Prostate cancer is the most frequent malignant neoplasm in individuals with prostates and the second most common cancer to cause death among Americans with prostates. The disease ranges from indolent malignancies, which may not need treatment, to more aggressive forms that should be treated. Current recommendations aim to guide clinicians and patients toward a balanced and individualized approach to screening to avoid unnecessary treatment while enabling early detection of aggressive prostate cancers. Such an approach to screening is especially important because of the harms associated with screening, such as false-positive results and consequent additional tests or biopsies, psychological distress, overdiagnosis, overtreatment, and adverse effects of treatment. Laboratory testing involves serum prostate-specific antigen (PSA) testing, tests for PSA derivatives, and tests for other biomarkers. Digital rectal examination (DRE) is not recommended for use as a standalone test but should be considered in conjunction with PSA results in those who have chosen to undergo screening for early detection of prostate cancer. Percent free PSA (%fPSA), PSA velocity (PSAV), prostate cancer antigen 3 (PCA3), and calculations such as the Prostate Health Index (PHI), are useful for risk stratification.
Quick Answers for Clinicians
The U.S. Preventive Services Task Force (USPSTF) recommended against routine prostate-specific antigen (PSA) screening in 2012; however, the 2018 USPSTF guideline states that PSA screening in those 55-69 years of age may have limited benefit for some and recommends individualized decision-making with regard to screening. A number of other organizations offer similar recommendations. (See Societal Recommendations for Prostate Cancer Screening table.)
Infection, ejaculation, trauma, recent procedures, benign conditions, and certain medications all can affect prostate-specific antigen (PSA) lab test results. See Prostate-Specific Antigen section for additional information.
Clinicians should be aware that prostate-specific antigen (PSA) testing has not been harmonized ; ie, the assay and its performance may vary between laboratories, which may lead to significant variation in results. Clinical guidelines for PSA testing may have been developed without a complete understanding of this variation. Thus, results require careful interpretation because variation in results may lead to inappropriate clinical decision-making and potentially adverse effects on patient care. Repeat PSA testing should be performed using the same assay and laboratory to maximize consistency.
Prostate-specific antigen (PSA) and other biomarker tests can help guide decisions about which patients should consider biopsy, but definitive diagnosis is based on biopsy and pathologist examination.
Indications for Testing
Laboratory testing for prostate cancer is appropriate in a variety of circumstances, such as for :
- Screening in individuals with prostates who elect to undergo testing for early detection of prostate cancer
- Risk stratification to aid in decisions about necessity or frequency of testing
- Follow-up in those with a previously elevated PSA or suspicious DRE result
- Monitoring in those undergoing active surveillance for indolent prostate cancer
- Monitoring for recurrence following prostate cancer treatment
Laboratory Testing
A variety of laboratory and risk calculation tests are used to determine who should consider undergoing biopsy to assess for prostate cancer; some of these same tests are used for prognostic assessment and for monitoring after diagnosis.
Screening
Prostate-Specific Antigen
PSA is a glycoprotein found mainly in the seminal plasma but also in the circulation and is not specific to cancer. Recent procedures (eg, urethral, biopsy) can result in increased serum PSA levels, as can infection, ejaculation, or trauma. PSA also can be elevated in individuals with benign conditions, such as prostatitis and benign prostatic hyperplasia (BPH), and PSA levels can be affected (decreased) by treatment with 5-alpha reductase inhibitors. In addition, normal PSA values do not rule out prostate cancer; some individuals have a normal PSA result but a suspicious DRE. Despite these limitations, evidence from clinical trials still supports serum PSA testing for the timely detection of prostate cancer and to guide clinical decisions concerning biopsy. A number of organizations recommend shared decision-making, which includes discussion of age, life expectancy, and risk factors, such as family history and race, to determine when to start screening with PSA. Results of a DRE (if performed) should be considered along with the PSA result. Refer to table below for specific recommendations.
Prostate-Specific Antigen Interpretation
A PSA above the median for one’s age group is associated with higher risk for prostate cancer development and with more aggressive cancer. The higher the PSA result is above the median, the higher the individual’s risk. The NCCN recommends that patients with a steady and marked increase in PSA be encouraged to have a biopsy. PSA levels of 4-10 ng/mL often prompt additional testing, but the NCCN recommends that any individual with a PSA >3 ng/mL be evaluated with repeat PSA testing as well as a DRE. For additional information concerning follow-up based on PSA test results, refer to the Prostate Cancer Early Detection Screening Algorithm.
