Prostate Cancer - PSA

Indications for Testing

Laboratory testing for prostate cancer is appropriate in a variety of circumstances, such as for  :

• Screening in men 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 men with a previously elevated PSA or suspicious DRE result
• Monitoring in men undergoing active surveillance for indolent cancer
• Monitoring for recurrence following treatment for prostate cancer

Laboratory Testing

A variety of laboratory and risk calculation tests are used to determine which men should consider undergoing biopsy; 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 men 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 men 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.  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 (cancer is discovered in approximately 30-35% of men with serum PSA results in this range), but NCCN now recommends that any man 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 men who have had a negative biopsy.  Caution should be used in interpreting biomarker test results.

In men who have not yet undergone biopsy but have a PSA of >3 ng/mL, NCCN recommends the following three tests be considered :

• %fPSA
• PHI
• 4Kscore

In men with a negative biopsy result but a higher risk for prostate cancer (eg, because of race, family history), NCCN suggests the following five tests be considered :

• PCA3
• %fPSA
• PHI
• 4Kscore
• ConfirmMDX

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 men with prostate cancer.  This testing is considered useful for 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 result of <25% detects 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

PSA velocity (PSAV) is the rate of change in PSA levels over time, and is based on three or more PSA test results obtained over a period of 18 months or longer. PSAV 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.  NCCN recommends that PSAV be considered along with other criteria such as age, race, family history, and comorbidity when considering whether to proceed with biopsy in men 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, particularly BPH, because lower PSAD values suggest BPH.  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. 

PCA3

PCA3 is a noncoding RNA specific to prostate tissue and is overexpressed in men with prostate cancer. Laboratory testing for PCA3 quantifies this overexpression in urine samples collected after DRE.  PCA3 measurements are particularly helpful in determining which men may need a repeat biopsy; men 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 men ≥50 years of age  for whom a urologist would recommend a repeat biopsy based on current standard of care.

Refer to the ARUP Laboratory Test Directory for additional information about PCA3 test result interpretation.

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 men ≥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 fPSA-total PSA ratio; 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 men ≥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 characteristics, including fPSA, total PSA, human kallikrein 2, intact PSA (a type of fPSA), age, DRE results, and results of a prior biopsy. The resulting score is the probability, expressed as a percent, that a high-grade cancer (Gleason score ≥7) will be detected on biopsy.  The 4Kscore test can be considered before biopsy and in men with a previous negative biopsy result who may be at increased risk for clinically relevant prostate cancer. 

ConfirmMDx

ConfirmMDx is used to assess prostate cancer risk in men who are considering a repeat biopsy.  The FDA has not approved the test, a multiplex epigenetic assay that measures hypermethylation of GSTP1, APC, and RASSF1 promoter regions in tissue samples.  ConfirmMDx can be considered before a repeat biopsy to help determine which men are at greater risk for a cancer diagnosis and to reduce unnecessary biopsies. 

Familial Risk Testing

Gene variants related to familial prostate cancer continue to be investigated, but the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors recommend referral to genetic counseling in the following circumstances :

• Two or more cases of prostate cancer diagnosed by 55 years of age in close relatives
• Three or more first-degree relatives with prostate cancer
• Aggressive prostate cancer (Gleason score >7) in the patient or in a first-degree relative, and two or more breast, ovarian, and/or pancreatic cancer cases in close relatives

Testing for hereditary cancers has increased in recent years, and panels are available that include genes associated with the risk of prostate cancer (eg, BRCA1, BRCA2, ATM, MLH1, MSH2, MSH6, HOXB13, CHEK2, NBN, PALB2, RAD51D, and TP53).

NCCN recommends that individuals who meet risk criteria for certain hereditary cancer syndromes be referred to a cancer genetics professional, and that the risk associated with such syndromes be included in discussions with men about prostate cancer screening. 

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.  

Genetic and Genomic Testing

Certain gene variants have been found to play a role in outcomes such as metastasis and castration resistance.  NCCN recommends that testing for variants (germline and somatic) in BRCA1, BRCA2, ATM, PALB2, and FANCA genes be considered in patients with regional or metastatic disease if testing was not already performed; patients with positive results should be referred for genetic counseling.  Germline genetic testing and genetic counseling should also be considered for all men with high-risk clinically localized prostate cancer.  Such testing may help guide decisions about the use of targeted treatments and/or clinical trial enrollment.

Individuals diagnosed with low risk or “favorable intermediate” risk disease may also choose to pursue testing with tumor-based molecular assays, such as Oncotype DX (not performed at ARUP Laboratories), for prognostic information, such as the risk of death if cancer is managed conservatively, or the risk of biochemical progression following specific treatment types. 

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.