Tools
Biomarker Assays for Elevated Prostate-Specific Antigen Risk Analysis
Introduction
Prostate cancer is one of the most frequently detected cancers in males, comprising approximately 1.4 million cases worldwide annually.[1] Moreover, it is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men, with an estimated 299,000 cases in 2024, according to the National Cancer Institute (NCI).[2] Approximately 1 in 8 men develop prostate cancer during their lifetime. However, due to the typically slow progression of the disease, the mortality rate is only 1 in 41 diagnosed men.
One of the most effective methods for screening, diagnosing, staging, assessing therapeutic response, and predicting prostate cancer is to use various biomarkers in the serum or urine. According to the NCI, a biomarker is a biological molecule detected in blood, urine, other body fluids, or tissues that can indicate an unhealthy process, condition, or disease. When properly used, biomarkers enable healthcare professionals to tailor various diagnostic modalities to patients while avoiding unnecessary diagnostic procedures and overtreatment.
The Early Detection Research Network is the NCI's initiative to identify, develop, and validate future biomarkers and newer technologies for earlier and more accurate cancer diagnosis. These biomarkers could be proteins, DNA, messenger RNA (mRNA), metabolites, prostate cancer cells or derivatives, exosomes, or measurements of various cell cycle processes such as cellular proliferation or apoptosis. Several commercial risk-stratification biomarkers for patients with persistently elevated levels of prostate-specific antigen (PSA) and suspected prostate cancer are now available.
In addition to helping with clinical decision-making in low- or intermediate-risk patients with equivocal PSA levels, surrogate biomarkers can potentially evaluate a particular patient's response to a new drug, procedure, or therapy and determine its utility for that individual. In this way, a biomarker can track the effectiveness of a treatment for a specific disease or condition. Such validated surrogate risk-stratification biomarkers often prevent patients from undergoing lengthy clinical trials, unnecessary biopsies, expensive imaging tests, or other invasive tissue diagnostics.[2]
An ideal biomarker should possess several key attributes—highly sensitive and specific, easy to use and interpret, cost-effective, readily available, reproducible, and quantifiable from an easily extractable specimen. In addition, it should have a high negative predictive value of at least 90%, approved by the Food and Drug Administration (FDA) and Clinical Laboratory Improvement Amendments (CLIA), and recommended by the National Comprehensive Cancer Network (NCCN).
Prostatic risk-stratification biomarkers are intended for use primarily in lower-risk and selected borderline patients with marginally elevated levels of PSA, typically between 4 and 10 ng/mL, where an adverse finding likely results in the avoidance of immediate further testing, prostatic imaging, biopsies, or other diagnostic procedures.[1][2] This activity reviews the current status of the available risk-stratification biomarkers and those undergoing investigation.
Etiology and Epidemiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology and Epidemiology
The International Agency for Research on Cancer estimates that 1,414,259 new cases of prostate cancer are diagnosed worldwide yearly, resulting in 375,304 deaths. In the United States, the SEER (Surveillance, Epidemiology, and End Results) database estimates about 299,000 new cases and 35,250 deaths due to prostate cancer in 2024. Prostate cancer accounts for 15% of all new cancer diagnoses and 5.7% of cancer-related deaths annually. However, 5-year relative survival is estimated to be 98.6%.
The incidence of prostate malignancy has a geographical variation, with the highest in Australia/New Zealand, North America, and parts of Europe, primarily due to the employment of PSA testing and an aging population. Even though prostate cancer mortality has relatively less variation worldwide, the rates are exceptionally high among the Black population in the Caribbean and sub-Saharan Africa, intermediate in the United States, and lowest in South Central Asia.
Sixty-six percent of prostate cancer cases are diagnosed in individuals older than 65, with the average age of initial diagnosis being 66. Although the exact etiology is unknown, genetic predisposition and family history are clearly associated with an increased risk of prostate cancer.[1][3] A small subset of patients with prostate cancer have a hereditary form of the disease. On average, these patients are diagnosed 6 to 7 years earlier than the general population. However, the clinical course and aggressiveness of cancers do not seem to differ.[4]
Genomic evaluation has identified more than 100 genes contributing to the risk of prostatic malignancy.[5][6][7] About 15% to 17% of the prostate cancer population have been identified as having germline mutations. Such mutations are independent of the cancer stage. A study of multigene testing among men with prostate cancer across the United States by Giri et al concluded that 15.6% of the study population had pathogenic variations of the genes studied, including BRCA1, BRCA2, HOXB13, MLH1, MSH2, PMS2, MSH6, EPCAM, ATM CHEK2, NBN, and TP53.[8][9] The most commonly found pathologic gene variation identified was BRCA2 (4.5%).[8] Nicolosi et al reported that 17.2% of the study population had a pathogenic germline variant, and genomic analysis could help identify high-risk families.[10][11][12]
The Identification of Men with a Genetic Predisposition to Prostate Cancer (IMPACT) study evaluated men aged 40 to 69 with BRCA1 or BRCA2 germline mutations by screening with PSA annually and targeted biopsy if PSA >3.0 ng/mL.[13] After about 3 years of research, it was found that BRCA2 mutation carriers were more likely to develop prostate cancer, have a younger age of onset, and develop more clinically apparent tumors compared to noncarriers.[13]
Many exogenous factors are associated with the likelihood of developing prostate cancer, including metabolic syndrome, diabetes, obesity, dyslipidemia, Agent Orange exposure, and various dietary factors.[2] Japanese men have less risk of prostate cancer compared to Western men, but the risk increases substantially if they migrate to the United States, implying an interplay of environmental, dietary, or lifestyle factors.[14] However, no proven dietary, lifestyle, or pharmacological therapy for the prevention of prostate cancer has been established.
Pathophysiology
Inflammation of the prostate gland, often caused by various genetic mutations, is the earliest sign of prostate cancer. This inflammation leads to oxidative damage, which causes telomeres at the ends of chromosomes to shorten, eventually initiating the development of prostate cancer. Several genes, including MYC, PTEN, NKX3.1, and the TMPRSS2-ERG gene fusion, have been identified in the initiation and development of prostate cancer, even though no single tumor suppressor gene is primarily responsible.
The TMPRSS2-ERG gene fusion activates the ERG oncogenic pathway, which is linked to the emergence of illness. The reactivation of cell cycle pathways causes unchecked cell proliferation, promoting the tumor's metastatic spread. Gene expression profiling of metastatic illness identifies overexpression in EZH2 mRNA and proteins. Due to its role in apoptosis and proliferation, EZH2 is currently under research as a new prostate cancer target.
Specimen Requirements and Procedure
Current and investigational biomarkers, including blood-based and urine-based assays, improve diagnostic accuracy by supplementing PSA testing. These biomarkers include derivatives of PSA, such as PSA density and velocity, and newer molecular forms, such as (-2) pro-PSA. Other significant biomarkers include the Prostate health index (PHI), the 4K score, prostate cancer antigen 3 (PCA3), and TMPRSS2-ERG gene fusions (see Table. Biomarkers Used for Prostate-Specific Antigen Testing).
Each biomarker offers unique advantages in detecting, diagnosing, and monitoring prostate cancer and is often integrated into risk assessment tools for better clinical decision-making. Their high negative predictive values allow clinicians to confidently rule out the need for further testing in many cases, thus preventing overdiagnosis and reducing the burden on patients and healthcare systems.
Table. Biomarkers Used for Prostate-Specific Antigen Testing
|
Biomarkers Tested |
Commercial Available Tests |
Specimen |
Cutoff |
Sensitivity |
Specificity |
Negative Predictive Value |
Approval/ Certification |
Recommendations by NCCN |
At-Home Collection Kit |
|
Prostate health index (PHI) |
Serum |
27 |
90% |
31.1%@ Sensitivity 90% [15] |
|
FDA |
IB and RB |
NA |
|
4K Score |
Serum |
7.5% |
89% |
29% |
95% [17] |
FDA |
IB and RB |
NA |
|
PCA3 |
Urine |
25 |
78% |
57% |
90% [18] |
FDA |
RB only | NA |
|
ExoDx Prostate Intelliscore |
Urine |
15.6 |
|
NA |
|
FDA |
IB and RB |
Available |
|
My Prostate Score 2.0 |
Urine, Serum |
No recommended cutoff | 93% | 33% [20] | 90% for any prostate cancer [21] |
CLIA |
Investigational | NA |
|
Select MDx |
Urine, Serum |
PSA <10 |
89% |
53% |
95% [22] |
CLIA |
IB and RB |
NA |
|
Prostarix risk score |
Urine |
NA | NA | NA | NA |
CLIA |
NA | NA |
IB, The clinical decision for the initial biopsy; RB, Repeat biopsy in prior negative biopsy; NA, Not available.
The NCCN has recognized the PHI, 4K Score, ExoDx Intelliscore, My Prostate Score, Select MDx, and ConfirmMDx (a tissue confirmation test).
Diagnostic Tests
Blood-Based Biomarkers
Prostate-specific antigen: PSA, a member of the kallikrein gene family, was first identified and isolated in 1979.[23] PSA is secreted by prostatic ductal and acinar epithelium and is highly organ-specific. PSA is circulated in free (fPSA) and protein-bound forms (complexed). The expression of PSA is androgen-dependent and is a crucial tool for the early detection, staging, treatment planning, and prognosis of prostate cancer. The widespread use of PSA testing in the 1990s led to increased prostate cancer diagnoses and a subsequent decline in mortality rates for this disease.
Even though PSA is an excellent and sensitive biomarker, the biomarker is organ-specific but not disease-specific. Prostatic basal layer and basement membrane violations allow PSA to escape prostate cells and enter the bloodstream, leading to an increase in serum PSA levels.[24][25] This increase in serum PSA levels may occur in several prostatic pathologies, such as benign prostatic hyperplasia, prostatitis, or prostate malignancy, or transiently with prostatic manipulation, as in prostate biopsies, prostatic massage, or urethral catheterization.[23][26][27][28][29]
Treatment with 5-alpha-reductase inhibitors has been shown to reduce PSA levels by approximately 50% when treated for ≥6 months.[30][31] Despite this, multiple guidelines still recommend PSA as the primary tool for initial prostate cancer screening. However, experts have yet to agree on the subset of patients to screen, the appropriate age to start screening, and other relevant factors to consider. All guidelines recommend that prostate cancer screening be an informed decision made after shared decision-making and a risk-benefit analysis. The most scientifically correct and reasonable guideline is from the American Urological Association (AUA), as it takes into account high-risk factors, the known incidence of prostate cancer appearing in some individuals before 50, and the longer life expectancy of men, which now averages 87 years.[2]
The following recommendations have been established by the AUA and the Society for Urologic Oncology (SUO):
- PSA screening in men younger than 40 is not recommended.
