AUA: Early Detection of Prostate Cancer (2023)

See Original Guidelines

See Prostate Cancer Screening Chapter Notes

• This guideline defines
  • Clinically significant prostate cancer as grade group ≥2 prostate cancer
  • Abnormal MRI as PI-RADS ≥3

• The guideline recommends utilizing validated risk calculators, particularly in the repeat biopsy setting.
• This guideline’s literature search is up to November 2022

Risk Factors for Developing Prostate Cancer

Black ancestry

• Prostate cancer incidence is highest amongst Blacks, with an estimated incidence 1.7x higher than Whites and 2x higher than Hispanics[1]

Germline mutations

• Breast Cancer Genes (BRCA)
  • BRCA1 and BRCA2 variants have increased risks of both prostate cancer onset and progression.
    • Stronger association between BRCA2 and aggressive cancer
    • Systematic PSA screening is indicated
  • Associated cancers (5): [2]
    1. Breast (male and female)
    2. Ovarian
    3. Prostate
    4. Pancreatic
    5. Melanoma
• Other mutations
  • ATM, MLH1, MSH2, MSH6, PMS2, HOXB13, NBS1, and CHEK2
    • These mutations need further study to evaluate their role in prostate cancer incidence and aggressiveness

Family history

• Criteria for "strong" family history (2):
  1. ≥1 brother or father OR ≥2 male relatives with one of the following (3):
     1. Diagnosed with prostate cancer at age <60 years
     2. Any of whom died of prostate cancer
     3. Any of whom had metastatic prostate cancer.
  2. Family history of other cancers with ≥2 cancers in hereditary breast and ovarian cancer syndrome or Lynch syndrome spectrum.
     • Hereditary breast and ovarian cancer syndrome
       • Most commonly associated with mutations in either the BRCA1 or BRCA2 gene
       • See associated cancers above
     • Lynch syndrome
       • Also known as hereditary non-polyposis colorectal cancer (HNPCC)
       • Due to inherited mutations in genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) that affect DNA mismatch repair
       • Associated cancers (10)[3]
         1. Colorectal
         2. Gastric
         3. Ovarian
         4. Small bowel
         5. Upper tract urothelial carcinoma
         6. Biliary tract
         7. Pancreatic
         8. Brain cancers (glioblastoma)
         9. Sebaceous gland adenomas
         10. Keratoacanthomas

• Patients with a "strong" family history should ideally be genotyped
  • Genotype is to ascertain whether there is presence of a pathogenic variant (e.g., BRCA1/2, Lynch Syndrome, ATM, CHEK2) or one or more of a growing set of identified germline DNA damage-repair mutations found in patients with metastatic prostate cancer diagnoses.

PSA screening

• When considering people for whom prostate cancer screening would be appropriate, use shared-decision making (SDM) and proceed based on a person’s values and preferences.
  • The use of publicly available decision aids may be helpful in SDM, where available, and are updated to the most current level of evidence.

Tests to use in prostate cancer screening

• Use PSA as the first screening test
  • Digital rectal exam (DRE)
    • Clinicians should not use DRE as the sole screening method.
      • The primary screening modality recommended for the early detection of prostate cancer is a PSA blood test.
    • Insufficient evidence to support adding DRE to PSA-based prostate cancer screening.
      • For various reasons, clinicians may choose to complement PSA screening with DRE based on SDM.
  • Stockholm-3 (STHLM-3)
    • Multiplex test combining
      • Clinical variables (age, first-degree family history of prostate cancer, and previous biopsy)
      • Blood biomarkers (total PSA, free PSA, ratio of free to total PSA, hK2, MIC-1, and MSMB)
      • Polygenic risk score (PRS)
    • Has been evaluated as a first-line screening test for predicting the risk of GG2+ prostate cancers.[4]
      • STHLM-3 found to have a higher predictive accuracy compared to PSA alone (area under the curve [AUC] 0.74 versus 0.56) and reduced unnecessary biopsies by 32%
      • Further validation in diverse populations to confirm these findings will be necessary to move forward into practice.
  • Polygenic risk score (PRS)
    • Genetic tests used to predict a person’s risk of developing prostate cancer.
    • Typically constructed as the weighted sum of a collection of genetic variants, usually single nucleotide polymorphisms (SNPs) defined as single base-pair variations from the reference genome[5]
    • Little evidence to mandate which SNP panel or PRS to use and where to threshold risk to create strata with different screening intensities.
    • At the time of evidence review, no PRS tool has been shown to discriminate between aggressive and indolent prostate cancer risk

