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

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 11|01|2025 POLICY LAST REVIEWED: 09|17|2025 OVERVIEW Various genetic and protein biomarkers are associated with prostate cancer. These tests have the potential to improve the accuracy of differentiating which men should undergo prostate biopsy or rebiopsy after a prior negative biopsy. The following tests are addressed in this policy: • Progensa PCA3 Assay (Hologic), CPT Code 81313 • ExoDx Prostate IntelliScore (EPI) (Exosome Diagnostics), CPT Code 0005U • Apifiny (Exact Sciences), CPT Code 0021U • MyProstateScore (MPS) (Lynx Dx), CPT Code 0113U • PanGIA Prostate (Genetics Institute of America), CPT Code 0228U • Prostate Health Index (phi) (Beckman Coulter), CPT Code 81479 • Prostate Core Mitomics Test (Mitomics), CPT Code 81479 MEDICAL CRITERIA Medicare Advantage Plans and Commercial Products Effective 7/1/2025, the following test(s) are considered medically necessary when the medical criteria in the online authorization tool for participating providers is met: • 4Kscore (CPT Code 81539) • ConfirmMDx (CPT Code 81551) • SelectMDx (CPT Code 0339U) MyProstateScore (MPS), CPT Code 0113U MPS may be considered medically necessary when the following criteria for numbers 1 through 3 are met: 1. The test is ordered only once per year by a physician or other qualified health care professional (i.e., NP, CNS, PA) AND one of the following: a. Prior to potential biopsy for men >/ 45 years old; OR b. Men who need a repeat biopsy in the setting of individuals thought to be at higher risk despite a prior negative biopsy with confirmed moderately elevated PSA (>3ng/ml and <10ng/ml; or PSA >/4ng/ml and < 10ng/ml in men > 75 years of age) *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. 2. AND no other relative indication for prostate biopsy including ANY of the following: a. DRE suspicious for cancer (e.g., nodules, induration, or asymmetry) b. Positive multiparametric MRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥3) (if available) c. Positive prior biopsy (cancer Grade Group ≥1, intraductal carcinoma (IDC), atypical intraductal proliferation (AIP)) 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) 3. AND no other relative contraindication for prostate biopsy including ANY of the following: Medical Coverage Policy | Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer

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a. <10 year life expectancy, or otherwise not a candidate for prostate cancer treatment b. Invasive treatment for benign prostatic disease or taking medications that influence serum PSA levels within 6 months. c. Active prostatitis on antibiotics

Medicare Advantage Plans and Commercial Products Unless otherwise noted, for any test filed with an Unlisted CPT code, the medical necessity criteria in the Genetic Testing Services policy would be used. Please see the Related Policies section.

PRIOR AUTHORIZATION
Medicare Advantage Plans and Commercial Products Prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products and is obtained via the online tool for participating providers for the following test(s):
• MyProstateScore (MPS)

There is no specific CPT coding for some of the services referenced in this policy. Therefore, an Unlisted CPT code should be used (see Coding Section for details). All Unlisted genetic testing CPT codes require prior authorization to determine what service is being rendered and if the service is covered or not medically necessary. See the Related Policies section.

Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal or other administrative processes related to prior authorization/medical necessity.

In no circumstance shall a laboratory or a physician/provider use a representative of a laboratory or anyone with a relationship to a laboratory and/or a third party to obtain authorization on behalf of the ordering physician, to facilitate any portion of the authorization process or any subsequent appeal of a claim where the authorization process was not followed and/or a denial for clinical appropriateness was issued, including any element of the preparation of necessary documentation of clinical appropriateness. If a laboratory or a third party is found to be supporting any portion of the authorization process, BCBSRI will deem the action a violation of this policy and severe action will be taken up to and including termination from the BCBSRI provider network. If a laboratory provides a laboratory service that has not been authorized, the service will be denied as the financial liability of the participating laboratory and may not be billed to the member.

