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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Pathology
Policy Number:030
Effective Date: 07/01/2019
Original Policy Date:06/09/2009
Last Review Date:12/10/2019
Date Published to Web: 11/01/2018
Subject:
Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Various genetic and protein biomarkers are associated with prostate cancer. These tests have the potential to improve the accuracy of differentiating between which men should undergo prostate biopsy and which rebiopsy after a prior negative biopsy. This policy addresses these types of tests for cancer risk assessment. Testing to determine cancer aggressiveness after a tissue diagnosis of cancer is addressed in a separate policy on 'Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management' (Policy #096 in the Pathology Section).

PopulationsInterventionsComparatorsOutcomes
Individuals:
    • Who are being considered for initial prostate biopsy
Interventions of interest are:
    • Testing for genetic and protein biomarkers of prostate cancer
Comparators of interest are:
    • Standard clinical examination including measurement of percent free prostate-specific antigen
Relevant outcomes include:
    • Overall survival
    • Disease-specific survival
    • Test validity
    • Resource utilization
    • Quality of life
Individuals:
    • Who are being considered for repeat prostate biopsy
Interventions of interest are:
    • Testing for genetic and protein biomarkers of prostate cancer
Comparators of interest are:
    • Standard clinical examination including measurement of percent free prostate-specific antigen
Relevant outcomes include:
    • Overall survival
    • Disease-specific survival
    • Test validity
    • Resource utilization
    • Quality of life

BACKGROUND

Prostate Cancer

Prostate cancer is the most common cancer, and the second most common cause of cancer death in men, with a predicted 174650 incidence cases and 31620 deaths expected in the U. S. in 2019.1,

Prostate cancer is a complex, heterogeneous disease, ranging from microscopic tumors unlikely to be life-threatening to aggressive tumors that can metastasize, leading to morbidity or death. Early localized disease can usually be treated with surgery and radiotherapy, although active surveillance may be adopted in men whose cancer is unlikely to cause major health problems during their lifespan or for whom the treatment might be dangerous. In patients with inoperable or metastatic disease, treatment consists of hormonal therapy and possibly chemotherapy. The lifetime risk of being diagnosed with prostate cancer for men in the U. S. is approximately 16%, while the risk of dying of prostate cancer is 3%.2, African American men have the highest prostate cancer risk in the U. S.; the incidence of prostate cancer is about 60% higher and the mortality rate is more than 2 to 3 times greater than that of white men.3, Autopsy results have suggested that about 30% of men age 55 and 60% of men age 80 who die of other causes have incidental prostate cancer4,, indicating that many cases of cancer are unlikely to pose a threat during a man’s life expectancy.

Grading

The most widely used grading scheme for prostate cancer is the Gleason system.5, It is an architectural grading system ranging from 1 (well-differentiated) to 5 (poorly-differentiated); the score is the sum of the primary and secondary patterns. A Gleason score of 6 or less is low-grade prostate cancer that usually grows slowly; 7 is an intermediate grade; 8 to 10 is high-grade cancer that grows more quickly. A revised prostate cancer grading system has been adopted by the National Cancer Institute and the World Health Organization.6, A cross-walk of these grading systems is shown in Table 1.

Table 1. Prostate Cancer Grading Systems
Grade GroupGleason Score (Primary and Secondary Pattern)Cells
16 or lessWell-differentiated (low grade)
27 (3 + 4)Moderately differentiated (moderate grade)
37 (4 + 3)Poorly differentiated (high grade)
48Undifferentiated (high grade)
59-10Undifferentiated (high grade)
Numerous genetic alterations associated with the development or progression of prostate cancer have been described, with the potential for the use of these molecular markers to improve the selection process of men who should undergo prostate biopsy or rebiopsy after an initial negative biopsy.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. The following laboratories are certified under the Clinical Laboratory Improvement Amendments: BioReference Laboratories and GenPath Diagnostics (subsidiaries of OPKO Health; 4Kscore®), ARUP Laboratories, Mayo Medical Laboratories, LabCorp, BioVantra, others (PCA3 assay), Clinical Research Laboratory (Prostate Core Mitomic Test™), MDx Health (SelectMDx, ConfirMDx), Innovative Diagnostics (phiTM), and ExoDx® Prostate (Exosome Diagnostics). To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