Other Biomarker and Risk Calculation Tests
Various biomarker tests, including those based on PSA derivatives, can be used to further assess the probability of prostate cancer before proceeding with biopsy, and can therefore help select patients who should consider biopsy. Biomarker assays are also useful to assess whether biopsy should be repeated in those who have had a negative biopsy. Caution should be used in interpreting biomarker test results.
In individuals who have not yet undergone biopsy but have a PSA of >3 ng/mL, the NCCN recommends at least one of the following tests be considered :
In individuals with a negative biopsy result but a higher risk for prostate cancer (eg, because of race, family history), the NCCN suggests the following tests be considered :
Percent Free Prostate-Specific Antigen
The percentage of total PSA that is unbound or free (%fPSA) is clinically informative because serum fPSA is markedly reduced in individuals with prostate cancer. Testing to determine %fPSA is considered useful in patients with a normal DRE but total PSA results of 4-10 ng/mL ; the ratio of free to total PSA helps to distinguish between cancerous and benign conditions. The risk is age dependent: the older the patient and the lower the %fPSA result, the higher the risk for prostate cancer. Evidence indicates that a %fPSA cutoff of <25% enables detection of 95% of prostate cancer cases.
Refer to the ARUP Laboratory Test Directory for additional information about prostate cancer probability based on %fPSA.
Prostate-Specific Antigen Velocity
PSAV is the rate of change in PSA levels over time. PSAV is based on three or more PSA test results obtained over a period of 18 months or longer. Results should be interpreted with caution because of the high biologic variability associated with individual PSA measurements. Some studies have correlated risk of death from prostate cancer with PSAV >0.35 ng/mL/year. The NCCN recommends that PSAV be considered along with other criteria such as age, race, family history, and comorbidities when considering whether to proceed with biopsy in individuals with low PSA levels. PSAV is not considered helpful in the context of high PSA levels (>10 ng/mL).
Prostate-Specific Antigen Density
PSA density (PSAD) is determined by measuring the volume of the prostate using transrectal ultrasound; it is calculated by dividing the PSA level (in ng/mL) by the prostate volume (in cc). PSAD can help differentiate between prostate cancer and benign conditions such as BPH, in which high PSA is secondary to large-volume prostrates. However, precise measurement of PSA and prostate volume can be challenging. PSAD offers limited benefit compared with other tests but may be useful in patients with previous prostate volume measurements.
Prostate Cancer Antigen 3
PCA3 is a noncoding RNA specific to prostate tissue and is overexpressed in those with prostate cancer. Laboratory testing for PCA3 quantifies this overexpression in urine samples collected after DRE. PCA3 measurements are particularly helpful in determining who may need a repeat biopsy; individuals with a PCA3 score of ≥25 are more likely to have prostate cancer detected on a repeat biopsy. PCA3 testing can be used in conjunction with other criteria to help determine the necessity of a repeat biopsy in individuals ≥50 years of age for whom a urologist would recommend a repeat biopsy based on current standard of care. This testing is not available through ARUP Laboratories.
Complexed Prostate-Specific Antigen
PSA exists in both free and complexed forms, one of which is the alpha-1-antichymotrypsin complexed form (cPSA). Clinical trial evidence indicates that the ratio of cPSA to total PSA may be informative in the same way that the %fPSA is informative. Use of cPSA has been approved for use along with DRE to detect prostate cancer in individuals ≥50 years of age.
Prostate Health Index
The PHI is based on a calculation that involves total PSA, fPSA, and a subcategory of free PSA called proPSA (also referred to as p2PSA). The PHI has increased sensitivity for prostate cancer detection compared with the ratio of fPSA to total PSA; the PHI also correlates with cancer grade and is useful for distinguishing high-grade cancers (Gleason score ≥7) from low-grade cancers. PHI may aid in distinguishing prostate cancer from benign prostatic conditions and in detecting prostate cancer in individuals ≥50 years of age with total PSA values of 4-10 ng/mL and with DRE findings that are not suspicious for cancer.
Refer to the ARUP Laboratory Test Directory for additional information about prostate cancer probability based on the PHI.
