Prostate-specific antigen (PSA) is the most widely used noninvasive diagnostic test for prostate cancer and as such, it has led to the diagnosis and subsequent treatment for millions of American men. Since PSA's introduction in 1989, the incidence of prostate cancer has risen, which has benefited many but perhaps has also led to the overtreatment of low-risk prostate cancer in others. Randomized clinical trials examining the role of PSA-based screening have either demonstrated a lack of or only marginal efficacy when it is applied as a screening test [1,2]. This has led some, including the US Preventive Services Task Force [3,4], to criticize its role as a prostate cancer screening test even as other professional societies recommends individualized discussion of PSA screening .
This controversy arises from the fact that PSA is not prostate cancer specific; other common, nonmalignant conditions such as benign prostatic hyperplasia, prostatitis, and even urinary tract infections may lead to its elevation . In practice, an elevated PSA will trigger a more specific, confirmatory test, the prostate biopsy, which is invasive and associated with bleeding and infectious complications [7,8]. Attempts to address this has resulted in a number of PSA derivative tests such as percentage-free PSA [9,10], age-specific PSA ranges , PSA velocity , and −2proPSA [13,14], but these are constrained by the same limitations as PSA itself – namely, confounding by benign prostatic conditions. At the heart of the PSA screening controversy is what to do if the PSA test is ‘abnormal’ in light of the limited sensitivity and specificity.
Currently, an abnormal PSA test often leads to a prostate biopsy, which when positive is often a low-risk cancer. However, many men are reluctant to undergo a biopsy-given fear of discomfort and complications. Indeed, the rise of resistant bacteria has increased the hospitalization rate after a prostate biopsy to nearly 3% largely due to ciprofloxacin resistence . Moreover, the anxiety incurred when a patient is told that he may have prostate cancer is considerable and difficult to quantify.
The US Preventive Services Task Force recommendation to not screen is based on using PSA as the sole test to drive the decision-making process . A possible alternative solution to not screening at all would be to improve the performance characteristic of the early detection process. One such approach is to supplement PSA with new biomarkers that provide prognostic information. The limitations of PSA as a stand-alone biomarker for early detection have led to an intensive search for other biomarkers.
Fortunately, a number of potential candidates have emerged thanks to high-throughput genomic, proteomic, and metabolomics efforts. Although PSA is a serum-based assay, biomarkers may be detected in all forms of body fluid, including urine. Indeed, the abundance of, and ease of, collecting voided urine holds the potential to quantitatively measure prostate cancer biomarkers that may be excreted or shed into the urine. This article will now focus on those biomarkers, which have been, or will likely be, translated into urinary assays.
PROSTATE CANCER ANTIGEN 3
Prostate cancer antigen 3 (PCA3, also known as Differential Display Code 3 or DD3) is the first urinary biomarker for prostate cancer to gain US Food and Drug Administration (FDA) approval. PCA3, a prostate-specific gene, that is present in 95% of prostate cancers  and significantly overexpressed in cancer tissue . PCA3 is known to be a noncoding messenger RNA (mRNA) with no resultant protein. Clinically, PCA3 mRNA is detectable in the urine and prostatic fluid of men with PCa. PCA3 mRNA levels are independent of prostate volume and serum PSA but may be higher with larger, more aggressive tumors . Although PCA3 has been approved in Europe as the uPM3 assay, PROGENSA PCA3 Assay has only been approved by the FDA since 2012 with an indication for men with prior negative prostate biopsies [19–22].
With an initial cutoff value set at 50, this assay demonstrated a sensitivity of 69% and specificity of 79% . The nucleic acid sequence-based amplification urine uPM3 assay has demonstrated similar results, with a cutoff of 0.5, sensitivity ranged from 66 to 82%, specificity from 76 to 89%, and negative predictive value from 84 to 87% [19,21]. To date, studies [23–25] have examined the performance of PCA3 and documented high sensitivity (52–58%) and specificity (72–87%) [23,26], even in the setting of a prior negative prostate biopsy. In an affirmation of the FDA indication, a recent meta-analysis examining PCA3 for guiding repeat prostate biopsies examined 11 studies of moderate to high quality . The synthesis of these data found that PCA3 cutoff of 20 using the Progensa assay resulted in an optimized sensitivity for men undergoing a repeat prostate biopsy. Consistent with prior work, these investigators found that at this cutoff, there would be a significant reduction in unnecessary biopsies, by more than half. They also concluded that the cutoff of 20 is preferable to cutoff of 35. These findings are further supported by the recent NCI Early Detection Research Network Validation Trial for PCA3 [28▪].