In February 2012, the Progensa® PCA3 Assay (Gen-Probe; now Hologic) was approved by the FDA through the premarket approval process. The Progensa PCA3 Assay has been approved by the FDA to aid in the decision for repeat biopsy in men 50 years or older who have had one or more negative prostate biopsies and for whom a repeat biopsy would be recommended based on the current standard of care. The Progensa PCA3 Assay should not be used for men with atypical small acinar proliferation on their most recent biopsy. FDA product code: OYM.

In June 2012, proPSA, a blood test used to calculate the Prostate Health Index (phi; Beckman Coulter) was approved by the FDA through the premarket approval process. The phi test is indicated as an aid to distinguish prostate cancer from a benign prostatic condition in men ages 50 and older with prostate-specific antigen levels of 4 to 10 ng/mL and with digital rectal exam findings that are not suspicious. According to the manufacturer, the test reduces the number of prostate biopsies. FDA product code: OYA.

Related Policies

  • Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management (Policy #096 in the Pathology Section)

Policy:
(NOTE: For services provided August 1, 2017 and after, Horizon Blue Cross Blue Shield of New Jersey collaborates with eviCore healthcare to conduct Medical Necessity Determination for certain molecular and genomic testing services for members enrolled in Horizon BCBSNJ fully insured products as well as Administrative Services Only (ASO) accounts that have elected to participate in the Molecular and Genomic Testing Program (“the Program”). Beginning August 1, 2017, the criteria and guidelines included in this policy apply to members enrolled in plans that have NOT elected to participate in the Program.

To access guidelines that apply for services provided August 1, 2017 and after to members enrolled in plans that HAVE elected to participate in the Program, please visit www.evicore.com/healthplan/Horizon_Lab.

For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)


1. 4Kscore testing is considered medically necessary when all of the following criteria are met:
    · No previous 4Kscore testing performed after the most recent negative biopsy when a result was successfully obtained, AND
    · No previous ConfirmMDx testing on the most recent negative biopsy when a result was successfully obtained, AND
    · Member is not under active surveillance for low stage prostate cancer, AND
    · Negative prostate biopsy within the past 24 months, AND
    · Member is considered at higher risk for prostate cancer by one or more of the following:
      o Family history of 1st degree relative with prostate cancer diagnosed younger than age 65 years, and/or
      o Family history of two or more first-degree relatives with prostate cancer diagnosed at any age, and/or
      o African American race, and/or
      o Known mutation in a gene associated with increased risk of prostate cancer (e.g., BRCA 1/2, HOXB13 (G84E mutation carriers), MLH1, MSH2, MSH6, PMS2, EPCAM), and/or
      o PSA level of greater than 10 ng/ml, and/or
      o PSA level increase of greater than 0.35 ng/ml/year if PSA level less than or equal to 10 ng/ml, and/or
      o PSA doubling time of less than 3 years, when initial PSA level is greater than or equal to 4 ng/ml and other causes of rising PSA (i.e., infection, inflammation) have been ruled out for individuals whose PSA doubling occurred in less than 2 years.