- Screening may be offered to men at high risk starting at age 40, such as those of Black ethnicity, those with a family history of prostate cancer, and those with BRCA1 and BRCA2 germline mutations.
- Routine screening for men at average risk may be offered starting at age 45.
- Two separate high PSA levels are necessary before further investigations are performed.
- Shared decision-making is recommended for men where PSA screening is being considered, proceeding based on the individual's values and preferences.
- Regular screening may be offered every 2 to 4 years but can be personalized based on patient preferences, age, PSA, prostate cancer risk, comorbidities, life expectancy, and general health considerations.
- Men with a reasonable life expectancy of ≤10 years should not be offered routine screening as they are unlikely to benefit from it.
- Routine PSA screening in men aged 70 and older should be based on shared decision-making and individual patient preferences, life expectancy, and general health.
- Screenings may be discontinued or the interval substantially lengthened for patients aged 75 or older if the PSA is <3 ng/mL.[2][32][33]
A baseline PSA level that predicts the likelihood of prostate malignancy detection and the chance of developing high-grade prostate malignancy can customize the rescreening intervals. According to several studies, screening intervals of 2 to 4 years are unlikely to miss curable prostate cancer.[32][34][35] Therefore, the AUA recommends a 2-year screening as a reasonable approach. The AUA suggests that men older than 60 with PSA levels below 1.0 ng/mL may benefit from prolonged screening intervals, such as 2 to 4 years.[32]
Prostate risk stratification biomarkers: The primary purpose of prostate risk stratification biomarker tests is to identify patients with a negative result who do not require further immediate testing, imaging, or biopsies.[2] These biomarkers are primarily intended for use in lower-risk and selected borderline patients, a subset with PIRADS 3 lesion on multiparametric magnetic resonance imaging (MRI), with slightly elevated levels of PSA, typically 4 to 10 ng/mL. In these cases, a negative test result can reasonably halt additional testing, prostate imaging, biopsies, and other diagnostic procedures, allowing for the resumption of routine screening.[1][2] Due to their high negative predictive value, these tests help clinicians determine the likelihood of detecting a clinically significant malignancy by further evaluation, which is low, and that further immediate investigation is unnecessary.[1]
However, this approach is not recommended if the PSA is >10 ng/mL or the patient is otherwise in the high-risk category. The high-risk group includes men of African descent; those with a family history of prostate malignancy; those with germline mutations that increase the risk for prostate cancer, such as BRCA1, ATM, CHEK2, and BRAC2; men with a family history of multiple malignancies or Lynch syndrome; and those with known exposure to Agent Orange.[2][36][37][38][39][40] These patients should proceed with a biopsy as a clinically significant malignancy is more likely than average. Therefore, clinicians can generally skip prostatic risk stratification biomarkers in high-risk patients with elevated levels of PSA.[1]
Prostate-specific antigen derivatives: Clinical decision-making is enhanced using PSA derivatives, such as PSA density, velocity, doubling time, age-adjusted values, and, recently, different molecular derivatives. PSA velocity is the rate of change of PSA over a year, whereas PSA density is the PSA-derived computation of total PSA (tPSA) divided by prostatic volume. The PSA doubling time measures how quickly a rising PSA level increases to double its value, gauging the rate-dependent exponential rise in serum PSA over time. These PSA-derived metrics are used for decision-making regarding prostate biopsy in an early detection setting.
Among the derivatives, PSA density shows substantially better predictive information compared to PSA velocity. A higher PSA density has a greater likelihood of clinically significant prostate cancer, particularly in smaller prostates, when a value of 0.15 ng/mL/cc was considered.[41]
Research suggests that a PSA density of 0.1 to 0.15 ng/mL/cc or higher is considered significant (higher risk). In contrast, a value lower than 0.09 ng/mL/cc is considered insignificant (<4% chance).[42][43][44] A PSA density of 0.15 ng/cc is typically the cutoff point.[45][46][47][48] PSA velocity and doubling time have limited diagnostic value but may aid in prognostification.[49]
Studies have shown a correlation between a low percentage of fPSA and aggressive pathological features.[50][51] The percentage of fPSA production was less in malignant prostates compared to men without.[52][53][54][55] This observation led to the development of fPSA testing as an adjunct to improve the accuracy of PSA as a prostate cancer biomarker.[56][57]
The United States FDA approved using fPSA as a biomarker to enhance screening in males with blood PSA levels of 4 to 10 ng/mL and a negative digital rectal examination. A percentage fPSA cutoff of 18% has improved the detection of prostate cancer in men when compared to tPSA alone. Such patients are recommended for prostate biopsy. The prostate malignancy detection was 56% in men with a percentage of fPSA <10 % compared to 8% when the percentage of fPSA was >25%.[57][58]
The NCCN recommends incorporating the percentage of fPSA for decision-making for prostate biopsy and recommends a cutoff of 10%.[59] However, it has no clinical implication in patients with tPSA >10 ng/mL or in the follow-up of known prostate cancer patients. The use of predictive calculators incorporating multiple clinical variables such as tPSA, fPSA percentage, and digital rectal examination (DRE) findings for shared decision-making has increased.[60][61][62]
Free prostate-specific antigen isoforms: The serum isoforms of fPSA, namely pro-PSA, benign PSA, and intact fPSA, exist in equal concentrations in serum and are promising biomarkers. Studies have shown significant levels of truncated forms of PSA in malignant prostate tissues such as (-2) pro-PSA. Applying (-2) pro-PSA has been validated as a screening biomarker before a biopsy.[15][16]
(-2) pro-PSA is also a strong predictor of histological aggressiveness, indicated by a Gleason score of ≥7). Studies have shown that (-2) pro-PSA is superior to PSA and fPSA percentage as a biomarker in predicting prostate malignancy in men planned for biopsy with a serum PSA of 4 to 10 ng/mL. In addition, it correlates with the pathological aggressiveness of the tumor.
Prostate health index: PHI is a blood-based biomarker that can predict the risk of aggressive prostate malignancy, indicated by a Gleason score of ≥7, at biopsy. This assay analyzes tPSA, fPSA, and (-2) pro-PSA levels. PHI was approved in 2012 by the FDA to diagnose prostate cancer in men aged 50 and older with a clinically negative DRE and PSA of 4 to 10 ng/mL.[63][64]
PHI has consistently shown superiority over tPSA and fPSA in the early detection of prostate cancer. As a result, it has been added to various web-based risk assessment calculators, such as the prostate cancer prevention trial (PCPT) calculator.[15][65] The NCCN recommended using PHI in early cancer detection in 2015. However, due to limited studies in the United States population, it is not recommended as first-line screening for all patients.
Human kallikrein 2 and 4K score: Human kallikrein 2 (hK2) shares many similarities with PSA. They are both regulated by androgens, are proteases, and have an identical specificity for the prostate.[66] However, in contrast to PSA, hK2 is a much more potent protease and is selectively expressed in cancerous tissue, where its expression correlates with the aggressiveness of malignancy, degree of differentiation, and biochemical recurrence.[66] Combining fPSA with hK2 has increased the cancer detection rate in the 4 to 10 ng/mL PSA range.
In the 4K score assay, the 4 kallikrein proteins—tPSA, fPSA, intact PSA, and hK2—were integrated. The 4K score has been included in the NCCN prostate cancer early detection guidelines.[67] The 4K score predicts the likelihood of biopsy-positive prostate cancer when paired with clinical characteristics, including age and prior negative biopsies. This biomarker also accurately predicts the aggressiveness of cancer.[68] Meta-analysis has been shown to improve the predictive accuracy of biopsy by 8% to 10% and decrease the rate of unwanted biopsies by 48% to 56%.[69] The 4K score also predicts the risk of distant metastasis even 20 years later in men with a PSA of ≥2 ng/mL. The NCCN has recommended the 4K score for appropriate patients.
Serum protein panel: The 3 prostate cancer biomarkers—FilamenA, FilamenB, and Keratin19—have been combined into a novel serum protein panel for disease screening and prognosis due to recent studies. A panel of these biomarkers with PSA outperformed PSA alone in diagnosing, predicting aggressiveness, and differentiating cancer from benign prostatic hyperplasia.[70]
Urine-Based Biomarkers
Prostate cancer antigen 3: The ease of collecting urine specimens and the knowledge regarding the exfoliation of prostate cells in the urine have made urine a source for potential biomarker research.[71] The transcriptome comparison of prostate cancer and normal tissues led to the identification of PCA3.[72] Formerly known as differential display code 3, PCA3 is a long noncoding mRNA. PCA3 does not encode a protein, but its mRNA transcripts from prostatic cytology can be detected and measured in urine.[73] The PCA3 gene is overexpressed in 95% of primary prostate cancer specimens but not in benign prostate tissue.[74][75]
Reverse transcription polymerase chain reaction (RT-PCR) evaluation revealed that PCA3 performs better compared to PSA in identifying prostatic malignancy.[76][77] Recently, with the advent of a transcription-mediated amplification assay, there has been an improved sensitivity compared to RT-PCR.[78]
The commercial assay of PCA3 was FDA-approved in the United States in 2012 to assist decision-making in men aged 50 and older with a previous negative biopsy. The European Association of Urology also recommends this test. A urine sample for PCA3 testing is obtained immediately after a prostate massage or DRE. Substantial research on the diagnostic value of PCA3 in post-prostatic massage urine has been performed, and all studies have shown that the PCA3 scores closely match the likelihood of a positive biopsy.[79][80][81] Unlike PSA, PCA3 levels are independent of prostate size.[82]
Studies have reported a 14% positive biopsy rate if PCA3 levels are below 5, compared to 70% when the PCA3 assay is >100.[80] PCA3 has been proven to have different sensitivity, specificity, and predictive values when choosing alternative cutoffs. The FDA used a threshold of 25 for its approval. Studies involving large patient cohorts have demonstrated the superiority of PCA3 over PSA alone for diagnosing prostate cancer.[83][84][85] PCA3 has been incorporated with other clinical parameters in various nomograms, such as the web-based PCPT risk calculator, to analyze the chance of a positive biopsy.[86]
TMPRSS2-ERG gene fusions and My Prostate Score 2: With the discovery of gene fusions in prostate malignancy, considerable research has been performed to harness its utility as prostate cancer biomarkers. The most common gene alteration involved with prostate cancer is the fusion of the androgen-regulated gene transmembrane protease, serine 2 (TMPRSS2), with the N-terminal deleted ERG coding region.[87] Between 50% and 60% of patients with prostate cancer of European ancestry have this gene fusion, which results in the oncogenic activation of ERG.[88] The use of gene fusion was most significant when combined with other biomarkers, such as PCA3.
