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Prostate cancer (PCa) is the second-leading cause of cancer death among men in the United States.1

Since its approval by the FDA in 1986,2 PSA tests have been used extensively worldwide for screening, diagnosis, and post-treatment surveillance of PCa.


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As a result, the universal uptake of PSA testing has led to the overdiagnosis and treatment of indolent PCa in a significant number of men, resulting in considerable morbidity, healthcare costs, and a questionable survival benefit.3 These factors contributed to the recent controversial decision by the U.S. Preventive Services Task Force (USPSTF) to recommend against routine PSA screening for PCa in asymptomatic men.4  

It is important to consider that PSA was developed as a marker of PCa recurrence following prostatectomy, and not as a screening tool. Elevated levels of PSA can be detected in men with benign prostatic hyperplasia (BPH), urinary retention,5 and prostatitis.6 While performance of digital rectal exam (DRE) is thought to increase the specificity of PCa screening, the positive predictive values (PPV) of DRE and serum PSA value below 10 ng/mL have been reported as less than 20% and 25%-30%, respectively.7,8 

For these reasons, up to 70% of men presenting with elevated PSA levels between 4-7 ng/mL have false-positive PSA tests that result in negative prostate biopsy (PBx).9

Furthermore, men who have had one or more prior negative PBx and continue to have a consistently elevated or rising PSA have become increasingly challenging to manage. While repeat PBx is often recommended, the transrectal procedure is not without risk. While uncommon, poor outcomes from biopsy-related sepsis are occurring more frequently due to changing antibiotic resistance patterns.10

Other complications include patient discomfort, urinary retention, hematuria, hematospermia, and rectal bleeding, although these are less serious that sepsis. Meanwhile, a seven-year follow-up study of 164 men with an initial negative PBx and elevated PSA showed that PCa was detected in only 11% of patients,11 although proportions as high as 20%-25% have been reported.

Balancing the risk of complications with repeat procedures versus the risk from undiagnosed PCa requires diligent patient counseling and informed patient decision making.

Due to the poor sensitivity and specificity of PSA as a screening tool, there has been considerable interest in identifying PCa-specific genes to guide management. Over the past decade, a number of novel PCa biomarkers have been discovered that show potential for detection and differentiation of indolent from aggressive PCa.

Since using tissue as a substrate for biomarker testing is invasive and expensive, testing of biomarkers in body fluids (urine, plasma, prostate serum, and semen) is considered a promising non-invasive strategy to test for PCa.  After prostate manipulation, epithelial cells are released into such biological fluids and enable detection by non-invasive methods.

Additionally, because urine is readily available, its utility as a biomarker source has been well studied for a number of conditions including PCa.12

Urinary biomarkers

Urine-based biomarkers rely on the presence of proteins, RNA, and DNA.  Although beyond the scope of this review, the feasibility of using urine as a method of PCa cell detection has been demonstrated with mixed results.13

Prostatic ducts release prostate cells directly into the urethra.12 Considering the distance of the peripheral zone from the urethra, urine-based testing theoretically should be less sensitive for peripherally-located cancers (where 80% of PCa tumors are found).  However, Nakanishi and colleagues showed no difference in the levels of the urinary prostate cancer antigen 3 gene (PCA3) between patients with peripheral versus transitional zone cancers.14 

Although not shown in randomized clinical studies, the concept of prostatic manipulation or massage prior to urine sample collection for biomarker studies has been accepted as a standardized way of urine collection. To maximize yield, experts suggest collecting urine samples immediately after a firm DRE. This is done by firmly pressing down on each lobe of the prostate surface three times to compress it by approximately 1 cm, rolling the index finger from lateral to medial, and from the base to the apex of the prostate.15,16

Over the past two decades, several PCa-specific genes or biomarkers have generated considerable interest in the scientific and urologic community. Although the role of the vast majority of these genes/biomarkers for screening purposes has not been fully determined, they have demonstrated promise in enhancing diagnostic accuracy, differentiating between low- and high-risk disease, and more appropriately selecting patients for repeat biopsy. Gu et al. described the association of prostate stem cell antigen (PSCA) gene over-expression with high Gleason score, advanced stage, and bone metastasis.17

Elevated levels of prostate-specific membrane antigen (PSMA), an integral trans-membrane glycoprotein, have been linked to aggressive metastatic PCa.18 Another well-studied potential biomarker is alpha-methylacyl-CoA racemase (AMCAR) expression, which has also been shown to be elevated in PCa specimens compared with normal prostate tissue.19 Other prostate-specific genes that have been described and are currently under investigation include TMPRSS2,20 NKX3.1, 21 PDEF,22 prostase,23 and specifically of interest to this review, DD3 (PCA3).24