Age to start prostate cancer screening

• If age < 40, PSA screening is NOT recommended
• If age > 40 and < 45
  • Offer screening if at increased risk of developing prostate cancer based on (3):
    1. Black ancestry
    2. Germline mutations
    3. "Strong" family history of prostate cancer
• If age >45-50, may begin prostate cancer screening and offer a baseline PSA test
  • Change from 2018 guidelines which recommended screening if age 55-69
    • The 2023 guidelines describe that earlier initiation of screening is supported by observational studies that have demonstrated a prognostic value of obtaining a baseline PSA in early midlife
    • The randomized trials that demonstrate a benefit for prostate cancer screening (Goteborg-1 and ERSPC) began at ages 50 and 55 years, respectively.
  • No randomized evidence showing a benefit to initiation of routine screening for prostate cancer before 45 years of age.

Frequency of prostate cancer screening/discontinuing screening

• Offer regular prostate cancer screening every 2 to 4 years to people aged 50 to 69 years.
• May personalize the re-screening interval, or decide to discontinue screening, following SDM, based on
  • Prostate cancer risk
    • If at increased risk of developing prostate cancer, based on Black ancestry, germline mutations, or strong family history, consider screening more frequently
  • PSA
    • If age 45-70 and
      • PSA 1-3 ng/mL, re-screening interval can be 1-4 years
      • PSA < 1 ng/mL, re-screening interval can be prolonged
    • If age 60 and PSA < 1 ng/mL (age-specific median), reasonable to significantly lengthen the re-screening interval or discontinue screening, based on SDM, provided there are no other risk factors, such as strong family history of prostate cancer
    • The Panel notes most studies regarding baseline PSA have been conducted in populations of primarily White patients.
      • The Southern Community Cohort Study (100% Black patients) showed that PSA levels in midlife were similar to those among White controls in prior studies and were strongly associated with risk of aggressive prostate cancer.
  • Age
    • If age age ≥75 and PSA is < 3 ng/mL, may discontinue or substantially lengthen the re-screening interval for patients.
  • Life expectancy
    • In select patients who are very healthy with an estimated life expectancy of at ≥10 years, ongoing screening every 2-4 years is reasonable
    • For patients with < 10 year estimated life expectancy, screening is not likely to provide a benefit in terms of disease-specific or overall mortality.
      • Based on current Social Security Administration (SSA) data, American men older than 77 years of age have less than a 10-year life expectancy.
    • Risk calculators have been developed to estimate a patient’s life expectancy
      • For the purpose of estimating life expectancy, the use of these tools is likely more reliable than individual clinician judgment.
      • Life expectancy risk calculators
        • US Social Security Administration
        • Memorial Sloan Ketettering Cancer Center Male Life Expectancy Survey
        • Cambridge Prognostic Groups
  • General health
  • Patient preference

Elevated PSA

• If newly elevated PSA, then repeat the PSA prior to a secondary biomarker, imaging, or biopsy.
  • In people with a newly elevated PSA, it will return to a normal level in 25-40% upon retesting.
  • Causes of transient increases in PSA
    • May meaningfully influence PSA
      1. Urinary tract infections
      2. Instrumentation (e.g., recent bladder catheterization, prostate biopsy or cystoscopy, urinary retention)
    • Unlikely to meaningfully influence PSA
      1. DRE
      2. Bicycle riding
      3. Ejaculation
         • Most controlled studies evaluating ejaculation suggest it either does not significantly impact or modestly increases (~10%) PSA.
  • A repeat PSA in a few months is recommended, though it can be shortened or lengthened depending on other clinical factors.
    • Half-life of PSA is 2 to 3 days.
• If PSA ≥ 2 ng/mL, strongly consider supplementary DRE to establish risk of clinically significant prostate cancer.
  • Highest utility of DRE in randomized trials is demonstrated in the workup of patients with an elevated PSA.
    • In contrast to a screening application, use of DRE subsequent to the screening encounter may be of value.
      • In patients undergoing prostate biopsy for an elevated PSA during screening, abnormal DRE improves the PPV for any prostate cancer and GG2+ detection