A multicentric study involving 1312 men compared post-DRE urine levels of TMPRSS2:ERG to PCA3 with serum PSA. The study demonstrated the clear superiority of the panel of TMPRSS2:ERG with PCA3 in detecting clinically significant malignancy at biopsy.[89] An assay developed by the University of Michigan, My Prostate Score 2 (MPS2), combines serum PSA, urine PCA3, and urine TMPRSS2:ERG gene fusion to estimate the probability of identifying prostate malignancy on biopsy and the likelihood of aggressive disease.[90] PCA3 and TMPRSS2:ERG gene fusion is presently incorporated into a PCPT risk calculator for decision-making for prostate biopsy in patients with persistently (at least 2) elevated levels of PSA to avoid unnecessary biopsies safely.[86] The NCCN has included MPS2 as one of its recommended prostate cancer risk stratification bioassays.
Select MDx: The Select MDx is an RT-PCR assay analyzing urine specimens after DRE along with other risk factors for early detection of prostate malignancy and decision-making regarding biopsy. This 3-gene panel assay has enhanced the identification of high-grade cancer by integrating HOXC6, TDRD1, and DLX1 mRNA levels in urine with other clinical indicators. In addition, Van Neste et al have validated it with other clinical decision-making tools, such as the PCA3 assay and PCPT risk calculator.[91] The NCCN has identified Select MDx as one of its recommended prostate cancer risk stratification assays.
Annexin A3: Annexin A3, a calcium-dependent phospholipid-binding protein, is found to be negatively associated with the detection of prostate malignancy when present in urine. Researchers have evaluated the utility of analyzing Annexin A3 levels in post-DRE urine as a stand-alone or in conjunction with serum PSA for clinical decision-making before a prostate needle biopsy.[92]
Investigators showed that Annexin A3 enhanced PSA's ability to predict malignancy in needle biopsy with an area under the curve (AUC) of 0.81. Cao et al studied a multiplex assay combining urine annexin A3, PCA3, TMPRSS2: ERG, and sarcosine for prostate biopsy decision-making.[93] The multi-marker assay was accurate, with an AUC of 0.84 in patients with a PSA of 4 to 10 ng/mL.[93]
ExoDx prostate intelliscore: Exosomes are tiny extracellular vesicles (40-150 nm) released by various cell types, including cancerous cells. They contain lipids, proteins, and nucleic acids. Prostate-derived exosomes serve as diagnostic and prognostic biomarkers as they are a source of proteins and microRNA.[94][95] Urinary exosome analysis offers benefits, including stable exosomes owing to their exosomal lipid bilayer, which protects the genetic content from enzymatic destruction. No unpleasant prostatic massage is needed before collecting the sample, and the test can be performed at home with the specimen mailed directly to the laboratory by the patient, saving staff time and paperwork. Exosomal RNA and protein content that are tested may be superior to less stable, chemical, nongenetic-based biomarkers.
ExoDx prostate intelliscore is a urine exosomal RNA-based assay to assess the expression of the prooncogenic genes ERG, PCA3, and SPDEF and generate a score. The test is recommended for males older than 50 with a PSA of 2 to 10 ng/mL who are being evaluated for a preliminary biopsy. This test is used with other standards of care criteria to assess the likelihood of Gleason 7 and above prostate cancer on an initial biopsy.[96][97]
This assay helps safely reduce unnecessary biopsies. This score predicted high-grade cancer (Gleason 7 and above) with a negative predictive value of >90%.[96] The test is far more patient-friendly compared to similar bioassays as it does not require a digital rectal exam or prostatic massage, unlike previous urine-based tests for prostate cancer. The kit is designed for home use and can be mailed directly to the diagnostic laboratory by the patient, making it particularly useful for patients without a rectum for digital prostatic massage or those for whom the procedure is not feasible.
A large cohort study involving 774 patients in the United States found that the ExoDx assay, in conjunction with standards of care features, outperformed the ExoDx assay or standards of care variables when used alone in predicting the presence of Gleason grade 7 or above and negative biopsies.[96] Several exosomal metabolites, including survivin and claudin 3, have also been higher in the plasma of patients with prostate cancer.[98][99][100] ExoDx is also one of the tests recommended by the NCCN for prostate cancer risk stratification bioassay testing.
Prostarix risk score: Prostarix risk score is a urine-based assay that assists clinicians in decision-making regarding biopsy in a grey zone, such as negative DRE or a mildly elevated PSA level setting.[101] The assay quantitatively analyses 4-metabolites, sarcosine, alanine, glycine, and glutamate, in urine employing liquid chromatography-mass spectrometry. The quantitative analysis of these amino acids helps to calculate the risk score and detect malignancy-related metabolic abnormalities. Studies have shown that the panel's performance in diagnosing prostate cancer (AUC=0.64) was superior to that of serum PSA (AUC=0.53) and the PCPT calculator alone (AUC=0.61).[102]
Prostate cancer cell lines in urine: Prostate cancer cells can be found in post-DRE urine using multiplex immunofluorescence cytology staining for AMACR, Nucleolin, DAPI, and Nkx3.1. In a study involving a cohort of 50 patients, this method achieved a sensitivity of 36% and a specificity of 100%.[103] Immunohistochemistry also studies cell lines for ERG, AMACR, and Prostein (prostate epithelium-specific).[104] In a cohort of 63 individuals, this assay has a sensitivity of 64% and a specificity of 68.8% for diagnosing prostate cancer.[104] The NCCN has recognized the PHI, 4K score, ExoDx intelliscore, My Prostate Score, Select MDx, and ConfirmMDx (a tissue-based confirmation test).
How To Best Use Risk-Stratification Bioassays in Prostate Cancer Screening
Although their precise role in prostate cancer screening is still being determined, experts have suggested that risk-stratification bioassays are most helpful in patients with persistently elevated PSA levels who are low-risk, borderline, or equivocal cases. In such cases, the result, if negative, is used to help make a clinical decision not to pursue further prostate cancer diagnostic testing or screening procedures immediately.[1][2] Regardless of the test used, about 75% test positive. This result is not an indication of cancer, only that their risk analysis biomarker assay could not safely exclude a possible clinically significant cancer. The majority of these patients ultimately demonstrate negative biopsies and do not have prostate cancer.
Risk stratification bioassays for prostate cancer may also have a role in monitoring patients on active surveillance and those with high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation, which are considered premalignant.[1][105][106][107][108][109] The risk calculators can be accessed from the following websites:
- Prostate Cancer Prevention Trial Risk Calculator 2.0 (UT Health San Antonio)
- The Prostate Cancer Risk Calculators (SWOP—The Prostate Cancer Research Foundation, Reeuwijk)
- Prostate Cancer Prevention Risk Calculator (UNC School of Medicine)
- SPCC Risk Calculator (Stanford Medicine)
Testing Procedures
An abnormally elevated PSA in a grey zone (4-10 ng/mL) warrants a repeat PSA and a DRE. Patients whose repeat PSA and DRE are normal may continue with routine follow-ups. However, if the repeat PSA is elevated or the DRE is abnormal, and a prostate malignancy is suspected, biomarkers aid in the decision-making regarding continuing observation versus proceeding directly to a biopsy. Various biomarkers, including PHI, 4K score, PCA3, ExoDx Intelliscore, and Select MDx, help make this decision by identifying patients at low risk.
Biomarkers may be used alone or as a variable in risk analysis calculators. For example, if a biopsy was already performed with a negative result, biomarkers can assist in deciding when or if to repeat the biopsy. According to the NCCN recommendations, if the initial biopsy is reported as atypia, suspicious for cancer, or high-grade prostatic intraepithelial neoplasia, biomarkers that improve the specificity of screening, including fPSA, 4K score, PHI, PCA3, Exo Dx Prostate score, and MPS2, may be considered (see Table. Urinary Biomarkers). Alternatively, this subset of patients may proceed with a multiparametric prostate MRI if no prior prostatic study is available.
Most urinary biomarker assays are performed after prostatic manipulation (massage), except the ExoDx EPI score, which is not required. Studies have shown that a DRE can enrich urinary biomarkers and enhance yield, the first void after a DRE is obtained and analyzed. Following a prostate massage, the first 10 to 50 mL of urine that is voided are centrifuged at 1000 to 2000 rotations per minute to produce precipitates of urine that may contain prostate cancer cells, cell fragments, and various biomolecules such as DNA, RNA, and proteins from these cells. Free proteins, DNA, RNA, other tiny molecules, and exosomes are all detected in the supernatant.
Exosome precipitation occurs as a result of further ultracentrifugation of the supernatant. The ExoDx Intelliscore is far more patient-friendly compared to other biomarkers, as it does not require a digital rectal exam or prostatic massage. Unlike other urine-based tests for prostate cancer, it is available as a kit for home usage that patients can mail directly back to the diagnostic laboratory.[73]
Table. Urinary Biomarkers
| Assay Name | Requires Prostatic Manipulation/Digital Rectal Exam | Specimen Used |
| PCA3 | Post-DRE void | Whole urine/precipitate |
|
My Prostate score of 2 (PCA3, TMPRSS2-ERG) |
Post-DRE void | Whole urine |
| Annexin A3 | Post-DRE void | Precipitate |
|
ExoDx Intelliscore |
Not necessary/not recommended |
Precipitate |
|
DLX1, HOXC6 |
Post-DRE void | Precipitate |
|
Prostate cancer cell lines |
Post-DRE void | Precipitate |
Clinical Significance
Serum PSA is the gold standard during initial investigation for initial prostate cancer screening and early detection. PSA as a biomarker is a sensitive tool, but its specificity is low. Various benign conditions, such as benign prostatic hyperplasia and prostatitis, and manipulations, such as DRE, biopsy, and catheterization, can increase PSA levels. Consequently, diagnosis with PSA alone can lead to overdiagnosis and unwanted biopsies, adding pressure on healthcare systems and causing unnecessary patient anxiety.
