of men) are not found to have prostate cancer on initial biopsy, and this leads to patient anxiety because of the false negative rate as a result of prostatectomy under-sampling and tumor heterogeneity/multifocality. These concerns drive many men to undergo repeat biopsy. In fact, the Surveillance, Epidemiology, and End Results (SEER) data indicates that ~ 12% of men with a prior negative biopsy have a repeat biopsy within one year and 44% of men younger than 70 years old have a repeat biopsy [11,24].
PSA screening for prostate cancer is challenged by the low sensitivity and poor specificity for prostate cancer detection. Risk assessment tools such as Prostate Cancer Prevention Trial risk calculator (PCPTRC) were originally developed to improve clinical risk assessment by combining multiple clinical features with PSA. In 2012, the USPSTF recommendation against PSA testing was due to the detection and aggressive overtreatment (surgery and radiation therapy) of low-grade PCa. Although the USPSTF revised its initial recommendation in 2018 based on study re-evaluation [27,28], the pendulum has swung away from PSA screening, and there is a risk the success in reducing PCa mortality will be lost. Since the 2012 USPSTF recommendation, an increase in metastatic prostate cancer has been observed, although it is actively debated [29]. The 2018 USPSTF update recommends PSA screening and shared decision making in men ages 55–69.
The ExoDx Prostate test – a genomic prostate biomarker of HGPCa, independent of clinical features or standard of care (SOC)- was developed and validated as a urine-based, exosomal gene signature from genes known to be involved in PCa initiation and progression: ERG, PCA3 and SPDEF [30–36].
The ExoDx Prostate test algorithm was developed and validated on the intended use cohort, i.e. men presenting for their initial biopsy with a PSA 2–10 ng/mL where it achieved an NPV of 91%, a sensitivity of 91% and 34% specificity [14,15]. It is well established in the literature that prevalence of prostate cancer is significantly lower in a prior negative biopsy population and that this clinical feature alone will favorably impact test performance when included in risk assessment models (and some commercial assays) [37–38]. To address this issue, we evaluated the accuracy of EPI in the prior negative biopsy population as the test does not include any clinical variables such as prior negative biopsy, PSA, DRE outcome, family history in generation of the final risk score.
An ExoDx Prostate score less than 15.6 would have potentially avoided biopsy in 26% of men, and a score of less than 20 would have avoided a biopsy in 35% of men without missing additional HGPCa. As 2019 NCCN guidelines provide management options between GG2 compared to GG3 categories at diagnosis, it is important to note only 3 patients with GG3 or higher-grade disease were missed at the 15.6 or the 20 cut-point when examining repeat biopsies [39]. The ExoDx Prostate assay demonstrated a comparable NPV in prior negative biopsy men compared to men undergoing initial biopsy.
Study limitations include the sample size and lack of a central pathology review, which may have introduced some variability, specifically when reporting small volume cancers and the fact that there were no men in the study who underwent multi-parametric MRI imaging pre-biopsy. During the study period (2014 and 2015), MRI imaging was not standard of care in the USA. Nevertheless, all the study participating centers represent large urology group practices and academic centers with highly experienced uropathologists. A second prospective study in prior negative biopsy men is underway in the US to address the increasing use of mpMRI imaging and fusion biopsy in this population.