Initial biopsy

Prostate MRI before biopsy

• MRI may be used prior to initial biopsy to increase the detection of GG2+ prostate cancer
  • Studies have demonstrated the clinical value of mpMRI and using this to guide biopsy decision-making can increase the likelihood of detecting clinically significant prostate cancer while lowering detection of insignificant disease. This is particularly true in patients with a prior negative prostate biopsy; data from patients who are biopsy naïve are less definitive.
  • While some data suggest the benefit of a prebiopsy MRI in biopsy-naïve patients, conflicting reports moderate the enthusiasm for a strong recommendation.
  • It is reasonable to obtain an mpMRI in biopsy-naïve patients prior to their first biopsy, but such a practice cannot be regarded as the standard approach based on the currently available evidence.
• Radiologists should utilize PI-RADS in the reporting of mpMRI imaging.
  • Detection rates by PI-RADS score for
    • Any prostate cancer
      • PR 1-2: 15%
      • PR 3: 25%
      • PR 4: 58%
      • PR 5: 85%
    • GG2+ prostate cancer
      • PR 1-2: 7%
      • PR 3: 11%
      • PR 4: 37%
      • PR 5: 70%
    • Of the 23 studies that were pooled for these results, 10 reported on a per lesion analysis and 13 reported on a per patient analysis using an index lesion.
  • Reader variability remains a challenge

Biopsy threshold

• May be tailored for select patients, similar to risk-stratified re-screening intervals
  • For patients with BRCA mutations, biopsy referral threshold should be 3 ng/mL
• Clinicians and patients may use validated risk calculators to inform the SDM process regarding prostate biopsy
  • Pre-biopsy risk calculators
    • ERSPC
    • PCPT V2
    • PBCG
      • In one study, investigators compared PBCG with PCPT and concluded that PCPT performed better in minority groups.
• PSA velocity should not be used as sole indication for secondary biomarker, imaging, or a biopsy.
• Adjunctive urine or serum markers may be used when further risk stratification would influence the decision regarding whether to proceed with biopsy.
  • Several blood and urine markers are available, alone or in combination, to further risk stratify patients with a mildly elevated PSA, typically between 2.5 and 10 ng/mL.
    • Serum based
      • Percent free PSA
        • Most widely available adjunctive test
        • Lower percent free PSA is associated with greater likelihood of identifying prostate cancer on biopsy.
      • PSA density
        • Higher PSA density (serum PSA [ng/mL] divided by imaging measures of prostate volume [cc]) is associated with the risk of identifying clinically significant prostate cancer on biopsy
        • The Panel recognizes the continuous nature of risk associated with the spectrum of PSA density values and cautions against use of threshold values in isolation
      • 4Kscore
      • IsoPSA
      • Proclarix
      • PHI
      • STHLM-3
    • Urine based
      • Post-DRE Urine
        • PCA3
        • MPS
        • SelectMDx
        • TMPRSS:ERG
      • Urine
        • ExoDx Prostate Intelliscore
        • MiR Sentinel
      • Tissue
        • Confirm MDx
    • Such tests may be of value among patients with modestly elevated PSA tests, especially in patients with a prior negative biopsy in whom PSA alone is not recommended as the sole trigger for rebiopsy.
• When the risk of clinically significant prostate cancer is sufficiently low based on available clinical, laboratory, and imaging data, clinicians and patients may forgo near-term prostate biopsy.

Pre-biopsy counselling

• Patients undergoing a prostate biopsy should be informed that there is a risk of identifying a cancer, with a sufficiently low risk of mortality, that could safely be monitored with active surveillance rather than treated
  • A brief pre-biopsy discussion about pathologic findings warranting active surveillance is expected to increase subsequent acceptance of active surveillance by patients and lower rates of treatment

Role of prostate biopsy in very elevated PSA

• If PSA > 50 ng/mL (and no clinical concerns for infection or other cause for increased PSA (e.g., recent prostate instrumentation)), may omit a prostate biopsy in cases if (2):
  1. Biopsy poses significant risk (e.g., anticoagulation, significant comorbidity, frailty)
  2. Need for prostate cancer treatment is urgent (e.g., impending spinal cord compression from metastases)
  • Imaging to establish extent of disease or confirm metastasis may be helpful if an immediate biopsy is not performed.