A PSA level eliminating the risk of prostate cancer does not exist. Instead, the likelihood of prostate cancer and an aggressive disease increases as the PSA rises. Instead of using an absolute PSA level to establish if a prostate biopsy is necessary, the clinician should consider other variables, including prostate volume, inflammation, medications, patient age, life expectancy, prior PSA levels, and comorbidities.
Prostate cancer biomarkers assist the clinician in decision-making in patients with PSA levels in the grey zone of 4 to 10 ng/mL to safely avoid unnecessary biopsies. The biomarkers can also predict clinically significant tumors and help tailor the treatment regimen. Biomarker assays are employed in a grey zone PSA level setting with a negative DRE. Biomarkers allow clinicians to discuss better-informed decision-making with patients.
Various additional tools, such as PSA derivatives, PSA kinetics, PSA molecular forms, PSA density calculations, and risk stratification biomarkers, can be used as standalone or in multiplex panels to arrive at an informed decision in equivocal situations. The new prostate cancer risk-stratification biomarkers are intended to assist the clinician in educating and informing patients for optimal shared decision-making.
Enhancing Healthcare Team Outcomes
The past decade saw a paradigm shift in the management of prostate malignancy. With advances in diagnostics, imaging, genetics, and metabolomics, the evaluation and management of prostate malignancy have become even more complex. However, there needs to be more consensus on various diagnostic and treatment protocols, and different expert guidelines fall short of offering concrete recommendations. Multidisciplinary agreement and coordination are crucial for improving prostate cancer outcomes.
To provide the patient with the best care possible, a team of specially qualified nurses, technicians, general practitioners, pharmacists, genetic counselors, psychotherapists, oncologists, radiologists, urologists, and allied healthcare workers must collaborate. The team must be able to educate, enlighten, and guide the patient for optimal care while avoiding unnecessary overdiagnosis and overtreatment. In addition, prostate cancer screening should follow published guideline recommendations and include shared decision-making techniques and procedures. Any team member who notes any departure from guidelines should be empowered to communicate their concerns to the team, including the clinicians.
Optimal use of risk stratification biomarker assays for prostate cancer can significantly reduce unnecessary diagnostic procedures and treatments. The healthcare team should be familiar with implementing these assays when appropriate and help educate the patient and family when necessary or requested. The screening, diagnosis, and treatment must be individualized based on age, high-risk characteristics, comorbid conditions, life expectancy, and personal preferences. The patient must be empowered to make apt decisions through interdisciplinary team consultations and proper communication between the patient and the clinicians. Overtreatment, due to side effects, can cause harm to the patient, adversely affecting his quality of life and placing the patient under undue psychological distress. Eligible patients may be spared from such adversities by utilizing active surveillance protocols.
References
Leslie SW, Soon-Sutton TL, R I A, Sajjad H, Skelton WP. Prostate Cancer. StatPearls. 2024 Jan:(): [PubMed PMID: 29261872]
Jain MA, Leslie SW, Sapra A. Prostate Cancer Screening. StatPearls. 2024 Jan:(): [PubMed PMID: 32310541]
Jansson KF, Akre O, Garmo H, Bill-Axelson A, Adolfsson J, Stattin P, Bratt O. Concordance of tumor differentiation among brothers with prostate cancer. European urology. 2012 Oct:62(4):656-61. doi: 10.1016/j.eururo.2012.02.032. Epub 2012 Feb 24 [PubMed PMID: 22386193]
Bratt O, Drevin L, Akre O, Garmo H, Stattin P. Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A Nationwide Population-Based Study. Journal of the National Cancer Institute. 2016 Oct:108(10):. pii: djw110. doi: 10.1093/jnci/djw110. Epub 2016 Jul 10 [PubMed PMID: 27400876]
Amin Al Olama A, Dadaev T, Hazelett DJ, Li Q, Leongamornlert D, Saunders EJ, Stephens S, Cieza-Borrella C, Whitmore I, Benlloch Garcia S, Giles GG, Southey MC, Fitzgerald L, Gronberg H, Wiklund F, Aly M, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, Mcdonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokołorczyk D, Kluzniak W, Cannon-Albright L, Brenner H, Butterbach K, Arndt V, Park JY, Sellers T, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Govindasami K, Guy M, Lophatonanon A, Muir K, Viñuela A, Brown AA, PRACTICAL Consortium, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, Australian Prostate Cancer BioResource, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, Freedman M, Conti DV, Easton D, Coetzee GA, Eeles RA, Kote-Jarai Z. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Human molecular genetics. 2015 Oct 1:24(19):5589-602. doi: 10.1093/hmg/ddv203. Epub 2015 May 29 [PubMed PMID: 26025378]
Olumi AF. Commentary on "identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array." Eeles RA, Olama AA, Benlloch S, Saunders EJ, Leongamornlert DA, Tymrakiewicz M, Ghoussaini M, Luccarini C, Dennis J, Jugurnauth-Little S, Dadaev T, Neal DE, Hamdy FC, Donovan JL, Muir K, Giles GG, Severi G, Wiklund F, Gronberg H, Haiman CA, Schumacher F, Henderson BE, Le Marchand L, Lindstrom S, Kraft P, Hunter DJ, Gapstur S, Chanock SJ, Berndt SI, Albanes D, Andriole G, Schleutker J, Weischer M, Canzian F, Riboli E, Key TJ, Travis RC, Campa D, Ingles SA, John EM, Hayes RB, Pharoah PD, Pashayan N, Khaw KT, Stanford JL, Ostrander EA, Signorello LB, Thibodeau SN, Schaid D, Maier C, Vogel W, Kibel AS, Cybulski C, Lubinski J, Cannon-Albright L, Brenner H, Park JY, Kaneva R, Batra J, Spurdle AB, Clements JA, Teixeira MR, Dicks E, Lee A, Dunning AM, Baynes C, Conroy D, Maranian MJ, Ahmed S, Govindasami K, Guy M, Wilkinson RA, Sawyer EJ, Morgan A, Dearnaley DP, Horwich A, Huddart RA, Khoo VS, Parker CC, Van As NJ, Woodhouse CJ, Thompson A, Dudderidge T, Ogden C, Cooper CS, Lophatananon A, Cox A, Southey MC, Hopper JL, English DR, Aly M, Adolfsson J, Xu J, Zheng SL, Yeager M, Kaaks R, Diver WR, Gaudet MM, Stern MC, Corral R, Joshi AD, Shahabi A, Wahlfors T, Tammela TL, Auvinen A, Virtamo J, Klarskov P, Nordestgaard BG, Røder MA, Nielsen SF, Bojesen SE, Siddiq A, Fitzgerald LM, Kolb S, Kwon EM, Karyadi DM, Blot WJ, Zheng W, Cai Q, McDonnell SK, Rinckleb AE, Drake B, Colditz G, Wokolorczyk D, Stephenson RA, Teerlink C, Muller H, Rothenbacher D, Sellers TA, Lin HY, Slavov C, Mitev V, Lose F, Srinivasan S, Maia S, Paulo P, Lange E, Cooney KA, Antoniou AC, Vincent D, Bacot F, Tessier DC; COGS-Cancer Research UK GWAS-ELLIPSE (part of GAME-ON) Initiative; Australian Prostate Cancer Bioresource; UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology; UK ProtecT (Prostate testing for cancer and Treatment) Study. Urologic oncology. 2014 Feb:32(2):211. doi: 10.1016/j.urolonc.2013.08.019. Epub [PubMed PMID: 24445293]
Level 3 (low-level) evidenceSchumacher FR, Olama AAA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, Dadaev T, Leongamornlert D, Anokian E, Cieza-Borrella C, Goh C, Brook MN, Sheng X, Fachal L, Dennis J, Tyrer J, Muir K, Lophatananon A, Stevens VL, Gapstur SM, Carter BD, Tangen CM, Goodman PJ, Thompson IM Jr, Batra J, Chambers S, Moya L, Clements J, Horvath L, Tilley W, Risbridger GP, Gronberg H, Aly M, Nordström T, Pharoah P, Pashayan N, Schleutker J, Tammela TLJ, Sipeky C, Auvinen A, Albanes D, Weinstein S, Wolk A, Håkansson N, West CML, Dunning AM, Burnet N, Mucci LA, Giovannucci E, Andriole GL, Cussenot O, Cancel-Tassin G, Koutros S, Beane Freeman LE, Sorensen KD, Orntoft TF, Borre M, Maehle L, Grindedal EM, Neal DE, Donovan JL, Hamdy FC, Martin RM, Travis RC, Key TJ, Hamilton RJ, Fleshner NE, Finelli A, Ingles SA, Stern MC, Rosenstein BS, Kerns SL, Ostrer H, Lu YJ, Zhang HW, Feng N, Mao X, Guo X, Wang G, Sun Z, Giles GG, Southey MC, MacInnis RJ, FitzGerald LM, Kibel AS, Drake BF, Vega A, Gómez-Caamaño A, Szulkin R, Eklund M, Kogevinas M, Llorca J, Castaño-Vinyals G, Penney KL, Stampfer M, Park JY, Sellers TA, Lin HY, Stanford JL, Cybulski C, Wokolorczyk D, Lubinski J, Ostrander EA, Geybels MS, Nordestgaard BG, Nielsen SF, Weischer M, Bisbjerg R, Røder MA, Iversen P, Brenner H, Cuk K, Holleczek B, Maier C, Luedeke M, Schnoeller T, Kim J, Logothetis CJ, John EM, Teixeira MR, Paulo P, Cardoso M, Neuhausen SL, Steele L, Ding YC, De Ruyck K, De Meerleer G, Ost P, Razack A, Lim J, Teo SH, Lin DW, Newcomb LF, Lessel D, Gamulin M, Kulis T, Kaneva R, Usmani N, Singhal S, Slavov C, Mitev V, Parliament M, Claessens F, Joniau S, Van den Broeck T, Larkin S, Townsend PA, Aukim-Hastie C, Gago-Dominguez M, Castelao JE, Martinez ME, Roobol MJ, Jenster G, van Schaik RHN, Menegaux F, Truong T, Koudou YA, Xu J, Khaw KT, Cannon-Albright L, Pandha H, Michael A, Thibodeau SN, McDonnell SK, Schaid DJ, Lindstrom S, Turman C, Ma J, Hunter DJ, Riboli E, Siddiq A, Canzian F, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Cui Z, Kraft P, Amos CI, Conti DV, Easton DF, Wiklund F, Chanock SJ, Henderson BE, Kote-Jarai Z, Haiman CA, Eeles RA, Profile Study, Australian Prostate Cancer BioResource (APCB), IMPACT Study, Canary PASS Investigators, Breast and Prostate Cancer Cohort Consortium (BPC3), PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Cancer of the Prostate in Sweden (CAPS), Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS), Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium. Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nature genetics. 2019 Feb:51(2):363. doi: 10.1038/s41588-018-0330-6. Epub [PubMed PMID: 30622367]