2. ConfirmMDx testing is considered medically necessary when all of the following criteria are met:
    · No previous ConfirmMDx testing on the same sample when a result was successfully obtained, AND
    · No previous 4Kscore testing performed after the most recent negative biopsy when a result was successfully obtained, AND
    · Member is not under active surveillance for low stage prostate cancer, AND
    · Negative prostate biopsy within the past 24 months, AND
    · Member is considered at higher risk for prostate cancer by one or more of the following:
      o Family history of 1st degree relative with prostate cancer diagnosed younger than age 65 years, and/or
      o Family history of two or more first-degree relatives with prostate cancer diagnosed at any age, and/or
      o African American race, and/or
      o Known mutation in a gene associated with increased risk of prostate cancer (e.g., BRCA 1/2, HOXB13 (G84E mutation carriers), MLH1, MSH2, MSH6, PMS2, EPCAM), and/or
      o PSA level of greater than 10 ng/ml, and/or
      o PSA level increase of greater than 0.35 ng/ml/year if PSA level less than or equal to 10 ng/ml, and/or
      o PSA doubling time of less than 3 years, when initial PSA level is greater than or equal to 4 ng/ml and other causes of rising PSA (i.e., infection, inflammation) have been ruled out for individuals whose PSA doubling occurred in less than 2 years.
3. Prostate cancer antigen 3 (PCA3) testing is considered medically necessary when all of the following criteria are met:
    · Age >50 years, AND
    · One or more previous negative prostate biopsies, AND
    · Continued clinical suspicion of prostate cancer based on DRE or elevation of PSA of >3 ng/mL, and for whom a repeat biopsy would be recommended by a urologist based on current standard of care, AND
    · Atypical small acinar proliferation (ASAP) was NOT identified on the most recent biopsy.

4. The following genetic and protein biomarkers for the diagnosis of prostate cancer are considered investigational:
      • Metabolomic profiles (eg, Prostarix™)
      • TMPRSS fusion genes
      • Candidate gene panels
      • Mitochondrial DNA mutation testing (eg, Prostate Core Mitomics Test™)
      • Prostate Health Index (phi)
      • HOXC6 and DLX1 testing (e.g., Select MDx)
      • PCA3, ERG, and SPDEF RNA expression in exosomes (e.g., ExoDx Prostate IntelliScore)
      • Autoantibodies ARF5, NKX3-1, 5'-UTR-BMI1, CEP 164, 3'-UTR-Ropporin, Desmocolin, AURKAIP-1, CSNK2A2 (e.g., Apinify).
5. Single nucleotide polymorphisms (SNPs) testing for cancer risk assessment of prostate cancer is considered investigational.

Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that the PROGENSA® PCA3 Assay is covered for certain limited diagnosis. For additional information and eligibility for PROGENSA® PCA3 Assay, refer to Local Coverage Determination (LCD): Biomarkers for Oncology (L35396). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46.

Noridian Healthcare Solutions, LLC, the Local Medicare Carrier for jurisdiction J-E, is providing limited coverage for the ConfirmMDx epigenetic assay for prostate cancer (MDxHealth, Irvine, CA) when LCD L36327 criteria is met. Coverage is limited to providers enrolled in the ConfirmMDx Certification and Training Registry (CTR) program. For additional information and eligibility, refer to Local Coverage Determination (LCD): MolDX-CDD: ConfirmMDx Epigenetic Molecular Assay (L36327). Available to be accessed at CMS Local Coverage Determinations by State Index search page: https://www.cms.gov/medicare-coverage-database/indexes/lcd-state-index.aspx.

There is no National Coverage Determination (NCD) or applicable Local Coverage Determination (LCD) for the below tests. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy for these tests:
• Metabolomic profiles (eg, Prostarix™)
• TMPRSS fusion genes
• Candidate gene panels
• Mitochondrial DNA mutation testing (eg, Prostate Core Mitomics Test™)
• Prostate Health Index (phi).

PROPRIETARY LABS (Labs that are the sole source for the diagnostic lab test)
For labs which are proprietary (that is, the sole source for the diagnostic lab test involved), Medicare Advantage Products will follow the Medicare Local Coverage Determination of the State where the proprietary lab is located.

Per FUTURE Local Coverage Determination (LCD):4Kscore Test Algorithm (L37792), effective 12/30/19, the 4Kscore test is covered for testing of men 45 years of age and older, prior to an initial biopsy or following a negative biopsy, when a confirmed* moderately elevated PSA (greater than 3 and less than 10 ng/mL; greater than or equal to 4 and less than 10 ng/mL in men greater than 75 years of age) is present and ALL of LCD L37792 criteria are met.

