BlueCross BlueShield of Tennessee Medical Policy Manual

Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer


Prostate cancer is a complex, heterogeneous disease. At the extremes of the spectrum, if left untreated, some prostate cancers behave aggressively, metastasize quickly, and cause mortality, while others are indolent and never progress to cause harm. Current challenges in prostate cancer care are risk assessment; early and accurate detection; monitoring low-risk patients undergoing surveillance only; prediction of recurrence after initial treatment; detection of recurrence after treatment; and assessing efficacy of treatment for advanced disease.

In response to the need for better biomarkers for risk assessment, diagnosis, and prognosis, a variety of exploratory research is ongoing. Some products of this work have already been translated or are in the process of being translated into commercially available tests, including:


See also:




Most men diagnosed with prostate cancer have a tumor that is unlikely to pose a threat to their life expectancies. A recent systematic analysis reported that up to 60% of prostate cancers diagnosed can be safely observed without a need for immediate treatment. However, in the U.S., because of the concern for possible undergrading of prostate cancer due to biopsy sampling error, 90% of men diagnosed with prostate cancer undergo radical prostatectomy and/or radiation, and approximately 66% will be confirmed to have indolent Gleason score 6 prostate cancers, a significant problem with overtreatment.

Detection of aggressive prostate cancer permits urologists to diagnose and treat those men most likely to benefit from aggressive intervention to avoid premature death. Conversely, those men harboring non-life-threatening disease would be able to avoid unnecessary interventions and subsequent poor quality of life and unnecessary costs.


Aubin, S. M., Reid, J., Sarno, M.J., Blase, A., Aussie, J., Rittenhouse, H., et al. (2010). PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial. Journal of Urology, 184 (5), 1947-1952. Abstract retrieved August 18, 2016 from PubMed database.

Auprich, M., Bjartell, A., Chun, F., de la Taille, A., Freedland, S., Haese, A., et al. (2011). Contemporary role of prostate cancer antigen 3 in the management of prostate cancer. European Urology, 60 (5), 1045-1054. Abstract retrieved August 18, 2016 from PubMed database.

BlueCross BlueShield Association. Medical Policy Reference Manual. (4:2015). Genetic and protein biomarkers for the diagnosis and cancer risk assessment of prostate cancer (2.04.33). Retrieved December 23, 2015 from BlueWeb. (77 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)

Canfield, S. E., Kibel, A. S., Kemeter, M. J., Febbo, P. G., Lawrence, H. J., & Moul, J. W. (2014). A guide for clinicians in the evaluation of emerging molecular diagnostics for newly diagnosed prostate cancer. Reviews in Urology, 16 (4), 172-180.

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.

Crawford, E. D., Shore, N. D., & Ventii, K. (2014, February). New biomarkers in prostate cancer. Oncology, 135-145.

Cullen, J., Rosner, I, L., Brand, T. C., Zhang, N., Tsiatis, A. C., Moncur, J., et al. (2014). A biopsy-based 17-gene genomic prostate score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer. European Urology, 0 (0).

Gittelman, M. C., Hertzman, B., Bailen, J., Williams, T., Kozoil, I., Henderson, R. J., et al. (2013). PCA3 molecular urine test as a predictor of repeat prostate biopsy outcome in men with previous negative biopsies: a prospective multicenter clinical study. Journal of Urology, 190 (1), 64-69. Abstract retrieved August 18, 2016 from PubMed database.

Klein, E. A., Cooperberg, M. R., Magi-Galluzzi, C., Simko, J. P., Falzarano, S. M., Maddala, T., et al. (2014). A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. European Urology, 66, 550-560.

Knezevic, D., Goddard, A., Natraj, N., Cherbavaz, D., Clark-Langone, K., Snable, J., et al. (2013). Analytical validation of the Oncotype DX prostate cancer assay - a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics, 14, 690.

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. (2016, February). NCCN clinical practice guidelines in oncology™. Prostate cancer early detection. (V.2.2016). Retrieved August 15, 2016 from   

Parekh, D., Punnen, S., Sjoberg, D., Asroff, S., Bailen, J., Cochran, J., et al. (2015). A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. European Urology, 68, 464-470. Abstract retrieved August 18, 2016 from PubMed database.

Partin, A. W., Van Neste, L., Klein, E. A., Marks, L. S., Gee, J. R., Troyer, D. A., et al. (2014). Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. Journal of Urology, 192 (4), 1081-1087. Abstract retrieved August 18, 2016 from PubMed database.

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.

Stewart, G. D., Van Neste, L., Delvenne, P., Delrée, P., Delga, A., McNeill, S. A., et al. (2013). Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. Journal of Urology, 189 (3), 1110-1116. Abstract retrieved August 18, 2016 from PubMed database.

U. S. Food and Drug Administration. (2012, February). Center for Devices and Radiological Health. Pre-market approval decisions for February 2012. 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)

Winifred S. Hayes, Inc. Genetic Test Evaluation (GTE) Report. (2014, June; last update search May 2015). PCA3 detection test for prostate cancer. Retrieved August 19, 2016 from .(96 articles and/or guidelines reviewed)




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