4Kscore
The 4Kscore is based on a variety of measurements and patient characteristics, including fPSA, total PSA, human kallikrein 2, intact PSA (a type of fPSA), age, DRE results, and previous biopsy results. The resulting score is the probability, expressed as a percent, that a high-grade cancer will be detected on biopsy. The 4Kscore test can be considered before biopsy and in those with a previous negative biopsy result who are considered to be at increased risk for clinically significant prostate cancer.
ExoDx Prostate (Intelliscore)
The ExoDx Prostate (Intelliscore), also called EPI, is a urine-based test that analyzes a three-gene exosome expression assay using PCA3 and ERG RNA, normalized to SPDEF. The EPI panel is designed to help distinguish aggressive cancers (ie, International Society of Urological Pathology [ISUP] Grade Group ≥2 cancers) from ISUP Grade Group 1 cancers and benign conditions at the point of an initial biopsy. The EPI test is intended for use in patients >50 years old with PSA levels between 2 and 10 ng/mL and no previous biopsy. The NCCN recommends EPI as an option for those being considered for an initial or repeat biopsy. This testing is not available through ARUP Laboratories.
SelectMDx
SelectMDx is an assay intended to reduce the number of unnecessary biopsies by aiding in the identification of individuals with clinically significant prostate cancer before a biopsy is performed. This assay, performed on urine collected after a DRE, measures the expression of DLX1 and HOXC6, which have both been associated with more aggressive prostate cancer. SelectMDx may be considered for individuals who have not yet undergone a biopsy. This testing is not available through ARUP Laboratories.
ConfirmMDx
ConfirmMDx is another option to assess prostate cancer risk in individuals who are considering a repeat biopsy. The U.S. Food and Drug Administration (FDA) has not approved the test, which is a multiplex epigenetic assay that measures hypermethylation of GSTP1, APC, and RASSF1 promoter regions in core biopsy tissue samples. ConfirmMDx can be considered before a repeat biopsy to help determine which individuals are at greater risk for a cancer diagnosis and to reduce unnecessary biopsies. This testing is not available through ARUP Laboratories.
Screening in Those With Familial Risk
The NCCN recommends that clinicians ask patients about known personal or familial germline variants that are associated with an increased risk of prostate cancer; individuals with known or suspected variants should be referred to a cancer genetics professional. In addition, individuals who meet risk criteria for certain hereditary cancer syndromes should be referred to a cancer genetics professional, and the risk associated with such syndromes should be included in discussions with patients about prostate cancer screening.
Refer to the Genetic and Genomic Testing section for additional information about genetic testing following prostate cancer diagnosis.
Diagnosis
Definitive diagnosis of prostate cancer requires biopsy and pathologist examination. Biopsy results inform subsequent evaluation, monitoring, and treatment recommendations.
Prognosis
Prostate cancer is categorized as low, medium, or high risk for disease progression and mortality based on PSA level, clinical stage, and tumor grade. Various characteristics suggest aggressive tumor behavior; these include higher PSAD (>0.10-0.15 ng/mL/cc), higher PSAV (>2 ng/mL/year), and a higher Gleason score or ISUP Grade Group.
Genetic and Genomic Testing
Germline Testing
At prostate cancer diagnosis, the NCCN recommends clinicians obtain information about individual and familial cancer history and known familial germline variants, as well as about details of previous genetic testing (direct-to-consumer genetic tests may not include all relevant variants). Germline genetic testing is recommended for all patients with high-risk, regional, or metastatic prostate cancer; Ashkenazi Jewish ancestry; intraductal/cribriform histology; family history of high-risk germline variants (eg, BRCA1, BRCA2); family history of prostate cancer (particularly if a first-degree relative or multiple relatives younger than 60 years have had prostate cancer, or relatives have died due to prostate cancer); or three or more cancers of any type on the same side of the family, particularly in those younger than 50 years.
Germline genetic testing should include analysis for germline variants in the homologous recombination genes BRCA1, BRCA2, ATM, PALB2, and CHEK2 and in the MLH1, MSH2, MSH6, and PMS2 genes; testing for HOXB13 gene variants may also be appropriate. Test results can guide treatment of patients with metastatic disease and help to identify those who are candidates for clinical trials. Genetic counseling before germline genetic testing is recommended, as is genetic counseling in the event of positive results or negative/uncertain results with suggestive family history.