*PSA elevation should be verified after a few weeks under standardized conditions (e.g. no ejaculation, manipulations, and urinary tract infections, no medications such as 5á-reductase) in the same laboratory or other Clinical Laboratory Improvement Amendments (CLIA) approved laboratory before considering a biopsy.

For additional information and eligibility, refer to FUTURE Local Coverage Determination (LCD):4Kscore Test Algorithm (L37792) and FUTURE Local Coverage Article:Billing and Coding: 4Kscore Test Algorithm (A56653). Available at: Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370.

ExoDx Prostate IntelliScore (EPI) is a proprietary test. Per National Government Services, Inc., Local Medicare Contractor ( Medicare Contractor Jurisdiction J- K), Local Coverage Determination (LCD): Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis (L37733) effective 12/01/19:

ExoDx Prostate IntelliScore (EPI) is covered once for men ≥ 50 years old prior to initial biopsy, with confirmed* moderately elevated PSA (>3 and <10 ng/mL; ≥4 and <10 ng/mL in men >75 years old) with BOTH of the following when %fPSA, PHI, 4Kscore or EPI biomarker test have not been performed prior:
    1. No other relative indication for prostate biopsy including ANY of the following:
        a. DRE suspicious for cancer
        b. Persistently elevated PSA
        c. Positive multiparametric MRI (if done)
        d. Other major risk factor for prostate cancer including:
            i. Ethnicity at higher risk for prostate cancer
            ii. First-degree relative with prostate cancer
            iii. High-penetrance prostate cancer risk gene(s) per NCCN (if known)
    2. No other relative contraindication for prostate biopsy including ANY of the following:
        a. <10 year life expectancy
        b. Benign disease not ruled out

*PSA elevation should be confirmed after a few weeks under standardized conditions (i.e., no ejaculation, manipulations, and urinary tract infections) in the same laboratory before considering a biopsy.

For additional information and eligibility for ExoDx Prostate IntelliScore (EPI), refer to:

Local Coverage Determination (LCD): Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis (L37733) effective 12/01/19. Available to be accessed at Local Coverage Determination by State Index at https://www.cms.gov/medicare-coverage-database/indexes/lcd-state-index.aspx

Local Coverage Article: Billing and Coding: Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis (A56609). Available to be accessed at Local Coverage Determination by State Index at https://www.cms.gov/medicare-coverage-database/indexes/lcd-state-index.aspx
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer
Gene-Based Tests for Screening, Detection, and/or Management of Prostate Cancer
PCA3, Diagnosis of Prostate Cancer
Prostate Cancer, PCA Test
uPM3
LabCorp Hypermethylated GSTP1 (“Glutathione S-transferase Gene [GSTP1, pi-class]) Methylation Assay
Hypermethylated GSTP1 (“Glutathione S-transferase Gene [GSTP1, pi-class]) Methylation Assay
GSTP1 (“Glutathione S-transferase Gene [GSTP1, pi-class] Methylation Assay)
Glutathione S-transferase Gene Methylation Assay
ConfirmMDx® (MDxHealth), Prostate Cancer
MDxHealth (ConfirmMDx®), Prostate Cancer
Kallikrein Markers, Diagnosis of Prostate Cancer
4Kscore Test, Diagnosis of Prostate Cancer
Metabolic Profiles, Diagnosis of Prostate Cancer
Prostarix, Diagnosis of Prostate Cancer
TMPRSS Fusion Genes, Diagnosis of Prostate Cancer
Candidate Gene Panels, Diagnosis of Prostate Cancer
Mitochondrial DNA Mutation Testing, Diagnosis of Prostate Cancer
Prostate Core Mitomics Test, Diagnosis of Prostate Cancer
Gene Hypermethylation Testing, Diagnosis of Prostate Cancer
Prostate Cancer, Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment
SNPs Testing, Prostate Cancer Risk Assessment
Single Nucleotide Polymorphisms, Prostate Cancer Risk Assessment
phi (Prostate Health Index)
Prostate Health Index (phi)
Select MDx
ExoDx Prostate IntelliScore
Apinify

References:
1. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: prostate cancer early detection. http://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NCCN clinical practice guidelines in oncology: prostate cancer early detection V.2.2019. © National Comprehensive Cancer Network rights reserved. Accessed October 14, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

2. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014. Bethesda, MD: National Cancer Institute; 2017.