POLICY STATEMENT The following test(s) are covered: • ExoDx Prostate IntelliScore (EPI) • Progensa PCA3

The following test is covered, but due to the instruction to file an Unlisted CPT code, prior authorization is required:
• Prostate Health Index (phi)

The following test(s) are considered medically necessary when the medical criteria above are met:
• MyProstateScore (MPS)

Effective 7/1/2025, the following test(s) may be considered medically necessary when the medical criteria in the online authorization tool for participating providers is met:
• 4Kscore • ConfirmMDx • SelectMDx

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

The following genetic and protein biomarkers for the diagnosis of prostate cancer are considered not covered for Medicare Advantage Plans and not medically necessary for Commercial Products as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome: • Apifiny • PanGIA Prostate • Mitochondrial DNA variant testing (eg, Prostate Core Mitomics Test) • Candidate gene panels

Single nucleotide variant testing for cancer risk assessment of prostate cancer is not covered as the evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Commercial Products Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19-81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information.

COVERAGE Benefits may vary between groups and contracts. Please refer to the appropriate section of the Benefit Booklet, Evidence of Coverage, or Subscriber Agreement for applicable laboratory testing and not medically necessary/not covered benefits/coverage.

BACKGROUND 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 United States is approximately 16%, while the risk of dying of prostate cancer is 3%. African-American men have the highest prostate cancer risk in the United States; 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 age 55 and 60% of men age 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.

Numerous genetic alterations associated with 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

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high-complexity testing. 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 (Hologic Gen-Probe) 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 current standard of care. The Progensa PCA3 Assay should not be used for men with atypical small acinar proliferation on their most recent biopsy.

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.

Biomarkers can help stratify men who have an elevated PSA into those more likely versus less likely to have aggressive disease. These non-invasive biomarker tests have demonstrated that they can (1) reduce the need for unnecessary biopsies in men unlikely to have prostate cancer or high-grade prostate cancer and/or (2) better define men at risk for higher-grade prostate cancer. There is adequate evidence to show that the incremental information provided by validated molecular biomarker tests for prostate cancer in samples of patients whose findings can be generalized to the Medicare population, changes physician management in a way that improves outcomes.

ExoDx Prostate (IntelliScore), also called EPI, evaluates a urine-based 3-gene exosome expression assay using PCA3 (PCa antigen 3) and ERG RNA (v-ets erythroblastosis virus E26 oncogene homologs) in urine, normalized to SPDEF (SAM-pointed domain-containing Etstranscription factor). Evidence on the association between the PCA3 gene and prostate cancer aggressiveness is described in the next section on repeat biopsy. Measurement in exosomes, which are small double-lipid membrane vesicles that are secreted from cells, is novel. Exosomes encapsulate a portion of the parent cell cytoplasm and contain proteins and mRNA. They are shed into biofluids (eg, blood, urine). This test does not require DRE.

Apifiny uses an algorithm to score the detection of 8 autoantibodies (ARF 6, NKX3-1, 5' -UTR-BMI1, CEP 164, 3' -UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2) in serum. The identified biomarkers play a role in processes such as androgen response regulation and cellular structural integrity and are proteins that are thought to play a role in prostate tumorigenesis.

MyProstateScore measures TMPRSS2-ERG gene fusion and calculates a probability score that incorporates serum PSA or the PCPT, and urineTMPRSS2-ERG and PCA3 scores.

PanGIA Prostate is a urine test that uses a device with binding pockets for small molecules, proteins, and cells. Results are uploaded to the cloud and a machine learning algorithm compares the results with a signature from patients who have had a positive biopsy and patients who have had a negative prostate biopsy. The report includes a diagnosis with the level of confidence in the diagnosis.