RECENT ARTICLES ON PROSTATE CANCER ANTIGEN 3
Since FDA approval, the literature has focused on applications of PCA3 to nomograms, and combinations with other diagnostic markers. In one study, investigators combined PCA3 information to clinical data among men undergoing an initial prostate biopsy . In these cases, an extended prostate biopsy was performed and urinary PCA3 was collected prior to the biopsy. Diagnostic accuracy of PCA3 was compared using receiver operating characteristic curves. These models demonstrated that a PCA3-based nomogram significantly outperformed the clinical models without PCA3. Importantly, they found that only a few men with high-grade prostate cancer would be missed, all the while, allowing up to 55% of men to avoid a prostate biopsy. Another group compared three nomograms that incorporated PCA3 and concluded that two provided good calibration and a high net benefit based on decision curve analyses. They also concluded that using these nomograms would have missed less than 6% of high-grade prostate cancers whereas 48% of prostate biopsies could have been avoided . Yet others have considered the head-to-head comparison of PCA3 with the 4k (four kallikrein) score. In this analysis, PCA3 and the 4k score were added to the European Randomized Study of Screening for Prostate Cancer risk calculator. In multivariable models, PCA3 and the 4k score appeared to be equivocal (area under the curve [AUC] 0.73 vs. 0.71, P = 0.18), whereas both markers improved the base risk estimation .
Another burgeoning area of research involving pca3 has been to examine the role of PCA3 in selecting men for MRI-directed biopsies. In a retrospective analysis of 163 men, investigators found that men with a multiparametric 3 tesla MRI abnormality suggestive of prostate cancer had a significantly higher level of PCA3 compared with those who did not (52 vs 21, P < 0.001) [32▪]. These findings are consistent with a prior report that concluded that sensitivity of PCA3 testing could be improved by addition of MRI in men who had previously negative biopsy .
In 2005, Tomlins and Chinnaiyan reported on a unique gene fusion involving the rearrangement of a member of the E26 transformation specific (ETS) oncogene family (erg) with the transmembrane protease serine 2 (TMPRSS2) . Prior to this report, fusions were not known to occur in prostate cancer. However, the investigators found that at least 50% of prostate cancer foci (involving 80% of prostate cancer cases) demonstrated this fusion. Importantly, this discovery holds potential to identify another common mechanism for the development of prostate cancer other than the oft-studied androgen pathway. In histological studies, this fusion has been found to be the most specific prostate cancer biomarker yet with several studies consistently finding greater than 99% specificity . Subsequently, a novel urinary assay was developed using the same technology platform as PCA3. Using this assay, Young and colleagues examined how the quantification of TMPRSS2:erg fusion related to tumor volume . In this study, erg+ cancer foci at the time of radical prostatectomy were assessed in terms of number of foci and also the summed linear tumor dimension (aggregate tumor size). With 41 radical prostatectomies, and a median of three tumor foci, they demonstrated a correlation with both the number of tumor foci and a total tumor dimension (P < 0.001). Given that they only looked at erg+ tumor foci, not surprisingly, PCA3 showed a weaker correlation .
Tomlins et al.  then reported on a series of more than 1300 men at multiple centers undergoing prostate biopsy and radical prostatectomy. In this sentinel article, Tomlins et al. correlated the urinary measure of TMPRSS2:erg fusion with prostate biopsy and postradical prostatectomy pathology. Using the prostate cancer prevention trial (PCPT) nomogram as the standard for comparison, he separated the biopsy cohorts into three risk groups: lowest, intermediate, and highest risk. By adding TMPRSS2:erg fusion and PCA3 to the PCPT nomogram, the adjusted risk prediction for cancer and for high-grade cancer improved significantly (P < 0.001) with AUC increasing 9–16%. Moreover, this study also examined significant cancer at prostatectomy and demonstrated that higher TMPRSS2:erg fusion levels in the urine before surgery correlated to clinically significant findings at final pathology . Following this publication, a number of other studies have reported on the use of TMPRSS2:erg fusion as a urinary assay. Typically, these have been in combination with PCA3 given that TMPRSS2:erg fusion has high specificity and sensitivity whereas pca3 has high sensitivity for prostate cancer.
