Prostate Cancer

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

What are current recommendations for prostate-specific antigen (PSA) screening?

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.)

What factors affect prostate-specific antigen (PSA) results?

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.

Can prostate-specific antigen (PSA) results using different assays and laboratories be directly compared?

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.

How do laboratory tests contribute to diagnosis of prostate cancer?

Prostate-specific antigen (PSA) and other biomarker tests can help guide decisions about which patients should consider biopsy, but definitive diagnosis of prostate cancer 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 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 may be decreased by treatment with medications such as 5-alpha reductase inhibitors and ketoconazole. In addition, normal PSA values do not rule out prostate cancer; some individuals with prostate cancer 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, and a number of organizations recommend shared decision-making to determine when to start screening with PSA. For more information, see the Societal Recommendations for Prostate Cancer Screening table.

A PSA above the median for an individual’s age group is associated with higher risk for prostate cancer development and 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 testing based on PSA test results, refer to the Prostate Cancer Early Detection Screening Algorithm.

Societal Recommendations for Prostate Cancer Screening
Society	Age and Risk Category	Screening Recommendation	Screening Frequency
NCCN	≥45-75 yrs with average risk	Informed testing	1- to 2-yr intervals if PSA is 1.0-3.0 ng/mL and DRE (if performed) is normal^a 2- to 4-yr intervals if PSA is <1.0 ng/mL and DRE (if performed) is normal PSA of <1.0 ng/mL in individuals ≥60 yrs indicates very low lifetime risk for prostate cancer metastases
	≥40-75 yrs with higher risk (ie, those of African ancestry, with suspicious family history, with germline variants that increase the risk of prostate cancer)	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	1- to 2-yr intervals if PSA is 1.0-3.0 ng/mL and DRE (if performed) is normal^a 2- to 4-yr intervals if PSA is <1.0 ng/mL and DRE (if performed) is normal 1-yr intervals may be considered PSA of <1.0 ng/mL in individuals ≥60 yrs indicates very low lifetime risk for prostate cancer metastases
	>75 yrs	Screening recommended only in healthy individuals with little or no comorbidity; widespread screening not recommended	1- to 4-yr interval if PSA is <4 ng/mL and DRE (if performed) is normal; clinical judgment should be used PSA of <3.0 ng/mL indicates very low lifetime risk for prostate cancer metastases
USPSTF	55-69 yrs, not high risk	Shared decision-making regarding screening, recognizing there is a small mortality benefit of screening that may balance risks; decision should be an individual one	Not defined due to lack of data, but mortality benefit appears to be associated with every-2-yr screening
	≥70 yrs	Screening is not recommended due to lack of mortality benefit (including for those expected to live 10-15 more yrs)	n/a
	<55 yrs and of African descent	Insufficient evidence to support a separate screening recommendation specific to this population, but clinicians are advised to inform individuals of risk for prostate cancer and benefits/harms of screening to aid in personal decision-making	n/a
	<55 yrs with family history of prostate cancer	Insufficient evidence to support a separate screening recommendation specific to this population, but clinicians are advised to inform individuals of risk for prostate cancer and benefits/harms of screening to aid in personal decision-making	n/a
AUA	<40 yrs, ≥70 yrs, or life expectancy <10-15 yrs	Screening not recommended due to lack of mortality benefit	n/a
	40-54 yrs, with average risk	Routine screening not recommended	n/a
	40-54 yrs, with higher risk (eg, positive family history, of African descent)	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	2-yr interval is recommended
	55-69 yrs	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	2-yr interval is recommended
	≥70 yrs, in excellent health	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	2-yr interval is recommended
ACS	≥50 yrs, average risk, life expectancy ≥10 yrs	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	2-yr interval is suggested if PSA is <2.5 ng/mL 1-yr interval is suggested if PSA is ≥2.5 ng/mL
	≥45 yrs and high risk (ie, those of African descent or with first-degree relative diagnosed at an early age)	Shared decision-making regarding decision to screen, evaluating risks, benefits, and personal values	2-yr interval is suggested if PSA is <2.5 ng/mL 1-yr interval is suggested if PSA is ≥2.5 ng/mL
	≥40 yrs at very high risk (multiple first-degree relatives diagnosed at an early age)	Shared decision-making, including discussion of risks/benefits of screening and patient preferences	2-yr interval is suggested if PSA is <2.5 ng/mL 1-yr interval is suggested if PSA is ≥2.5 ng/mL
	<40 yrs, no symptoms of prostate cancer, or <10-yr life expectancy	Insufficient evidence to recommend screening with PSA	n/a
^aIn the event of PSA >3 ng/mL and/or suspicious DRE, work up for benign disease and repeat testing; if PSA is >3 ng/mL on repeat testing, consider further testing (%fPSA, PHI, 4Kscore). AUA, American Urological Association; ACS, American Cancer Society; NCCN, National Comprehensive Cancer Network; USPSTF, U.S. Preventive Services Task Force Sources: NCCN, 2021; USPSTF, 2018; Carter, AUA, 2013; ACS, 2019				n/a

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. For more information about a selection of these biomarker tests, see the Additional Prostate Cancer Biomarker Tests table.