3. Odedina FT, Akinremi TO, Chinegwundoh F, et al. Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa. Infect Agent Cancer. Feb 10 2009;4 Suppl 1:S2. PMID 19208207.

4. Bell KJ, Del Mar C, Wright G, et al. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int J Cancer. Oct 1 2015;137(7):1749-1757. PMID 25821151.

5. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep. Mar 1966;50(3):125-128. PMID 5948714.

6. National Cancer Institute. SEER Database. 2018; https://seer.cancer.gov/seerinquiry/index.php?page=view&id=20170036&type=q. Accessed October 26, 2018.

7. Blue Cross and Blue Shield Technology Evaluation Center (TEC). Special report: recent developments in prostate cancer genetics and genetic testing. TEC Assessments. 2008;Volume 23:Tab 7. PMID.

8. Hoogendam A, Buntinx F, de Vet HC. The diagnostic value of digital rectal examination in primary care screening for prostate cancer: a meta-analysis. Fam Pract. Dec 1999;16(6):621-626. PMID 10625141.

9. Gosselaar C, Roobol MJ, Roemeling S, et al. The role of the digital rectal examination in subsequent screening visits in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam. Eur Urol. Sep 2008;54(3):581-588. PMID 18423977.

10. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate- specific antigen level < or =4.0 ng per milliliter. N Engl J Med. May 27 2004;350(22):2239-2246. PMID 15163773.

11. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. Apr 25 1991;324(17):1156-1161. PMID 1707140.

12. Aus G, Bergdahl S, Lodding P, et al. Prostate cancer screening decreases the absolute risk of being diagnosed with advanced prostate cancer--results from a prospective, population-based randomized controlled trial. Eur Urol. Mar 2007;51(3):659-664. PMID 16934392.

13. Buzzoni C, Auvinen A, Roobol MJ, et al. Metastatic prostate cancer incidence and prostate-specific antigen testing: new insights from the European randomized study of screening for prostate cancer. Eur Urol. Nov 2015;68(5):885-890. PMID 25791513.

14. Arnsrud Godtman R, Holmberg E, Lilja H, et al. Opportunistic testing versus organized prostate-specific antigen screening: outcome after 18 years in the Goteborg randomized population-based prostate cancer screening trial. Eur Urol. Sep 2015;68(3):354-360. PMID 25556937.

15. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. Aug 2010;11(8):725-732. PMID 20598634.

16. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. Mar 26 2009;360(13):1320-1328. PMID 19297566.

17. Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. Mar-Apr 2010;60(2):70-98. PMID 20200110.

18. Rosario DJ, Lane JA, Metcalfe C, et al. Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study. BMJ. Jan 09 2012;344:d7894. PMID 22232535.

19. Liss M, Ehdaie B, Loeb S, et al. The Prevention and Treatment of the More Common Complications Related to Prostate Biopsy Update. 2012; updated 2016; https://www.auanet.org/guidelines/prostate-needle-biopsy- complications. Accessed October 23, 2017.

20. Lavallee LT, Binette A, Witiuk K, et al. Reducing the harm of prostate cancer screening: repeated prostate- specific antigen testing. Mayo Clin Proc. Jan 2016;91(1):17-22. PMID 26688045.

21. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. Jan 2017;67(1):7-30. PMID 28055103.

22. Ruiz-Aragon J, Marquez-Pelaez S. [Assessment of the PCA3 test for prostate cancer diagnosis: a systematic review and meta-analysis]. Actas Urol Esp. Apr 2010;34(4):346-355. PMID 20470697.

23. Mackinnon AC, Yan BC, Joseph LJ, et al. Molecular biology underlying the clinical heterogeneity of prostate cancer: an update. Arch Pathol Lab Med. Jul 2009;133(7):1033-1040. PMID 19642730.