Giri VN, Hegarty SE, Hyatt C, O'Leary E, Garcia J, Knudsen KE, Kelly WK, Gomella LG. Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing. The Prostate. 2019 Mar:79(4):333-339. doi: 10.1002/pros.23739. Epub 2018 Nov 18 [PubMed PMID: 30450585]
Giri VN, Morgan TM, Morris DS, Berchuck JE, Hyatt C, Taplin ME. Genetic testing in prostate cancer management: Considerations informing primary care. CA: a cancer journal for clinicians. 2022 Jul:72(4):360-371. doi: 10.3322/caac.21720. Epub 2022 Feb 24 [PubMed PMID: 35201622]
Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. The New England journal of medicine. 2016 Aug 4:375(5):443-53. doi: 10.1056/NEJMoa1603144. Epub 2016 Jul 6 [PubMed PMID: 27433846]
Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD, Wiley KE, Isaacs SD, Johng D, Wang Y, Bizon C, Yan G, Gielzak M, Partin AW, Shanmugam V, Izatt T, Sinari S, Craig DW, Zheng SL, Walsh PC, Montie JE, Xu J, Carpten JD, Isaacs WB, Cooney KA. Germline mutations in HOXB13 and prostate-cancer risk. The New England journal of medicine. 2012 Jan 12:366(2):141-9. doi: 10.1056/NEJMoa1110000. Epub [PubMed PMID: 22236224]
Lynch HT, Kosoko-Lasaki O, Leslie SW, Rendell M, Shaw T, Snyder C, D'Amico AV, Buxbaum S, Isaacs WB, Loeb S, Moul JW, Powell I. Screening for familial and hereditary prostate cancer. International journal of cancer. 2016 Jun 1:138(11):2579-91. doi: 10.1002/ijc.29949. Epub 2016 Feb 5 [PubMed PMID: 26638190]
Page EC, Bancroft EK, Brook MN, Assel M, Hassan Al Battat M, Thomas S, Taylor N, Chamberlain A, Pope J, Raghallaigh HN, Evans DG, Rothwell J, Maehle L, Grindedal EM, James P, Mascarenhas L, McKinley J, Side L, Thomas T, van Asperen C, Vasen H, Kiemeney LA, Ringelberg J, Jensen TD, Osther PJS, Helfand BT, Genova E, Oldenburg RA, Cybulski C, Wokolorczyk D, Ong KR, Huber C, Lam J, Taylor L, Salinas M, Feliubadaló L, Oosterwijk JC, van Zelst-Stams W, Cook J, Rosario DJ, Domchek S, Powers J, Buys S, O'Toole K, Ausems MGEM, Schmutzler RK, Rhiem K, Izatt L, Tripathi V, Teixeira MR, Cardoso M, Foulkes WD, Aprikian A, van Randeraad H, Davidson R, Longmuir M, Ruijs MWG, Helderman van den Enden ATJM, Adank M, Williams R, Andrews L, Murphy DG, Halliday D, Walker L, Liljegren A, Carlsson S, Azzabi A, Jobson I, Morton C, Shackleton K, Snape K, Hanson H, Harris M, Tischkowitz M, Taylor A, Kirk J, Susman R, Chen-Shtoyerman R, Spigelman A, Pachter N, Ahmed M, Ramon Y Cajal T, Zgajnar J, Brewer C, Gadea N, Brady AF, van Os T, Gallagher D, Johannsson O, Donaldson A, Barwell J, Nicolai N, Friedman E, Obeid E, Greenhalgh L, Murthy V, Copakova L, Saya S, McGrath J, Cooke P, Rønlund K, Richardson K, Henderson A, Teo SH, Arun B, Kast K, Dias A, Aaronson NK, Ardern-Jones A, Bangma CH, Castro E, Dearnaley D, Eccles DM, Tricker K, Eyfjord J, Falconer A, Foster C, Gronberg H, Hamdy FC, Stefansdottir V, Khoo V, Lindeman GJ, Lubinski J, Axcrona K, Mikropoulos C, Mitra A, Moynihan C, Rennert G, Suri M, Wilson P, Dudderidge T, IMPACT Study Collaborators, Offman J, Kote-Jarai Z, Vickers A, Lilja H, Eeles RA. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers. European urology. 2019 Dec:76(6):831-842. doi: 10.1016/j.eururo.2019.08.019. Epub 2019 Sep 16 [PubMed PMID: 31537406]
Breslow N, Chan CW, Dhom G, Drury RA, Franks LM, Gellei B, Lee YS, Lundberg S, Sparke B, Sternby NH, Tulinius H. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyons, France. International journal of cancer. 1977 Nov 15:20(5):680-8 [PubMed PMID: 924691]
Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, Partin AW, Klee GG, Slawin KM, Marks LS, van Schaik RH, Chan DW, Sokoll LJ, Cruz AB, Mizrahi IA, Catalona WJ. The prostate health index selectively identifies clinically significant prostate cancer. The Journal of urology. 2015 Apr:193(4):1163-9. doi: 10.1016/j.juro.2014.10.121. Epub 2014 Nov 15 [PubMed PMID: 25463993]
Loeb S, Shin SS, Broyles DL, Wei JT, Sanda M, Klee G, Partin AW, Sokoll L, Chan DW, Bangma CH, van Schaik RHN, Slawin KM, Marks LS, Catalona WJ. Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer. BJU international. 2017 Jul:120(1):61-68. doi: 10.1111/bju.13676. Epub 2016 Nov 22 [PubMed PMID: 27743489]
Borque-Fernando Á, Rubio-Briones J, Esteban LM, Dong Y, Calatrava A, Gómez-Ferrer Á, Gómez-Gómez E, Gil Fabra JM, Rodríguez-García N, López González PÁ, García-Rodríguez J, Rodrigo-Aliaga M, Herrera-Imbroda B, Soto-Villalba J, Martínez-Breijo S, Hernández-Cañas V, Soto-Poveda AM, Sánchez-Rodríguez C, Carrillo-George C, Hernández-Martínez YE, Okrongly D. Role of the 4Kscore test as a predictor of reclassification in prostate cancer active surveillance. Prostate cancer and prostatic diseases. 2019 Mar:22(1):84-90. doi: 10.1038/s41391-018-0074-5. Epub 2018 Aug 14 [PubMed PMID: 30108375]
Gittelman MC, Hertzman B, Bailen J, Williams T, Koziol I, Henderson RJ, Efros M, Bidair M, Ward JF. PCA3 molecular urine test as a predictor of repeat prostate biopsy outcome in men with previous negative biopsies: a prospective multicenter clinical study. The Journal of urology. 2013 Jul:190(1):64-9. doi: 10.1016/j.juro.2013.02.018. Epub 2013 Feb 14 [PubMed PMID: 23416644]
Level 1 (high-level) evidenceMcKiernan J, Noerholm M, Tadigotla V, Kumar S, Torkler P, Sant G, Alter J, Donovan MJ, Skog J. A urine-based Exosomal gene expression test stratifies risk of high-grade prostate Cancer in men with prior negative prostate biopsy undergoing repeat biopsy. BMC urology. 2020 Sep 1:20(1):138. doi: 10.1186/s12894-020-00712-4. Epub 2020 Sep 1 [PubMed PMID: 32873277]
Sanda MG, Feng Z, Howard DH, Tomlins SA, Sokoll LJ, Chan DW, Regan MM, Groskopf J, Chipman J, Patil DH, Salami SS, Scherr DS, Kagan J, Srivastava S, Thompson IM Jr, Siddiqui J, Fan J, Joon AY, Bantis LE, Rubin MA, Chinnayian AM, Wei JT, and the EDRN-PCA3 Study Group, Bidair M, Kibel A, Lin DW, Lotan Y, Partin A, Taneja S. Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer. JAMA oncology. 2017 Aug 1:3(8):1085-1093. doi: 10.1001/jamaoncol.2017.0177. Epub [PubMed PMID: 28520829]
Salami SS, Schmidt F, Laxman B, Regan MM, Rickman DS, Scherr D, Bueti G, Siddiqui J, Tomlins SA, Wei JT, Chinnaiyan AM, Rubin MA, Sanda MG. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urologic oncology. 2013 Jul:31(5):566-71. doi: 10.1016/j.urolonc.2011.04.001. Epub 2011 May 19 [PubMed PMID: 21600800]
Haese A, Trooskens G, Steyaert S, Hessels D, Brawer M, Vlaeminck-Guillem V, Ruffion A, Tilki D, Schalken J, Groskopf J, Van Criekinge W. Multicenter Optimization and Validation of a 2-Gene mRNA Urine Test for Detection of Clinically Significant Prostate Cancer before Initial Prostate Biopsy. The Journal of urology. 2019 Aug:202(2):256-263. doi: 10.1097/JU.0000000000000293. Epub 2019 Jul 8 [PubMed PMID: 31026217]
Level 1 (high-level) evidenceDavid MK, Leslie SW. Prostate Specific Antigen. StatPearls. 2024 Jan:(): [PubMed PMID: 32491427]
Armitage TG, Cooper EH, Newling DW, Robinson MR, Appleyard I. The value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer. British journal of urology. 1988 Dec:62(6):584-9 [PubMed PMID: 2464397]
Etzioni RD, Howlader N, Shaw PA, Ankerst DP, Penson DF, Goodman PJ, Thompson IM. Long-term effects of finasteride on prostate specific antigen levels: results from the prostate cancer prevention trial. The Journal of urology. 2005 Sep:174(3):877-81 [PubMed PMID: 16093979]
Level 1 (high-level) evidenceDalton DL. Elevated serum prostate-specific antigen due to acute bacterial prostatitis. Urology. 1989 Jun:33(6):465 [PubMed PMID: 2471345]