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:

%fPSA
PHI
SelectMDx
4Kscore
ExoDx Prostate (Intelliscore) (EPI)

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:

%fPSA
PHI
4Kscore
EPI
PCA3
ConfirmMDX

Additional Prostate Cancer Biomarker Tests
Test Name	Test Description	Clinical Utility
4Kscore	Based on a variety of factors, provides a score that is the probability of high-grade cancer being detected on biopsy	May be considered before biopsy and in those with a previous negative biopsy result who are considered to be at increased risk for prostate cancer
ConfirmMDx	Assesses hypermethylation of the promoter regions of GSTP1, APC, and RASSF1	May be useful for individuals being considered for repeat biopsy to aid in identifying those at higher risk for prostate cancer diagnosis
EPI	Urine test that measures PCA3 and ERG RNA, normalized to SPDEF	Aids in distinguishing aggressive cancers from less aggressive cancers and benign conditions May be useful for individuals being considered for initial or repeat biopsy
%fPSA	Ratio of free to total PSA	May be useful in patients ≥50 yrs with normal DRE but total PSA of 4-10 ng/mL, particularly in those who have previously undergone biopsy
PCA3	Detects PCA3 in urine samples collected after DRE	May be considered alongside other criteria in determining whether repeat biopsy is needed in individuals ≥50 yrs
PHI	Based on a calculation involving PSA, fPSA, and proPSA (a subcategory of fPSA)	May be useful in patients ≥50 yrs with normal DRE but total PSA of 4-10 ng/mL Higher scores indicate a higher probability of cancer May assist in distinguishing between cancerous and benign conditions and in distinguishing high-grade cancers from low-grade cancers
PSAV	≥3 PSA test results obtained over ≥18 mos to determine the rate of change in PSA levels	May be considered alongside other criteria in determining whether biopsy should be performed when PSA levels are low Not helpful with PSA levels >10 ng/mL
SelectMDx	Measures expression of DLX1 and HOXC6 in urine collected after DRE	May reduce the likelihood of unnecessary biopsy May be considered for individuals who have not undergone biopsy
Source: NCCN, 2022

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 PSAV 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 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 and for individuals with a personal history of both prostate and breast cancer. It may be considered for patients who have intermediate-risk prostate cancer with intraductal/cribriform histology or who have prostate cancer and a personal history of certain other cancers (ie, biliary tract, colorectal, exocrine pancreatic, gastric, glioblastoma, melanoma, pancreatic, small intestinal, and upper tract urothelial cancers).

Patients with certain family histories or ancestry should also be offered germline genetic testing. Testing is recommended in individuals with Ashkenazi Jewish ancestry or with a family history of high-risk germline variants (eg, BRCA1, BRCA2). Additionally, testing is recommended in individuals with a family history of prostate cancer or other cancers such as breast cancer, ovarian cancer, and Lynch syndrome-related cancers, particularly when these cancers are diagnosed at younger ages. For a detailed list of when a family history necessitates genetic testing, see the NCCN guidelines.

Germline genetic testing should include analysis for germline variants in the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2. Testing for HOXB13 gene variants may also be appropriate. Test results can guide treatment of patients with metastatic disease, help identify those who are candidates for clinical trials, and clarify cancer risk for family members. 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.

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. Additionally, molecular tumor analysis may result in findings that warrant germline genetic testing, and patients should be informed of this before testing.

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.

Gene expression tests such as Decipher, Prolaris, and Oncotype DX Prostate can be considered for prognostic purposes.

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.

In individuals with localized prostate cancer and in those receiving androgen deprivation therapy, PSA concentrations should be assessed every 3-6 months to monitor for progression.

In individuals who have undergone definitive initial therapy, PSA testing is recommended every 6-12 months for the first 5 years and then annually thereafter, unless more frequent monitoring is clinically indicated. DRE is recommended every 12 months during surveillance but may be omitted if PSA is undetectable. 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.