24. Partin AW, Brawer MK, Subong EN, et al. Prospective evaluation of percent free-PSA and complexed-PSA for early detection of prostate cancer. Prostate Cancer Prostatic Dis. Jun 1998;1(4):197-203. PMID 12496895.

25. Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst. Apr 19 2006;98(8):529-534. PMID 16622122.

26. van Vugt HA, Roobol MJ, Kranse R, et al. Prediction of prostate cancer in unscreened men: external validation of a risk calculator. Eur J Cancer. Apr 2011;47(6):903-909. PMID 21163642.

27. Rosenkrantz AB, Verma S, Choyke P, et al. Prostate magnetic resonance imaging and magnetic resonance imaging targeted biopsy in patients with a prior negative biopsy: a consensus statement by AUA and SAR. J Urol. Dec 2016;196(6):1613-1618. PMID 27320841.

28. Russo GI, Regis F, Castelli T, et al. A systematic review and meta-analysis of the diagnostic accuracy of Prostate Health Index and 4-Kallikrein Panel Score in predicting overall and high-grade prostate cancer. Clin Genitourin Cancer. Aug 2017;15(4):429-439 e421. PMID 28111174.

29. Parekh DJ, Punnen S, Sjoberg DD, et al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol. Sep 2015;68(3):464-470. PMID 25454615.

30. Stattin P, Vickers AJ, Sjoberg DD, et al. Improving the specificity of screening for lethal prostate cancer using prostate-specific antigen and a panel of kallikrein markers: a nested case-control study. Eur Urol. Aug 2015;68(2):207-213. PMID 25682340.

31. Loeb S, Shin SS, Broyles DL et al. Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer. BJU Int., 2016 Oct 16;120(1). PMID 27743489.

32. Konety B, Zappala SM, Parekh DJ, et al. The 4Kscore(R) test reduces prostate biopsy rates in community and academic urology practices. Rev Urol. 2015;17(4):231-240. PMID 26839521.

33. Pecoraro V, Roli L, Plebani M, et al. Clinical utility of the (-2)proPSA and evaluation of the evidence: a systematic review. Clin Chem Lab Med. Jul 1 2016;54(7):1123-1132. PMID 26609863.

34. Catalona WJ, Partin AW, Sanda MG et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J. Urol., 2011 Mar 23;185(5). PMID 21419439.

35. Tosoian JJ, Druskin SC, Andreas D, et al. Use of the Prostate Health Index for detection of prostate cancer: results from a large academic practice. Prostate Cancer and Prostatic Diseases. 2017//06/ 2017;20(2):228-233.

36. White J, Shenoy BV, Tutrone RF, et al. Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting. Prostate Cancer Prostatic Dis. Apr 2018;21(1):78-84. PMID 29158509.

37. Sanda MG, Feng Z, Howard DH, et al. Association between combined TMPRSS2:ERG and PCA3 RNA urinary testing and detection of aggressive prostate cancer. JAMA Oncol. Aug 1 2017;3(8):1085-1093. PMID 28520829.

38. Tomlins SA, Day JR, Lonigro RJ, et al. Urine TMPRSS2:ERG Plus PCA3 for individualized prostate cancer risk assessment. Eur Urol. Jul 2016;70(1):45-53. PMID 25985884.

39. Ankerst DP, Goros M, Tomlins SA et al. Incorporation of Urinary Prostate Cancer Antigen 3 and TMPRSS2:ERG into Prostate Cancer Prevention Trial Risk Calculator. Eur Urol Focus, 2018 Feb 10;5(1). PMID 29422418.

40. Van Neste L, Hendriks RJ, Dijkstra S, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol. Nov 2016;70(5):740-748. PMID 27108162.

41. McKiernan J, Donovan MJ, O'Neill V, et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol. Jul 1 2016;2(7):882-889. PMID 27032035.