Biopsy technique

If MRI performed prior to biopsy

• If no abnormal lesions on prostate MRI but concern for elevated risk for GG2+ prostate cancer, proceed with a systematic biopsy.
  • ≈1 in 10 patients who have a negative prostate MRI may have GG2+ cancer on biopsy,
    • Negative predictive value (NPV) of a “negative” MRI (defined as PIRADS 1 to 2) to detect GG2+ prostate cancer among biopsy-naïve patients was 91%.
  • A systematic biopsy should include a minimum of 12 cores
  • Various templates employing these principles exist for transrectal and transperineal approaches.
• For biopsy-naïve patients with abnormal lesions on prostate MRI, perform targeted biopsies and may also perform a systematic template biopsy.
  • Adding a systematic biopsy to the target only approach
    • Advantage:
      • Optimizes cancer yield, potentially finding more GG2+ cancer
        • Incremental yield of off-target biopsy samples may be influenced by the sampling error associated with software image registration at targeted biopsy
    • Disadvantages:
      • Potentially finding more GG1 cancer
      • May increase patient discomfort and other biopsy-associated complications due to larger number of cores
• Software registration of MRI and ultrasound images during fusion biopsy may be used, when available.
  • Targeted prostate biopsy of a visible lesion on mpMRI can be performed using software-based registration of mpMRI images and real-time ultrasound or cognitive registration.
    • Conflicting evidence on cancer detection rates comparing software-based vs. cognitive registration
    • Disadvantages of software based fusion biopsy program:
      • Technical issues (e.g., software bugs, system crashes)
      • Operator error
      • Unusual anatomy (e.g., large prostates, previous transurethral resections of the prostate).
        • The ability to perform cognitive fusion techniques using anatomic fiducial markers such as intraprostatic cysts may augment software-based fusion approaches in some cases such as to minimize the risk of misregistration.
    • Clinicians who adopt the cognitive fusion technique exclusively should undergo advanced training in MRI interpretation to optimize cancer detection.
• ≥2 needle biopsy cores per target should be obtained in patients with suspicious prostate lesion(s) on MRI.
  • ≥2 cores per target provides the most reproducible and accurate cancer detection rate.
    • The optimal number of biopsy cores per MRI target may differ based on multiple factors including
      • Patient characteristics (e.g., age, PSA, biopsy naïve versus prior biopsy)
      • Target characteristics (e.g., size, location, PIRADS classification)
      • Biopsy approach/technique (e.g., software fusion versus cognitive fusion, transrectal vs. transperineal).
    • The incremental value in cancer detection is diminished after obtaining >3 cores per target.
  • For prostate cancer risk group stratification, all cores from the same MRI target should be considered as a single core.

Approach

• Transrectal or transperineal biopsy route may be used when performing a biopsy.
  • Cancer detection rates associated with transrectal versus transperineal biopsy route are not significantly different.
  • Advantages of transperineal approach
    • May detect anterior and apical cancers at a higher rate
      • Prospective, randomized data are lacking and existing data are contradictory.
    • Lower risk of infection
      • Prospective, randomized data are lacking to make a definitive conclusion.
  • Advantages of transrectal approach
    • Patient preference/comfort
    • Patient cannot be placed into the lithotomy position
    • Clinician training/experience or lack of appropriate equipment for the transperineal approach.
  • Transperineal biopsies may have some value in patients (3):
    1. Infectious complications with a prior biopsy
    2. Higher risk for biopsy-related infection
    3. Anterior lesions that may not be as easily accessible transrectally

