Biomarkers are "chemicals" found in blood, urine or tissue that can indicate both normal and abnormal processes. One of the most well-known biomarker tests is the PSA, which detects abnormally high blood levels of prostate specific antigen to screen for cancer. Although PSA testing can help detect prostate cancer at an early stage, having an elevated PSA (> 3 mg/ml) does not mean that an individual has cancer.

The use of PSA testing has traditionally focused on the amount of PSA found circulating in the free or unbound (fPSA) form. When expressed as a ratio of total prostate-specific antigen (tPSA) to free prostate-specific antigen, it can improve early detection, staging and monitoring of prostate cancer. The proportion of free PSA to total PSA, using a cut-off of 25%, is more sensitive and specific than the traditional PSA test.

Other combination serum tests that have a high predictive value are:

The Prostate Health Index (PHI) is a serum test for PSA, free PSA and p2PSA where results are combined to calculate the probability of prostate cancer.
The Kallikrein markers (i.e., 4Kscore) test measures fPSA, tPSA, human kallikrein-related peptidase 2 (hK2) and intact PSA. This test also considers age, digital rectal exam results and prior biopsy status.

PSA exists not only in unbound but also in several complex forms. Prostate cancer antigen 3 (PCA3) is a non-protein-coding messenger RNA (mRNA) that is highly overexpressed in prostate cancer tissue. A urine test was developed to measure PCA3 levels (e.g., Progensa® PCA3 Assay) given the strong association between PCA3 mRNA levels and prostate cancer. The PCA3 has a high negative predictive value for men with a prior negative biopsy using a PCA3 cut-off score of >25.

An epigenetic (biologic mechanism that activates/de-activates a gene) assay that may improve the stratification of individuals being considered for repeat prostate biopsy is testing for hypermethylation of GSTP1, APC, and RASSF1 (e.g., ConfirmMDx®) on the tissue from a biopsied prostate tumor. This test may help determine which individuals should consider subsequent biopsies.

POLICY

Novel biomarker testing for the diagnosis and management of prostate cancer is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
All other novel biomarker testing for the screening, detection, stratification, and management of prostate cancer are considered investigational.

MEDICAL APPROPRIATENESS

Novel biomarker testing for the diagnosis and management of prostate cancer is considered medically appropriate if ANY ONE of the following are met:
- Prior to initial biopsy if ALL of the following are met:
- - PSA greater than 3 ng/mL
  - ONE or more of the following biomarker tests are used:
  - - Percent free PSA (%fPSA)
    - Prostate Health Index (PHI)
    - Kallikrein markers (i.e., 4Kscore)
- Individual with at least one negative biopsy and ALL of the following are met:
- - Clinical suspicion of prostate cancer
  - ONE or more of the following tests are used:
  - - Percent free PSA (%fPSA)
    - Prostate Health Index (PHI)
    - Kallikrein markers (i.e., 4Kscore)
    - PCA3
    - GSTP1, APC, and RASSF1 hypermethylation testing (e.g., ConfirmMDx®)

IMPORTANT REMINDERS

Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g. statement.
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan or government program (e.g., TennCare), the express terms of the health plan or government program will govern.

ADDITIONAL INFORMATION

While the list of other biomarker tests (e.g., SelectMDx™, ExoDx™ Prostate [IntelliScore], Mi-Prostate™ Score) is growing rapidly, validation through further testing is needed.

SOURCES

American Urological Association (AUA) / American Society for Radiation Oncology (ASTRO) / Society of Urologic Oncology (SUO). (2018, June). Early detection of prostate cancer: AUA guideline. Retrieved August 29, 2019 from www.auanet.org/guidelines.

American Urological Association (AUA) / American Society for Radiation Oncology (ASTRO) / Society of Urologic Oncology (SUO). (2022). Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Retrieved February 16, 2023 from www.auanet.org/guidelines.

BlueCross BlueShield Association. Evidence Positioning System. (12:2022). Genetic and protein biomarkers for the diagnosis and cancer risk assessment of prostate cancer (2.04.33). Retrieved February 16, 2023 from https://www.evidencepositioningsystem.com/. (74 articles and/or guidelines reviewed)

Bryant, R. J., Sjoberg, D. D., Vickers, A. J., Robinson, M. C., Kumar, R., Marsden, L., et al. (2015). Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT Study. Journal of the National Cancer Institute, 107 (7), 1-9. (Level 4 evidence)

Carlsson, S., Maschino, A., Schroder, F., Bangma, C., Steyerberg, E., van der Kwast, T., et al. (2013). Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European randomized study of screening for prostate cancer section Rotterdam. European Urology, 64 (5), 693-699. (Level 2 evidence)

CMS.gov: Centers for Medicare & Medicaid Services. Palmetto GBA. (2022, March). MolDX: 4Kscore® assay. (LCD ID L36763). Retrieved February 16, 2023 from https://www.cms.gov.

European Association of Urology (EAU). (2019). Guidelines on prostate cancer. Retrieved March 10, 2021 from https://uroweb.org.

Fenton, J.J., Weyrich, M.S., Durbin, S., Liu, Y., Bang, H., & Melnikow, J. (2018). Prostate-specific antigen-based screening for prostate cancer evidence report and systematic review for the US preventive service task force. JAMA, 319 (18), 1901-1913. (Level 1 evidence)

Konety, B., Zappala, S. M., Parekh, D. J., Osterhout, D., Schock, J., Chudler, R. M., (2015). The 4Kscore® Test reduces prostate biopsy rates in community and academic urology practices. Reviews in Urology, 17 (4), 231-240. (Level 1 evidence)

National Comprehensive Cancer Network. (2024, March). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate cancer Early Detection. (V.2.2024). Retrieved June 7, 2024 from the National Comprehensive Cancer Network.

Punnen, S., Pavan, N., & Parekh, D. (2015). Finding the wolf in sheep’s clothing: the 4Kscore is a novel blood test that can accurately identify the risk of aggressive prostate cancer. Reviews in Urology, 17 (1), 3-13. (Level 2 evidence)

Tutrone, R., Donovan, M.J., Torkler, P., Tadigotla, V., Mclain, T., & Noerholm, M., et al. (2020). Clinical utility of the exosome based ExoDx prostate (IntelliScore) EPI test in men presenting for initial biopsy with a PSA 2–10 ng/mL Prostate Cancer Prostatic Diseases. 23 (4), 607-614. [E-pub ahead of print] doi: 10.1038/s41391-020-0237-z. (Level 1 evidence)

U. S. Food and Drug Administration. (2012, February). Center for Devices and Radiological Health. Pre-market approval decisions for February 2012 (Progensa® PCA3 Assay). Retrieved August 26, 2016 from http://www.accessdata.fda.gov.

Wei, J. T., Feng, Z., Partin, A. W., Brown, E., Thompson, I., Sokoll, L., (2014). Can urinary PCA3 supplement PSA in the early detection of prostate cancer? Journal of Clinical Oncology, 32 (36), 4066-4072. (Level 1 evidence)

ORIGINAL EFFECTIVE DATE: 11/1/2004

MOST RECENT REVIEW DATE: 7/11/2024

ID_BT

Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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