BlueCross BlueShield of Tennessee Medical Policy Manual

Novel Biomarkers for the Diagnosis and Management of Prostate Cancer

Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018


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:

PSA exists not only in unbound but also in several complex forms. PSA3 (e.g., Progensa® PCA3 Assay) is a urine test for prostate tissue specific RNA that is overexpressed in 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 (biological mechanisms 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.





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


American Urological Association (AUA) / American Society for Radiation Oncology (ASTRO) / Society of Urologic Oncology (SUO). (2018, June). Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Retrieved August 29, 2019 from

BlueCross BlueShield Association. Evidence Positioning System. (12:2020). Genetic and protein biomarkers for the diagnosis and cancer risk assessment of prostate cancer (2.04.33). Retrieved March 8, 2021 from (67 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)

European Association of Urology (EAU). (2019). Guidelines on prostate cancer. Retrieved March 10, from

eviCore healthcare. (2021, January). Investigational and experimental molecular and genomic testing lab management guidelines. Retrieved March 11, 2021 from

eviCore healthcare. (2021, January). SelectMDx lab management guidelines. Retrieved March 11, 2021 from

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. (2021, January). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate cancer early detection. (V.1.2021). Retrieved March 8, 2021 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. (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.

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

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)




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