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

POLICY NUMBER

A.2.04.33

DESCRIPTION

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 the Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management medical policy. Magnetic resonance imaging-targeted biopsy of suspicious lesions is assessed in the Magnetic Resonance Imaging-Targeted Biopsy of the Prostate medical policy.

Prostate Cancer

Prostate cancer is the most common cancer, and the second most common cause of cancer death in men. 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%. 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. Autopsy results have suggested that about 30% of men over the age of 55 and 60% of men over the age of 80 who die of other causes have incidental prostate cancer, 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. It is an architectural grading system ranging from 1 (well-differentiated) to 5 (undifferentiated); 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. A cross-walk of these grading systems is shown in Table 1.

Table 1. Prostate Cancer Grading Systems

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.

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 (CLIA). Laboratories that offer laboratory-developed tests must be licensed under the CLIA for high-complexity testing. The following laboratories are certified under the CLIA : 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 (PHI™), and ExoDx® Prostate (Exosome Diagnostics). To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.

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 1 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 medical policies - 

POLICY

The following genetic and protein biomarkers for the diagnosis of prostate cancer are considered investigational:

• Kallikrein markers (eg, 4Kscore Test)

• Prostate Health Index (phi)

• HOXC6 and DLX1 testing (eg, SelectMDx)

• PCA3, ERG, and SPDEF RNA expression in exosomes (eg, ExoDx Prostate IntelliScore)

• Autoantibodies ARF 6, NKX3-1, 5' -UTR-BMI1, CEP 164, 3' -UTR-Ropporin, Desmocollin, AURKAIP-1, and CSNK2A2 (eg, Apifiny)

• PCA3 testing (eg, Progensa PCA3 Assay)

• TMPRSS:ERG fusion genes (eg, MyProstate Score)

• Gene hypermethylation testing (eg, ConfirmMDx)

• Mitochondrial DNA variant testing (eg, Prostate Core Mitomics Test)

• PanGIA Prostate

• Candidate gene panels.

Single nucleotide variant testing for cancer risk assessment of prostate cancer is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

03/01/2023: New policy added to replace Gene-Based Tests for Screening, Detection and/or Management of Prostate Cancer.

07/01/2023: Code Reference section updated to make note of deleted CPT code.

09/25/2023: Code Reference section updated to add new CPT code 0403U, effective 10/01/2023.

12/21/2023: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to remove genetic counseling information. Code Reference section updated to add new 2024 CPT codes 0424U and 0433U, effective 01/01/2024.

10/01/2024: Code Reference section updated to add new CPT codes 0495U and 0497U. Removed deleted CPT code 0053U.

03/07/2025: Policy reviewed. Policy statements unchanged. Code Reference section updated to add CPT codes 0047U, 81542, and 81551.

04/01/2025: Code Reference section updated to add new CPT codes 0534U and 0550U, effective 04/01/2025.

07/18/2025: Code Reference section updated to add new CPT code 0572U. Effective 07/01/2025.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.33

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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