Level 3 (low-level) evidenceMarks LS, Andriole GL, Fitzpatrick JM, Schulman CC, Roehrborn CG. The interpretation of serum prostate specific antigen in men receiving 5alpha-reductase inhibitors: a review and clinical recommendations. The Journal of urology. 2006 Sep:176(3):868-74 [PubMed PMID: 16890642]
Ercole CJ, Lange PH, Mathisen M, Chiou RK, Reddy PK, Vessella RL. Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. The Journal of urology. 1987 Nov:138(5):1181-4 [PubMed PMID: 2444720]
Level 2 (mid-level) evidenceStamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. The New England journal of medicine. 1987 Oct 8:317(15):909-16 [PubMed PMID: 2442609]
Guess HA, Heyse JF, Gormley GJ. The effect of finasteride on prostate-specific antigen in men with benign prostatic hyperplasia. The Prostate. 1993:22(1):31-7 [PubMed PMID: 7678930]
Salisbury BH, Tadi P. 5-Alpha-Reductase Inhibitors. StatPearls. 2024 Jan:(): [PubMed PMID: 32310390]
Wei JT, Barocas D, Carlsson S, Coakley F, Eggener S, Etzioni R, Fine SW, Han M, Kim SK, Kirkby E, Konety BR, Miner M, Moses K, Nissenberg MG, Pinto PA, Salami SS, Souter L, Thompson IM, Lin DW. Early Detection of Prostate Cancer: AUA/SUO Guideline Part I: Prostate Cancer Screening. The Journal of urology. 2023 Jul:210(1):46-53. doi: 10.1097/JU.0000000000003491. Epub 2023 Apr 25 [PubMed PMID: 37096582]
Wei JT, Barocas D, Carlsson S, Coakley F, Eggener S, Etzioni R, Fine SW, Han M, Kim SK, Kirkby E, Konety BR, Miner M, Moses K, Nissenberg MG, Pinto PA, Salami SS, Souter L, Thompson IM, Lin DW. Early Detection of Prostate Cancer: AUA/SUO Guideline Part II: Considerations for a Prostate Biopsy. The Journal of urology. 2023 Jul:210(1):54-63. doi: 10.1097/JU.0000000000003492. Epub 2023 Apr 25 [PubMed PMID: 37096575]
Hugosson J, Roobol MJ, Månsson M, Tammela TLJ, Zappa M, Nelen V, Kwiatkowski M, Lujan M, Carlsson SV, Talala KM, Lilja H, Denis LJ, Recker F, Paez A, Puliti D, Villers A, Rebillard X, Kilpeläinen TP, Stenman UH, Godtman RA, Stinesen Kollberg K, Moss SM, Kujala P, Taari K, Huber A, van der Kwast T, Heijnsdijk EA, Bangma C, De Koning HJ, Schröder FH, Auvinen A, ERSPC investigators. A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer. European urology. 2019 Jul:76(1):43-51. doi: 10.1016/j.eururo.2019.02.009. Epub 2019 Feb 26 [PubMed PMID: 30824296]
Level 1 (high-level) evidenceFrånlund M, Månsson M, Godtman RA, Aus G, Holmberg E, Kollberg KS, Lodding P, Pihl CG, Stranne J, Lilja H, Hugosson J. Results from 22 years of Followup in the Göteborg Randomized Population-Based Prostate Cancer Screening Trial. The Journal of urology. 2022 Aug:208(2):292-300. doi: 10.1097/JU.0000000000002696. Epub 2022 Apr 15 [PubMed PMID: 35422134]
Level 1 (high-level) evidenceChen YC, Page JH, Chen R, Giovannucci E. Family history of prostate and breast cancer and the risk of prostate cancer in the PSA era. The Prostate. 2008 Oct 1:68(14):1582-91. doi: 10.1002/pros.20825. Epub [PubMed PMID: 18646000]
Level 2 (mid-level) evidenceGrill S, Fallah M, Leach RJ, Thompson IM, Freedland S, Hemminki K, Ankerst DP. Incorporation of detailed family history from the Swedish Family Cancer Database into the PCPT risk calculator. The Journal of urology. 2015 Feb:193(2):460-5. doi: 10.1016/j.juro.2014.09.018. Epub 2014 Sep 19 [PubMed PMID: 25242395]
Barber L, Gerke T, Markt SC, Peisch SF, Wilson KM, Ahearn T, Giovannucci E, Parmigiani G, Mucci LA. Family History of Breast or Prostate Cancer and Prostate Cancer Risk. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Dec 1:24(23):5910-5917. doi: 10.1158/1078-0432.CCR-18-0370. Epub 2018 Aug 6 [PubMed PMID: 30082473]
Ren ZJ, Cao DH, Zhang Q, Ren PW, Liu LR, Wei Q, Wei WR, Dong Q. First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis. BMC cancer. 2019 Sep 2:19(1):871. doi: 10.1186/s12885-019-6055-9. Epub 2019 Sep 2 [PubMed PMID: 31477094]
Level 1 (high-level) evidenceMahal BA, Chen YW, Muralidhar V, Mahal AR, Choueiri TK, Hoffman KE, Hu JC, Sweeney CJ, Yu JB, Feng FY, Kim SP, Beard CJ, Martin NE, Trinh QD, Nguyen PL. Racial disparities in prostate cancer outcome among prostate-specific antigen screening eligible populations in the United States. Annals of oncology : official journal of the European Society for Medical Oncology. 2017 May 1:28(5):1098-1104. doi: 10.1093/annonc/mdx041. Epub [PubMed PMID: 28453693]
Omri N, Kamil M, Alexander K, Alexander K, Edmond S, Ariel Z, David K, Gilad AE, Azik H. Association between PSA density and pathologically significant prostate cancer: The impact of prostate volume. The Prostate. 2020 Dec:80(16):1444-1449. doi: 10.1002/pros.24078. Epub 2020 Sep 24 [PubMed PMID: 32970856]
Maggi M, Panebianco V, Mosca A, Salciccia S, Gentilucci A, Di Pierro G, Busetto GM, Barchetti G, Campa R, Sperduti I, Del Giudice F, Sciarra A. Prostate Imaging Reporting and Data System 3 Category Cases at Multiparametric Magnetic Resonance for Prostate Cancer: A Systematic Review and Meta-analysis. European urology focus. 2020 May 15:6(3):463-478. doi: 10.1016/j.euf.2019.06.014. Epub 2019 Jul 4 [PubMed PMID: 31279677]
Level 3 (low-level) evidenceNordström T, Akre O, Aly M, Grönberg H, Eklund M. Prostate-specific antigen (PSA) density in the diagnostic algorithm of prostate cancer. Prostate cancer and prostatic diseases. 2018 Apr:21(1):57-63. doi: 10.1038/s41391-017-0024-7. Epub 2017 Dec 19 [PubMed PMID: 29259293]
Yusim I, Krenawi M, Mazor E, Novack V, Mabjeesh NJ. The use of prostate specific antigen density to predict clinically significant prostate cancer. Scientific reports. 2020 Nov 17:10(1):20015. doi: 10.1038/s41598-020-76786-9. Epub 2020 Nov 17 [PubMed PMID: 33203873]
Kortenbach KC, Løgager V, Thomsen HS, Boesen L. Comparison of PSA density and lesion volume strategies for selecting men with equivocal PI-RADS 3 lesions on bpMRI for biopsies. Abdominal radiology (New York). 2023 Feb:48(2):688-693. doi: 10.1007/s00261-022-03720-0. Epub 2022 Nov 1 [PubMed PMID: 36318331]
Lei Y, Li TJ, Gu P, Yang YK, Zhao L, Gao C, Hu J, Liu XD. Combining prostate-specific antigen density with prostate imaging reporting and data system score version 2.1 to improve detection of clinically significant prostate cancer: A retrospective study. Frontiers in oncology. 2022:12():992032. doi: 10.3389/fonc.2022.992032. Epub 2022 Sep 23 [PubMed PMID: 36212411]
Level 2 (mid-level) evidenceDrevik J, Dalimov Z, Uzzo R, Danella J, Guzzo T, Belkoff L, Raman J, Tomaszewski J, Trabulsi E, Reese A, Singer EA, Syed K, Jacobs B, Correa A, Smaldone M, Ginzburg S. Utility of PSA density in patients with PI-RADS 3 lesions across a large multi-institutional collaborative. Urologic oncology. 2022 Nov:40(11):490.e1-490.e6. doi: 10.1016/j.urolonc.2022.08.003. Epub 2022 Sep 23 [PubMed PMID: 36163229]
Rodríguez Cabello MA, Méndez Rubio S, Platas Sancho A, Carballido Rodríguez J. Diagnostic evaluation and incorporation of PSA density and the prostate imaging and data reporting system (PIRADS) version 2 classification in risk-nomograms for prostate cancer. World journal of urology. 2022 Oct:40(10):2439-2450. doi: 10.1007/s00345-022-04118-9. Epub 2022 Aug 8 [PubMed PMID: 35941245]
Carter HB, Partin AW, Luderer AA, Metter EJ, Landis P, Chan DW, Fozard JL, Pearson JD. Percentage of free prostate-specific antigen in sera predicts aggressiveness of prostate cancer a decade before diagnosis. Urology. 1997 Mar:49(3):379-84 [PubMed PMID: 9123702]
Masieri L, Minervini A, Vittori G, Lanciotti M, Lanzi F, Lapini A, Carini M, Serni S. The role of free to total PSA ratio in prediction of extracapsular tumor extension and biochemical recurrence after radical prostatectomy in patients with PSA between 4 and 10 ng/ml. International urology and nephrology. 2012 Aug:44(4):1031-8 [PubMed PMID: 22315156]
Shariat SF, Abdel-Aziz KF, Roehrborn CG, Lotan Y. Pre-operative percent free PSA predicts clinical outcomes in patients treated with radical prostatectomy with total PSA levels below 10 ng/ml. European urology. 2006 Feb:49(2):293-302 [PubMed PMID: 16387412]
Level 2 (mid-level) evidenceCatalona WJ, Beiser JA, Smith DS. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. The Journal of urology. 1997 Dec:158(6):2162-7 [PubMed PMID: 9366336]
Christensson A, Björk T, Nilsson O, Dahlén U, Matikainen MT, Cockett AT, Abrahamsson PA, Lilja H. Serum prostate specific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer. The Journal of urology. 1993 Jul:150(1):100-5 [PubMed PMID: 7685416]