For individuals who are being considered for an initial prostate biopsy who receive testing for genetic and protein biomarkers of prostate cancer (eg, PanGIA Prostate, Apifiny), the evidence includes systematic reviews, meta-analyses, and primarily observational studies. Relevant outcomes are overall survival, disease- specific survival, test validity, resource utilization, and quality of life. The evidence supporting clinical utility varies by test. Comparative studies are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are being considered for repeat biopsy who receive testing for genetic and protein biomarkers of prostate cancer (eg, Prostate Core Mitomics Test), the evidence includes systematic reviews

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

and meta-analyses and primarily observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, resource utilization, and quality of life. The performance of biomarker testing for guiding rebiopsy decisions is lacking. The tests are associated with a diagnosis of prostate cancer and aggressive prostate cancer, but studies on clinical validity are limited and do not compare performance characteristics with standard risk prediction models. Direct evidence supporting clinical utility has not been shown. No data are currently available on physician decisions on rebiopsy or on the longer-term clinical outcomes of men who did not have a biopsy based on test results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

CODING Medicare Advantage Plans and Commercial Products

The following CPT code(s) are covered:

This code is generally used to represent the Progensa® PCA3 Assay but can also be used for non-brand name testing:
81313 PCA3/KLK3 (prostate specific antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer)

This code can be used for ExoDx Prostate IntelliScore (EPI): 0005U Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score

The following CPT code(s) are considered medically necessary when the medical criteria above are met.

This code can be used for MyProstateScore (MPS): 0113U Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage, by RNA amplification and fluorescence-based detection, algorithm reported as risk score

The following CPT code(s) may be considered medically necessary when the medical criteria in the online authorization tool for participating providers is met: • 4Kscore (OPKO Health), CPT Code 81539 • ConfirmMDx (MDx Health), CPT Code 81551 • SelectMDx (MDx Health), CPT Code 0339U

The following CPT code(s) are not covered for Medicare Advantage Plans and are not medically necessary for Commercial Products.

This code can be used for Apifiny:
0021U Oncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3-1, 5'-UTR-BMI1, CEP 164, 3'- UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score

This code can be used for PanGIA Prostate:
0228U Oncology (prostate), multianalyte molecular profile by photometric detection of macromolecules adsorbed on nanosponge array slides with machine learning, utilizing first morning voided urine, algorithm reported as likelihood of prostate cancer

The following Unlisted CPT code requires prior authorization. The code can be used for any test identified in this policy that does not have a specific CPT code, including Prostate Health Index (phi).
81479 Unlisted molecular pathology procedure

RELATED POLICIES

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 6 (401) 274-4848 WWW.BCBSRI.COM

Biomarker Testing Mandate
Genetic Testing Services Medical Necessity Proprietary Laboratory Analyses (PLA) Serum Tumor Markers for Breast and Gastrointestinal Malignancies Unlisted Procedures Urinary Biomarkers for Cancer Screening, Diagnosis and Surveillance

PUBLISHED Provider Update, January/July/November 2025 Provider Update, February/June/August/November 2023 Provider Update, March 2022 Provider Update, May 2020 Provider Update, August 2019

REFERENCES

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2. Centers for Medicare and Medicaid Services (CMS). Local Coverage Article: Billing and Coding: Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis (A56609)
3. Centers for Medicare and Medicaid Services (CMS). Local Coverage Determination (LCD): MolDX: Molecular Diagnostic Tests (MDT) (L36807)
4. Centers for Medicare and Medicaid Services (CMS). Local Coverage Article: Billing and Coding: MolDX: Molecular Diagnostic Tests (MDT) (A57772)
5. Centers for Medicare and Medicaid Services (CMS). Local Coverage Determination (LCD): MolDX: Molecular Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer (L39007)
6. Centers for Medicare and Medicaid Services (CMS). Local Coverage Article: Billing and Coding: Billing and Coding: MolDX: Molecular Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer (A58724)
7. Centers for Medicare and Medicaid Services (CMS). Local Coverage Determination (LCD): Molecular Pathology Procedures (L34519)
8. Centers for Medicare and Medicaid Services (CMS). Local Coverage Article: Billing and Coding: Molecular Pathology and Genetic Testing (A58918)
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