ARUP offers a hereditary breast and ovarian cancer panel that includes germline analysis of the BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, ATM, PALB2, and CHEK2 genes. (Refer to the Laboratory Test Directory for more information about this panel.)
Somatic Testing
The NCCN recommends somatic testing for variants in homologous recombination DNA repair genes (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12) in patients with metastatic disease.
This testing can also be considered in those with regional disease. Test results can guide treatment and help determine clinical trial eligibility.
The presence of BRCA1, BRCA2, ATM, PALB2, and CHEK2 somatic variants or a strong family history of cancer warrants referral to a genetic counselor and confirmatory germline testing; although somatic testing can uncover germline variants, somatic tests are not validated for germline evaluation.
Somatic testing may need to be repeated in patients with progressive disease following treatment.
In patients with metastatic disease, the NCCN recommends testing for microsatellite instability (MSI) status and mismatch repair (MMR) deficiency. Tumor testing for MSI status and MMR deficiency should also be considered in patients with regional disease or castration-naïve metastatic disease. In patients with high MSI status or MMR deficiency, referral to a genetic counselor is recommended for evaluation of Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) or other hereditary cancer syndromes.
Individuals diagnosed with low risk or “favorable intermediate” risk disease may choose to pursue testing with tumor-based molecular assays such as the Oncotype DX Genomic Prostate Score (GPS) test (not available through ARUP Laboratories) for prognostic information.
Monitoring
PSA concentrations should be measured periodically to evaluate patients for disease progression during active surveillance, and PSA results should be considered in light of other clinical and radiologic evidence; an increase in PSA alone does not confirm disease progression. PSA testing every 6 months and DRE every 12 months is recommended during surveillance, unless more frequent monitoring is clinically indicated. Active surveillance may require periodic biopsies as well.
After radical prostatectomy, PSA will generally decrease to an undetectable level. Radiation therapy should also result in a low PSA concentration. A subsequent increase in PSA of ≥2 ng/mL above the PSA nadir is considered biochemical recurrence (BCR), which may precede local recurrence or metastasis by 7-8 years.
ARUP Laboratory Tests
Preferred initial screening test for prostate cancer; use in conjunction with DRE
Use to monitor patients for cancer recurrence
Results from different assay methods or kits cannot be used interchangeably
Quantitative Electrochemiluminescent Immunoassay
Acceptable initial test for prostate cancer screening; preferred test is total PSA in conjunction with DRE
May help in distinguishing cancer from benign conditions
Quantitative Electrochemiluminescent Immunoassay
Preferred initial screening test for prostate cancer; use in conjunction with DRE
May be used to monitor patients for cancer recurrence
Quantitative Electrochemiluminescent Immunoassay
Do not use for initial prostate cancer screening; preferred test is PSA, total, in conjunction with DRE
May provide additional prostate cancer risk information for patients with mildly elevated total PSA and negative DRE
Alternative to PCA3 testing in indeterminate PSA cases
Results from different assay methods or kits cannot be used interchangeably
Quantitative Electrochemiluminescent Immunoassay
Aids in detection of prostate cancer in individuals ≥50 years of age with prostates when used in conjunction with a DRE
May also be used as an aid to manage and monitor patients with prostate cancer
Chemiluminescent Immunoassay
Beckman Coulter phi may be used in individuals with prostates to aid in distinguishing prostate cancer from benign prostatic conditions or to aid in detecting prostate cancer in those ≥50 years of age with total PSA ≥4.0 to ≤10.0 ng/mL and with DRE findings that are not suspicious for cancer.
Quantitative Chemiluminescent Immunoassay
Use to stratify risk of aggressive prostate cancer in patients ≥40 yrs of age who have elevated PSA and are being considered for biopsy
Do not use if prostate cancer was previously diagnosed, DRE was performed within last 4 days, any procedure or therapy was used to treat symptomatic BPH within past 6 months, any invasive urologic procedure associated with a secondary PSA evaluation was performed within past 6 months, or 5-ARI therapy was administered within past 6 months
Electrochemiluminescent Immunoassay
Do not use for initial prostate cancer screening; preferred test is total PSA in conjunction with DRE
May be used to monitor disease after radical prostatectomy
Results from different assay methods or kits cannot be used interchangeably
Quantitative Electrochemiluminescent Immunoassay
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Components: Total PSA, free PSA, %FPSA, intact PSA, and hK2