Leinonen J, Lövgren T, Vornanen T, Stenman UH. Double-label time-resolved immunofluorometric assay of prostate-specific antigen and of its complex with alpha 1-antichymotrypsin. Clinical chemistry. 1993 Oct:39(10):2098-103 [PubMed PMID: 7691441]
Stenman UH, Hakama M, Knekt P, Aromaa A, Teppo L, Leinonen J. Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer. Lancet (London, England). 1994 Dec 10:344(8937):1594-8 [PubMed PMID: 7527116]
Level 2 (mid-level) evidencePartin AW, Brawer MK, Subong EN, Kelley CA, Cox JL, Bruzek DJ, Pannek J, Meyer GE, Chan DW. Prospective evaluation of percent free-PSA and complexed-PSA for early detection of prostate cancer. Prostate cancer and prostatic diseases. 1998 Jun:1(4):197-203 [PubMed PMID: 12496895]
Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, deKernion JB, Walsh PC, Scardino PT, Lange PH, Subong EN, Parson RE, Gasior GH, Loveland KG, Southwick PC. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998 May 20:279(19):1542-7 [PubMed PMID: 9605898]
Level 1 (high-level) evidenceHuang Y, Li ZZ, Huang YL, Song HJ, Wang YJ. Value of free/total prostate-specific antigen (f/t PSA) ratios for prostate cancer detection in patients with total serum prostate-specific antigen between 4 and 10 ng/mL: A meta-analysis. Medicine. 2018 Mar:97(13):e0249. doi: 10.1097/MD.0000000000010249. Epub [PubMed PMID: 29595681]
Level 1 (high-level) evidenceCarroll PH, Mohler JL. NCCN Guidelines Updates: Prostate Cancer and Prostate Cancer Early Detection. Journal of the National Comprehensive Cancer Network : JNCCN. 2018 May:16(5S):620-623. doi: 10.6004/jnccn.2018.0036. Epub [PubMed PMID: 29784740]
Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, Fouad MN, Gelmann EP, Kvale PA, Reding DJ, Weissfeld JL, Yokochi LA, O'Brien B, Clapp JD, Rathmell JM, Riley TL, Hayes RB, Kramer BS, Izmirlian G, Miller AB, Pinsky PF, Prorok PC, Gohagan JK, Berg CD, PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. The New England journal of medicine. 2009 Mar 26:360(13):1310-9. doi: 10.1056/NEJMoa0810696. Epub 2009 Mar 18 [PubMed PMID: 19297565]
Level 1 (high-level) evidenceAnkerst DP, Koniarski T, Liang Y, Leach RJ, Feng Z, Sanda MG, Partin AW, Chan DW, Kagan J, Sokoll L, Wei JT, Thompson IM. Updating risk prediction tools: a case study in prostate cancer. Biometrical journal. Biometrische Zeitschrift. 2012 Jan:54(1):127-42. doi: 10.1002/bimj.201100062. Epub 2011 Nov 17 [PubMed PMID: 22095849]
Level 3 (low-level) evidenceSchröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, Kwiatkowski M, Lujan M, Lilja H, Zappa M, Denis LJ, Recker F, Berenguer A, Määttänen L, Bangma CH, Aus G, Villers A, Rebillard X, van der Kwast T, Blijenberg BG, Moss SM, de Koning HJ, Auvinen A, ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. The New England journal of medicine. 2009 Mar 26:360(13):1320-8. doi: 10.1056/NEJMoa0810084. Epub 2009 Mar 18 [PubMed PMID: 19297566]
Level 1 (high-level) evidenceAgnello L, Vidali M, Salvaggio G, Agnello F, Lo Sasso B, Gambino CM, Ciaccio M. Prostate Health Index (PHI) as a triage tool for reducing unnecessary magnetic resonance imaging (MRI) in patients at risk of prostate cancer. Clinical biochemistry. 2024 May:127-128():110759. doi: 10.1016/j.clinbiochem.2024.110759. Epub 2024 Apr 6 [PubMed PMID: 38583655]
Rius Bilbao L, Aguirre Larracoechea U, Valladares Gomez C, Remmers S, Mar Medina C, Phi Basque Study Group. Incorporating PHI in decision making: external validation of the Rotterdam risk calculators for detection of prostate cancer. World journal of urology. 2024 Mar 13:42(1):141. doi: 10.1007/s00345-024-04833-5. Epub 2024 Mar 13 [PubMed PMID: 38478041]
Level 1 (high-level) evidenceTosoian JJ, Druskin SC, Andreas D, Mullane P, Chappidi M, Joo S, Ghabili K, Agostino J, Macura KJ, Carter HB, Schaeffer EM, Partin AW, Sokoll LJ, Ross AE. Use of the Prostate Health Index for detection of prostate cancer: results from a large academic practice. Prostate cancer and prostatic diseases. 2017 Jun:20(2):228-233. doi: 10.1038/pcan.2016.72. Epub 2017 Jan 24 [PubMed PMID: 28117387]
Potter SR, Partin AW. Tumor markers: an update on human kallikrein 2. Reviews in urology. 2000 Fall:2(4):221-2 [PubMed PMID: 16985755]
Carroll PR, Parsons JK, Andriole G, Bahnson RR, Castle EP, Catalona WJ, Dahl DM, Davis JW, Epstein JI, Etzioni RB, Farrington T, Hemstreet GP 3rd, Kawachi MH, Kim S, Lange PH, Loughlin KR, Lowrance W, Maroni P, Mohler J, Morgan TM, Moses KA, Nadler RB, Poch M, Scales C, Shaneyfelt TM, Smaldone MC, Sonn G, Sprenkle P, Vickers AJ, Wake R, Shead DA, Freedman-Cass DA. NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016. Journal of the National Comprehensive Cancer Network : JNCCN. 2016 May:14(5):509-19 [PubMed PMID: 27160230]
Carlsson S, Maschino A, Schröder F, Bangma C, Steyerberg EW, van der Kwast T, van Leenders G, Vickers A, Lilja H, Roobol MJ. Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European Randomized Study of Screening for Prostate Cancer section Rotterdam. European urology. 2013 Nov:64(5):693-9. doi: 10.1016/j.eururo.2013.04.040. Epub 2013 May 2 [PubMed PMID: 23683475]
Level 1 (high-level) evidenceVoigt JD, Zappala SM, Vaughan ED, Wein AJ. The Kallikrein Panel for prostate cancer screening: its economic impact. The Prostate. 2014 Feb:74(3):250-9. doi: 10.1002/pros.22746. Epub 2013 Oct 26 [PubMed PMID: 24166488]
Level 1 (high-level) evidenceRavipaty S, Wu W, Dalvi A, Tanna N, Andreazi J, Friss T, Klotz A, Liao C, Garren J, Schofield S, Diamandis EP, Klein EA, Dobi A, Srivastava S, Tekumalla P, Kiebish MA, Vishnudas V, Sarangarajan RP, Narain NR, Akmaev VR. Clinical Validation of a Serum Protein Panel (FLNA, FLNB and KRT19) for Diagnosis of Prostate Cancer. Journal of molecular biomarkers & diagnosis. 2017:8(2):. pii: 323. doi: 10.4172/2155-9929.1000323. Epub 2017 Feb 8 [PubMed PMID: 29682400]
Level 1 (high-level) evidenceTruong M, Yang B, Jarrard DF. Toward the detection of prostate cancer in urine: a critical analysis. The Journal of urology. 2013 Feb:189(2):422-9. doi: 10.1016/j.juro.2012.04.143. Epub 2012 Sep 24 [PubMed PMID: 23017522]
Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N, Isaacs WB. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer research. 1999 Dec 1:59(23):5975-9 [PubMed PMID: 10606244]
Fujita K, Nonomura N. Urinary biomarkers of prostate cancer. International journal of urology : official journal of the Japanese Urological Association. 2018 Sep:25(9):770-779. doi: 10.1111/iju.13734. Epub 2018 Aug 21 [PubMed PMID: 30129068]
Rigau M, Olivan M, Garcia M, Sequeiros T, Montes M, Colás E, Llauradó M, Planas J, Torres Id, Morote J, Cooper C, Reventós J, Clark J, Doll A. The present and future of prostate cancer urine biomarkers. International journal of molecular sciences. 2013 Jun 17:14(6):12620-49. doi: 10.3390/ijms140612620. Epub 2013 Jun 17 [PubMed PMID: 23774836]
Level 3 (low-level) evidenceMartignano F, Rossi L, Maugeri A, Gallà V, Conteduca V, De Giorgi U, Casadio V, Schepisi G. Urinary RNA-based biomarkers for prostate cancer detection. Clinica chimica acta; international journal of clinical chemistry. 2017 Oct:473():96-105. doi: 10.1016/j.cca.2017.08.009. Epub 2017 Aug 12 [PubMed PMID: 28807541]
Hessels D, Klein Gunnewiek JM, van Oort I, Karthaus HF, van Leenders GJ, van Balken B, Kiemeney LA, Witjes JA, Schalken JA. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. European urology. 2003 Jul:44(1):8-15; discussion 15-6 [PubMed PMID: 12814669]
Level 2 (mid-level) evidencevan Gils MP, Hessels D, Hulsbergen-van de Kaa CA, Witjes JA, Jansen CF, Mulders PF, Rittenhouse HG, Schalken JA. Detailed analysis of histopathological parameters in radical prostatectomy specimens and PCA3 urine test results. The Prostate. 2008 Aug 1:68(11):1215-22. doi: 10.1002/pros.20781. Epub [PubMed PMID: 18500693]
Groskopf J, Aubin SM, Deras IL, Blase A, Bodrug S, Clark C, Brentano S, Mathis J, Pham J, Meyer T, Cass M, Hodge P, Macairan ML, Marks LS, Rittenhouse H. APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clinical chemistry. 2006 Jun:52(6):1089-95 [PubMed PMID: 16627561]
Alshalalfa M, Verhaegh GW, Gibb EA, Santiago-Jiménez M, Erho N, Jordan J, Yousefi K, Lam LLC, Kolisnik T, Chelissery J, Seiler R, Ross AE, Karnes RJ, Schaeffer EM, Lotan TT, Den RB, Freedland SJ, Davicioni E, Klein EA, Schalken JA. Low PCA3 expression is a marker of poor differentiation in localized prostate tumors: exploratory analysis from 12,076 patients. Oncotarget. 2017 Aug 1:8(31):50804-50813. doi: 10.18632/oncotarget.15133. Epub 2017 Feb 7 [PubMed PMID: 28881605]
Deras IL, Aubin SM, Blase A, Day JR, Koo S, Partin AW, Ellis WJ, Marks LS, Fradet Y, Rittenhouse H, Groskopf J. PCA3: a molecular urine assay for predicting prostate biopsy outcome. The Journal of urology. 2008 Apr:179(4):1587-92. doi: 10.1016/j.juro.2007.11.038. Epub 2008 Mar 4 [PubMed PMID: 18295257]