In one such study, 45 men undergoing the biopsy were utilized to develop a simple clinical algorithm to predict prostate cancer on biopsy. In their approach, all men with a PSA greater than or equal to 10 would undergo a biopsy whereas men with a PSA less than 10 would only undergo biopsy if they had detectable levels of TMPRSS2:erg fusion or PCA3 in the urine . Their analyses, although on a small number of cases, would suggest that the combination of urinary biomarkers with PSA perform better than individual markers alone. Subsequently, another large multicenter series was published based in Europe [39▪]. In this trial from six centers, post-digital rectal exam urine samples were collected prior to prostate biopsy prospectively in 497 cases. The authors compared base models using the European Randomized Study of Screening for Prostate Cancer with the same models with TMPRSS2:erg fusion and PCA3 added. In their receiver operating characteristic analyses, they found that addition of these urinary biomarkers increased area under curve by at least 4%, with the improvements for predicting Gleason score, and clinical stage largely coming from the addition of TMPRSS2:erg fusion. They concluded that incorporation of these new urinary biomarkers into clinical practice likely may lead to a considerable reduction in the need for prostate biopsy [39▪]. Other investigators have built upon the TMPRSS2:erg fusion body of work by considering other combinations of fusion markers. In one such study, other ETS transcription factor genes (ETV1,4,5) and common variants of the TMPRSS2:erg fusion were combined as a panel of gene fusion markers. In doing so, these investigators found that this panel was an independent predictor of high-grade cancer allowing clinical stratification of prostate cancer risk at the time of diagnosis .
These findings were then corroborated when Tallon et al.  incorporated TMPRSS2:erg fusion, PCA3 and the Prostate Health Index (PHI) into models predicting prostate cancer aggressiveness, defined as Gleason seven or higher cancer and tumor volume greater than or equal to 0.5 cc at radical prostatectomy. Although they found that PHI was the best predictor of Gleason score, they also noted that TMPRSS2:erg fusion and PHI were independent predictors of extracapsular involvement by cancer. In contrast, only PCA3 appeared to be associated with cancer multifocality. They also demonstrated nicely in a series of multivariate analyses that adding these urinary biomarkers and PHI can significantly improve AUC by 10–13.8%, thereby further validating the concept of multiplex biomarkers in clinical practice .
Taken together, the series of published articles examining TMPRSS2:erg fusion and PCA3 demonstrate that they are consistently associated with prostate cancer diagnosis on biopsy, associated with various clinical pathological parameters at biopsy and radical prostatectomy, and add value to decision-making in the clinical setting. Not surprisingly, attempts to examine the urinary biomarkers in other prostate cancer settings are underway.
In one such study, investigators asked whether or not TMPRSS2:erg fusion along with PCA3 can stratify the risk of having aggressive cancer among men undergoing active surveillance for low-risk prostate cancer. The setting of this study was the Canary Prostate Active Surveillance Study in which cases had urine collected at study entry [42▪]. The levels of these urinary biomarkers were compared to the number of positive cancer cores, and cancer grade on their baseline biopsy, and seemed to stratify the risk of having aggressive cancer. However, in their receiver operating characteristic curve analyses, the addition of these two urinary biomarkers to PSA at baseline did not significantly improve the AUC of the PSA only model [42▪]. Despite this, it remains an intriguing question whether or not these urinary biomarkers may be relevant in predicting subsequent biopsy and pathological findings in men undergoing active surveillance.