Repeat biopsy

• If prostate biopsy demonstrates
  • Malignancy: discuss management of localized prostate cancer (+/- staging studies, if applicable)
  • High-grade Prostatic Intraepithelial Neoplasia
    • If focal (one core): should not perform immediate repeat biopsy.
      • Risk of any cancer detected (not just high-grade) in subsequent biopsies is 20-30%, which is the same risk following an initial benign biopsy.
    • Multifocal: may proceed with additional risk evaluation.
      • Risk of GG2+ detection in repeat biopsies of patients with multifocal HGPIN is ≈30%, which is not higher than in those without this finding.
      • Repeat biopsy after multifocal HGPIN should be based on PSA and DRE evolution, and mpMRI findings.
  • Atypia
    • Atypical small acinar proliferation (ASAP): should perform additional testing.
      • ASAP alone on needle biopsy is associated with a 30-50% risk of prostate cancer detection on repeat biopsy, with ≈10-20% of these being GG2+.
      • Additional testing may include repeat systematic needle biopsy with consideration of mpMRI +/- targeted biopsy, PSA, and biomarkers (serum- or urine-based)
    • Atypical intraductal proliferation (AIP): should perform additional testing.
      • AIP describes lesions with greater architectural complexity and/or cytologic atypia than would be expected in HGPIN but lacking definitive criteria for the diagnosis of intraductal carcinoma (IDC-P). AIP encompasses many of the lesions formerly designated cribriform HGPIN, exhibiting loose cribriform architecture with moderate cytologic atypia, but lacking marked pleomorphism or necrosis.
      • AIP, as either the sole finding or together with GG1 cancer only, warrants additional testing, which may include early repeat systematic needle biopsy or MRI +/- targeted biopsy. The timing of additional testing should be based on reassessment of risk
  • Negative: reassess risk of undetected or future development of GG2+ disease
    • At the time of re-evaluation after negative biopsy, clinicians should use a risk assessment tool that incorporates the protective effect of prior negative biopsy.
      • The guideline recommends utilizing validated risk calculators, particularly calculators that incorporate previous negative biopsy and mpMRI use in the repeat biopsy setting.
        • ERSPC
        • PCPT V2
        • PBCG
      • PSA level alone should not be used to decide whether to repeat the prostate biopsy in patients with a previous negative biopsy.
    • Based on risk assessment, SDM whether to
      • Discontinue screening
        • Screening should not be discontinued based solely on a negative prostate biopsy.
      • Continue screening
        • If continuing screening after a negative biopsy, patient should be re-evaluated within the normal screening interval (2-4 years) or sooner, depending on risk of clinically significant prostate cancer and life expectancy.
      • Perform adjunctive testing for early reassessment of risk.
        • If concern remains elevated for GG2+ based on PSA density, previous MRI findings, or other factors, consider adjunctive testing (blood, urine, or tissue tests), or MRI (if not previously performed) to further risk stratify the patient if results are likely to influence the decision regarding repeat biopsy or otherwise substantively change the patient’s management.
          • Biomarker testing
            • After a negative initial biopsy in patients with low probability for harboring GG2+ prostate cancer, clinicians should not reflexively perform biomarker testing.
              • In patients with a negative biopsy, with low probability for GG2+ disease, it is unlikely that additional biomarker tests will be informative.
            • ConfirmMDx
              • The only tissue-based biomarker assessing epigenetic changes in GSTP1, APC, RASSF1 in negative biopsy tissue
              • Developed in the MATLOC study and validated in the DOCUMENT study to detect any prostate cancer and not specifically for GG2+ disease.
            • Unclear how to integrate the use of these tests with mpMRI in prostate cancer early detection.
            • It is imperative clinicians are familiar with biomarkers, understand what information or data each test provides, and consider whether additional information will impact management decisions before ordering a test.
          • MRI prior to repeat biopsy
            • In patients undergoing repeat biopsy with no prior prostate MRI, a prostate MRI should be obtained prior to biopsy.
            • In patients with indications for a repeat biopsy who
              • Do not have a suspicious lesion on MRI, may proceed with a systematic biopsy.
                • Factors that may identify patients likely to have clinically significant prostate cancer after a negative biopsy and a negative MRI include
                  • PSA density > 0.15 ng/mL
                  • PHI density value > 0.44
                  • PSA velocity of ≥0.27 ng/mL/year
              • Have a suspicious lesion on MRI, should perform targeted biopsies of the suspicious lesion and may also perform a systematic template biopsy.
                • Ultimately, the decision to perform systematic sampling in addition to target sampling should be based on an integrated evaluation of MRI factors such as quality and confidence in target presence and clinical factors such as PSA, technique of initial biopsy, and time since prior systematic biopsy.

References

• Wei, John T., et al. "Early Detection of Prostate Cancer: AUA/SUO Guideline Part I: Prostate Cancer Screening." The Journal of Urology (2023): 10-1097.
• Wei, John T., et al. "Early Detection of Prostate Cancer: AUA/SUO Guideline Part II: Considerations for a Prostate Biopsy." The Journal of Urology (2023): 10-1097.