Roobol MJ, Schröder FH, van Leeuwen P, Wolters T, van den Bergh RC, van Leenders GJ, Hessels D. Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test. European urology. 2010 Oct:58(4):475-81. doi: 10.1016/j.eururo.2010.06.039. Epub 2010 Jul 9 [PubMed PMID: 20637539]
Level 1 (high-level) evidenceHaese A, de la Taille A, van Poppel H, Marberger M, Stenzl A, Mulders PF, Huland H, Abbou CC, Remzi M, Tinzl M, Feyerabend S, Stillebroer AB, van Gils MP, Schalken JA. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. European urology. 2008 Nov:54(5):1081-8. doi: 10.1016/j.eururo.2008.06.071. Epub 2008 Jun 26 [PubMed PMID: 18602209]
Lee GL, Dobi A, Srivastava S. Prostate cancer: diagnostic performance of the PCA3 urine test. Nature reviews. Urology. 2011 Mar:8(3):123-4. doi: 10.1038/nrurol.2011.10. Epub [PubMed PMID: 21394175]
Hessels D, Schalken JA. Urinary biomarkers for prostate cancer: a review. Asian journal of andrology. 2013 May:15(3):333-9. doi: 10.1038/aja.2013.6. Epub 2013 Mar 25 [PubMed PMID: 23524531]
Wang T, Qu X, Jiang J, Gao P, Zhao D, Lian X, Li X. Diagnostic significance of urinary long non-coding PCA3 RNA in prostate cancer. Oncotarget. 2017 Aug 29:8(35):58577-58586. doi: 10.18632/oncotarget.17272. Epub 2017 Apr 20 [PubMed PMID: 28938580]
Ankerst DP, Hoefler J, Bock S, Goodman PJ, Vickers A, Hernandez J, Sokoll LJ, Sanda MG, Wei JT, Leach RJ, Thompson IM. Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of low- vs high-grade prostate cancer. Urology. 2014 Jun:83(6):1362-7. doi: 10.1016/j.urology.2014.02.035. Epub [PubMed PMID: 24862395]
Sreenath TL, Dobi A, Petrovics G, Srivastava S. Oncogenic activation of ERG: A predominant mechanism in prostate cancer. Journal of carcinogenesis. 2011:10():37. doi: 10.4103/1477-3163.91122. Epub 2011 Dec 31 [PubMed PMID: 22279422]
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science (New York, N.Y.). 2005 Oct 28:310(5748):644-8 [PubMed PMID: 16254181]
Rice KR, Chen Y, Ali A, Whitman EJ, Blase A, Ibrahim M, Elsamanoudi S, Brassell S, Furusato B, Stingle N, Sesterhenn IA, Petrovics G, Miick S, Rittenhouse H, Groskopf J, McLeod DG, Srivastava S. Evaluation of the ETS-related gene mRNA in urine for the detection of prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010 Mar 1:16(5):1572-6. doi: 10.1158/1078-0432.CCR-09-2191. Epub 2010 Feb 16 [PubMed PMID: 20160063]
Tomlins SA, Aubin SM, Siddiqui J, Lonigro RJ, Sefton-Miller L, Miick S, Williamsen S, Hodge P, Meinke J, Blase A, Penabella Y, Day JR, Varambally R, Han B, Wood D, Wang L, Sanda MG, Rubin MA, Rhodes DR, Hollenbeck B, Sakamoto K, Silberstein JL, Fradet Y, Amberson JB, Meyers S, Palanisamy N, Rittenhouse H, Wei JT, Groskopf J, Chinnaiyan AM. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Science translational medicine. 2011 Aug 3:3(94):94ra72. doi: 10.1126/scitranslmed.3001970. Epub [PubMed PMID: 21813756]
Level 2 (mid-level) evidenceVan Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA, de Jong H, Hessels D, Smit FP, Melchers WJ, Leyten GH, de Reijke TM, Vergunst H, Kil P, Knipscheer BC, Hulsbergen-van de Kaa CA, Mulders PF, van Oort IM, Van Criekinge W, Schalken JA. Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score. European urology. 2016 Nov:70(5):740-748. doi: 10.1016/j.eururo.2016.04.012. Epub 2016 Apr 20 [PubMed PMID: 27108162]
Schostak M, Schwall GP, Poznanović S, Groebe K, Müller M, Messinger D, Miller K, Krause H, Pelzer A, Horninger W, Klocker H, Hennenlotter J, Feyerabend S, Stenzl A, Schrattenholz A. Annexin A3 in urine: a highly specific noninvasive marker for prostate cancer early detection. The Journal of urology. 2009 Jan:181(1):343-53. doi: 10.1016/j.juro.2008.08.119. Epub 2008 Nov 13 [PubMed PMID: 19012935]
Cao DL, Ye DW, Zhang HL, Zhu Y, Wang YX, Yao XD. A multiplex model of combining gene-based, protein-based, and metabolite-based with positive and negative markers in urine for the early diagnosis of prostate cancer. The Prostate. 2011 May 15:71(7):700-10. doi: 10.1002/pros.21286. Epub 2010 Oct 18 [PubMed PMID: 20957673]
Duijvesz D, Luider T, Bangma CH, Jenster G. Exosomes as biomarker treasure chests for prostate cancer. European urology. 2011 May:59(5):823-31. doi: 10.1016/j.eururo.2010.12.031. Epub 2010 Dec 29 [PubMed PMID: 21196075]
Filella X, Foj L. Prostate Cancer Detection and Prognosis: From Prostate Specific Antigen (PSA) to Exosomal Biomarkers. International journal of molecular sciences. 2016 Oct 26:17(11): [PubMed PMID: 27792187]
McKiernan J, Donovan MJ, O'Neill V, Bentink S, Noerholm M, Belzer S, Skog J, Kattan MW, Partin A, Andriole G, Brown G, Wei JT, Thompson IM Jr, Carroll P. A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy. JAMA oncology. 2016 Jul 1:2(7):882-9. doi: 10.1001/jamaoncol.2016.0097. Epub [PubMed PMID: 27032035]
Donovan MJ, Noerholm M, Bentink S, Belzer S, Skog J, O'Neill V, Cochran JS, Brown GA. A molecular signature of PCA3 and ERG exosomal RNA from non-DRE urine is predictive of initial prostate biopsy result. Prostate cancer and prostatic diseases. 2015 Dec:18(4):370-5. doi: 10.1038/pcan.2015.40. Epub 2015 Sep 8 [PubMed PMID: 26345389]
Intasqui P, Bertolla RP, Sadi MV. Prostate cancer proteomics: clinically useful protein biomarkers and future perspectives. Expert review of proteomics. 2018 Jan:15(1):65-79. doi: 10.1080/14789450.2018.1417846. Epub 2017 Dec 20 [PubMed PMID: 29251021]
Level 3 (low-level) evidenceWorst TS, von Hardenberg J, Gross JC, Erben P, Schnölzer M, Hausser I, Bugert P, Michel MS, Boutros M. Database-augmented Mass Spectrometry Analysis of Exosomes Identifies Claudin 3 as a Putative Prostate Cancer Biomarker. Molecular & cellular proteomics : MCP. 2017 Jun:16(6):998-1008. doi: 10.1074/mcp.M117.068577. Epub 2017 Apr 9 [PubMed PMID: 28396511]
Khan S, Jutzy JM, Valenzuela MM, Turay D, Aspe JR, Ashok A, Mirshahidi S, Mercola D, Lilly MB, Wall NR. Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. PloS one. 2012:7(10):e46737. doi: 10.1371/journal.pone.0046737. Epub 2012 Oct 16 [PubMed PMID: 23091600]
Level 2 (mid-level) evidenceSartori DA, Chan DW. Biomarkers in prostate cancer: what's new? Current opinion in oncology. 2014 May:26(3):259-64. doi: 10.1097/CCO.0000000000000065. Epub [PubMed PMID: 24626128]
Eifler JB, Feng Z, Lin BM, Partin MT, Humphreys EB, Han M, Epstein JI, Walsh PC, Trock BJ, Partin AW. An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011. BJU international. 2013 Jan:111(1):22-9. doi: 10.1111/j.1464-410X.2012.11324.x. Epub 2012 Jul 26 [PubMed PMID: 22834909]
Level 3 (low-level) evidenceFujita K, Pavlovich CP, Netto GJ, Konishi Y, Isaacs WB, Ali S, De Marzo A, Meeker AK. Specific detection of prostate cancer cells in urine by multiplex immunofluorescence cytology. Human pathology. 2009 Jul:40(7):924-33. doi: 10.1016/j.humpath.2009.01.004. Epub 2009 Apr 14 [PubMed PMID: 19368959]
Nickens KP, Ali A, Scoggin T, Tan SH, Ravindranath L, McLeod DG, Dobi A, Tacha D, Sesterhenn IA, Srivastava S, Petrovics G. Prostate cancer marker panel with single cell sensitivity in urine. The Prostate. 2015 Jun 15:75(9):969-75. doi: 10.1002/pros.22981. Epub 2015 Mar 23 [PubMed PMID: 25808739]
Level 3 (low-level) evidenceTsampoukas G, Manolas V, Brown D, Dellis A, Deliveliotis K, Moussa M, Papatsoris A. Atypical small acinar proliferation and its significance in pathological reports in modern urological times. Asian journal of urology. 2022 Jan:9(1):12-17. doi: 10.1016/j.ajur.2021.04.008. Epub 2021 Apr 30 [PubMed PMID: 35198392]
Adamczyk P, Wolski Z, Butkiewicz R, Nussbeutel J, Drewa T. Significance of atypical small acinar proliferation and extensive high-grade prostatic intraepithelial neoplasm in clinical practice. Central European journal of urology. 2014:67(2):136-41. doi: 10.5173/ceju.2014.02.art4. Epub 2014 Jun 23 [PubMed PMID: 25140226]
Bostwick DG, Liu L, Brawer MK, Qian J. High-grade prostatic intraepithelial neoplasia. Reviews in urology. 2004 Fall:6(4):171-9 [PubMed PMID: 16985598]
Level 2 (mid-level) evidenceZhou M. High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma of the prostate. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2018 Jan:31(S1):S71-79. doi: 10.1038/modpathol.2017.138. Epub [PubMed PMID: 29297491]
Morote J, Schwartzmann I, Celma A, Roche S, de Torres IM, Mast R, Semidey ME, Regis L, Santamaria A, Planas J, Trilla E. The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia. BJU international. 2022 May:129(5):627-633. doi: 10.1111/bju.15568. Epub 2021 Aug 25 [PubMed PMID: 34375498]