42. Schipper M, Wang G, Giles N, et al. Novel prostate cancer biomarkers derived from autoantibody signatures. Transl Oncol. Apr 2015;8(2):106-111. PMID 25926076.

43. Cui Y, Cao W, Li Q, et al. Evaluation of prostate cancer antigen 3 for detecting prostate cancer: a systematic review and meta-analysis. Sci Rep. May 10 2016;6:25776. PMID 27161545.

44. Nicholson A, Mahon J, Boland A, et al. The clinical effectiveness and cost-effectiveness of the PROGENSA(R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation. Health Technol Assess. Oct 2015;19(87):1-192. PMID 26507078.

45. Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol. Dec 20 2014;32(36):4066-4072. PMID 25385735.

46. Vickers AJ, Gupta A, Savage CJ, et al. A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening. Cancer Epidemiol Biomarkers Prev. Feb 2011;20(2):255-261. PMID 21148123.

47. Ruffion A, Devonec M, Champetier D, et al. PCA3 and PCA3-based nomograms improve diagnostic accuracy in patients undergoing first prostate biopsy. Int J Mol Sci. 2013;14(9):17767-17780. PMID 23994838.

48. Ruffion A, Perrin P, Devonec M, et al. Additional value of PCA3 density to predict initial prostate biopsy outcome. World J Urol. Aug 2014;32(4):917-923. PMID 24500192.

49. Merdan S, Tomlins SA, Barnett CL, et al. Assessment of long-term outcomes associated with urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion at repeat biopsy. Cancer. Nov 15 2015;121(22):4071-4079. PMID 26280815.

50. Djavan B, Waldert M, Zlotta A, et al. Safety and morbidity of first and repeat transrectal ultrasound guided prostate needle biopsies: results of a prospective European prostate cancer detection study. J Urol. Sep 2001;166(3):856-860. PMID 11490233.

51. Lujan M, Paez A, Santonja C, et al. Prostate cancer detection and tumor characteristics in men with multiple biopsy sessions. Prostate Cancer Prostatic Dis. 2004;7(3):238-242. PMID 15289810.

52. Stewart GD, Van Neste L, Delvenne P, et al. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. J Urol. Mar 2013;189(3):1110- 1116. PMID 22999998.

53. Partin AW, Van Neste L, Klein EA, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol. Oct 2014;192(4):1081-1087. PMID 24747657.

54. Waterhouse RL, Jr., Van Neste L, Moses KA, et al. Evaluation of an Epigenetic Assay for predicting repeat prostate biopsy outcome in African American men. Urology. Apr 13 2018. PMID 29660369.

55. Van Neste L, Partin AW, Stewart GD, et al. Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. Prostate. Sep 2016;76(12):1078-1087. PMID 27121847.

56. Partin AW, W VANC, Trock BJ, et al. Clinical evaluation of an epigenetic assay to predict missed cancer in prostate biopsy specimens. Trans Am Clin Climatol Assoc. 2016;127:313-327. PMID 28066067.

57. Food and Drug Administration. Summary of Safety and Effectiveness Data. PMA P090026. Quantitative test for determination of [-2]proPSA levels. Silver Spring, MD: Food and Drug Administration; 2012.

58. Aubry W, Lieberthal R, Willis A, et al. Budget impact model: epigenetic assay can help avoid unnecessary repeated prostate biopsies and reduce healthcare spending. Am Health Drug Benefits. Jan 2013;6(1):15-24. PMID 24991343.

59. Robinson K, Creed J, Reguly B, et al. Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay. Prostate Cancer Prostatic Dis. Jun 2010;13(2):126-131. PMID 20084081.

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62. Xiao K, Guo J, Zhang X, et al. Use of two gene panels for prostate cancer diagnosis and patient risk stratification. Tumour Biol. Aug 2016;37(8):10115-10122. PMID 26820133.

63. American Urological Association. Detection of prostate cancer. 2013; http://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm. Accessed August 17, 2017.

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

    81313
    81479
    81539
    81551
    81599
    0005U
    0021U
HCPCS

* CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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