Early detection, diagnosis, and treatment of prostate cancer have significantly reduced the mortality of this disease. However, the inherent limitations of PSA (prostate specific antigen) screening coupled with changing guidance pertaining to its use, has increased the need for better risk assessment tests after PSA screening to determine which men should proceed to biopsy, versus those that can defer. While PSA screening has contributed to a decrease in mortality, it has also led to an overdiagnosis and overtreatment of clinically insignificant prostate cancer. Some patients were being overtreated for indolent, low-grade disease that would rarely metastasize or cause death. These concerns were largely due to the fact that PSA is not a cancer-specific marker and can be elevated for a variety of reasons.
In 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine use of PSA screening. A 2018 update to the USPSTF guideline recommends that, “For men aged 55 to 69 years, the decision to undergo periodic prostate-specific antigen (PSA)-based screening for prostate cancer should be an individual one.” Despite this, PSA remains a widely used, and valuable biomarker. The challenge lies in achieving an approach that identifies high-grade cancer while minimizing detection of low-grade, low-risk, indolent disease.
In addition to the challenges of when and how to use PSA screening, doctors face another dilemma: what happens when a patient’s PSA level comes back in the gray zone?
Given the limitations of PSA screening, there is a clear need for a biomarker test to increase the specificity of PSA (see statement in the NCCN* Guidelines) and lead to better risk stratification for high grade or clinically significant prostate cancer. Ideally, this testing would make it possible to better stratify the risk of finding high-grade prostate cancer to identify patients most in need of intervention. Some procedures used in combination with PSA screening include digital rectal exams (DRE) and multi-parametric magnetic resonance imaging (mpMRI). But these tests have their own limitations. For example, mpMRI may fail to identify small or multifocal tumors; while digital rectal exams tend to be subjective.
Exosomes are a type of extracellular vesicle produced by all living cells. One purpose they serve is to facilitate intercellular communication. Exosomes consist of a protective outer lipid bilayer. Inside the outer membrane, exosomes contain a cargo of proteins, lipids, DNA, miRNA and mRNA. Exosomes are shed by the thousands by all cells, and their molecular content can provide important details about their cells of origin. In addition to their role in normal physiology, exosomes have also been implicated in cancer progression and the tumor microenvironment (among other findings), which may affect proliferation and migration rates of cancer cells.
Thanks to advances in exosome isolation technology, it is now possible to isolate exosomes from any biofluid and analyze their cargo for key biomarker signatures. Importantly, the analysis of exosome cargo can give insights into cancer cell activity and has been developed for use in diagnostic testing. For prostate cancer, exosomes can be captured non-invasively from urine samples without requiring procedures such as a DRE; clinical validation studies have shown that exosomal biomarkers make it possible to distinguish high-grade from low-grade cancer.
The ExoDx Prostate Test (EPI)
Exosome-based testing for prostate cancer risk stratification has been brought to market as the ExoDx™ Prostate Test. This simple, urine-based test is indicated for men aged 50 or older with PSA levels in the gray zone (2-10 ng/mL). It can be used before proceeding to an invasive biopsy procedure, and results can help physicians and patients determine whether to progress to biopsy or to defer, on a case-by-case basis. This liquid biomarker offers an independent genomic perspective not reliant on PSA, PSA isoforms or any other clinical features. It is complementary to other clinical assessments such as DRE, MRI imaging, family history etc., to make more complete assessments of a patient’s risk of having high-grade prostate cancer.
The ExoDx Prostate Test utilizes a first catch urine sample without the need for a DRE, making it the only prostate cancer early detection biomarker with an option for easy at-home sample collection for the patient. The test's biomarker algorithm includes 3 genes (PCA3, SPDEF, and ERG) associated with clinically significant (high grade) prostate cancer. The algorithm weights each gene’s expression and calculates a risk score (0-100) representing the patient’s risk of finding high-grade prostate cancer (Gleason score ≥7) upon biopsy. The test was designed to better enable physicians and patients in making shared decisions on the need for a prostate biopsy.
ExoDx Clinical Validation and Utility Studies
Multiple clinical validation and clinical utility studies in men aged 50 years + with PSA levels in the gray zone (intended use patient population) have resulted in consistent, reproducible and clinically actionable results. The test was first validated in two prospective, large-scale clinical studies spanning more than 1,000 patients across 28 clinical sites in the USA.1,2 Both validation studies reported the test had a negative predictive value of 91.3% and a sensitivity of 92% for high grade prostate cancer (≥GG2).
In a more recent prospective, multi-center, randomized clinical utility study with a blinded control arm – the only level 1 evidence biomarker study for prostate cancer early detection -- the ExoDx Prostate Test detected 30% more cases of high-grade prostate cancer compared to a standard-of-care control arm; this was due to more men at higher risk for high-grade prostate cancer proceeding to biopsy based on high test scores (72% of patients proceeded with a biopsy when recommended, versus 39% in the control arm who did not receive ExoDx Prostate Test scores).3
Based on these and other studies, the ExoDx Prostate Test is now included in prostate cancer screening guidelines issued by both the NCCN* and AUA/SUO**; and has been used for risk stratification assessment in over one hundred thousand patients since the test was introduced for clinical use. The test is covered by Medicare and a number of private insurance carriers for men who are being considered for both initial and repeat biopsy in men with a prior negative biopsy.
To learn more, please visit www.exosomedx.com.
*National Comprehensive Cancer Network
**American Urological Association/Society of Urologic Oncology