OTHER URINARY BIOMARKERS UNDER INVESTIGATION
Although TMPRSS2:erg fusion and PCA3 are both commercially available in the USA [PCA3 from HOLOGIC/Progensa (Gen-Probe (Hologic), San Diego, CA) and TMPRSS2:erg fusion may be ordered as part of the MI Prostate Score, MIPS, from the University of Michigan], ongoing work for a series of other biomarkers that may be quantified in the urine are on the way.
Going back to 2008, Tomlins et al.  described serine peptidase inhibitor, Kazal type 1 (SPINK1) expression as a possible molecular alteration among TMPRSS2:erg fusion – negative cancers. Using a meta-analysis, they not only identified this new biomarker but suggested that it may be an independent predictor for biochemical recurrence following prostate cancer surgery. However, other urinary tissues that also express the marker may confound SPINK1 as a urinary test. The same group also described another novel biomarker. In this case, a long noncoding RNA  was found to be a promoter of aggressive prostate cancer via the SWItch (SWI)/Sucrose Non-Fermentable (SNF) complex. This biomarker, SCHLAP1 (Second Chromosome Loss Associated with Prostate – 1) was observed to be overexpressed in a subset of aggressive prostate cancer cases including men with metastases and who have died from prostate cancer [45▪▪]. Further work demonstrated that this long noncoding RNA actually had cellular function (regulation of the chromatin modifying complex SWI/SNF) thereby antagonizing tumor suppressor.
Related to long noncoding RNAs is the idea of micro-RNA as a biomarker. These single-stranded RNA molecules are believed to function as posttranscription regulators of gene expression. Profiling these expression patterns are intriguing and in one study of 29 men (prostate cancer, benign prostatic hyperplasia, or healthy men), differential expression of two micro-RNAs (1825, 484) were found to be associated with prostate cancer . Although far from conclusive, pursuing micro-RNAs and other noncoding forms of RNA hold promise for development of new biomarkers and also a better understanding of prostate oncogenesis.
Although this review focused on PCA3 and TMPRSS2:erg fusion, other potential urinary biomarkers include GSTP1, PSMA, and a variety of exosomes are under active investigation. These have typically been found to be promising but technical issues such as detection, and stability of the analyte in urine, have yet to be overcome .
Someday, urinary biomarkers will help identify patients for which specific interventions are more likely to be successful. To date, only TMPRSS2:erg fusion has a clinical trial underway. In this trial, clinical scientists seek to determine whether or not TMPRSS2:erg fusion status are indicative of poly(ADP ribose) polymerase inhibitor response among men with high-risk cancer. Poly(ADP ribose) polymerase is necessary for cancer cells to repair damage and is a critical interacting partner of the TMPRSS2:erg fusion. Therefore, inhibition could improve response to androgen deprivation. Others have proposed the use of small molecules such as pyrrole imidazole polyamide to break the fusion site as a means to repress prostate cancer tumor growth  and targeting SPINK1 .
LIMITATIONS OF URINARY BIOMARKERS
Despite the progress made on urinary biomarkers for prostate cancer, significant gaps in knowledge remain. First, is the uncertain role of these biomarkers in the cancer screening setting. We understand, that PSA as a stand-alone biomarker results in overdetection but could the combination of PSA with these new urinary biomarkers improve performance such that screening can be limited to the detection of only those with high-grade cancer? Second, combinations of biomarkers have primarily focused on PCA3 and TMPRSS2:erg fusion. Given the burgeoning number of biomarkers, the potential combinations increase geometrically and deserve study. Indeed, it is likely that a panel of biomarkers will perform better than simple pairing. Third, robust longitudinal studies of these biomarkers to examine trends over time in men with and without prostate cancer have yet to be performed. Finally, many of the pipeline urinary biomarkers still require further prevalidation and validation studies to move them into the clinical arena.
Recent literature would support that urinary biomarkers have a clear role to supplement risk evaluation for men undergoing prostate biopsy and for prognostication. Only two have been more thoroughly vetted, PCA3 and TMPRSS2:erg fusion, and are commercially available. Future studies will likely focus on panels that combine urine, blood, and perhaps even tissue biomarkers, in addition to known clinical risk factors. On average, the use of these urine biomarkers will allow the clinician to make better recommendations to their patients.
Financial support and sponsorship
Conflicts of interest
Research funding support from NCI, Exosome.
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