CurrentBlue Cross Blue Shield - Rhode IslandPolicy N/A

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

Defines medical necessity, coverage, prior authorization, and coding for specific genetic and protein biomarker tests used to guide initial and repeat prostate biopsy decisions for Medicare Advantage and Commercial members of Blue Cross Blue Shield - Rhode Island.

Policy Summary

PayerBlue Cross Blue Shield - Rhode Island

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

Policy CodePolicy N/A

Change TypeNo material change

Effective DateMar 1, 2025

Next Review DateMar 1, 2025

Key ActionObtain prior authorization for 4Kscore and certain listed tests (and for unlisted molecular pathology 81479) as required before ordering.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

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Coverage Criteria for Prostate Biomarker Tests

inv-01: 4Kscore — Covered when ALL of the following are met

The 4Kscore test will be considered medically reasonable and necessary when all the following are met:

4Kscore criteria: All components of the 4Kscore algorithm are present; patient is ≥45 years of age; confirmed moderately elevated PSA (greater than 3 and less than 10 ng/mL, or ≥4 and <10 ng/mL in men >75 years); no other absolute contraindication to prostate biopsy; shared decision-making between ordering provider and beneficiary is documented; testing performed in a CLIA/FDA‑accredited laboratory; analytes measured have demonstrated clinical validity and utility; ordering physician is a prostate specialist (exceptions for remote geographic locations).PSA: >3 and <10 ng/mL (or ≥4 and <10 ng/mL if >75 years)

Relative indications (eg, suspicious DRE, persistent PSA rise, positive mpMRI, high‑risk ethnicity, family history, high‑penetrance gene) and relative contraindications must be supported in the medical record and documented at time of ordering.

inv-02: ConfirmMDx and SelectMDx — Covered when ALL of the following are met

ConfirmMDx and SelectMDx may be considered medically necessary when ALL of the following criteria are met:

ConfirmMDx/SelectMDx criteria: No established diagnosis of prostate cancer; for men <75 years PSA (or adjusted PSA) and/or repeat PSA >3 ng/mL and/or DRE findings very suspicious for cancer; for men >75 years PSA (or adjusted PSA) ≥4 and <10 ng/mL and/or DRE very suspicious for cancer; beneficiary is a candidate for initial or repeat prostate biopsy per consensus guideline (eg, NCCN, ASCO, AUA); prior biopsy must be negative or show non‑malignant but abnormal histopathology (eg, ASAP or HGPIN); exception permitting testing with PSA >10 ng/mL only when the biomarker has been validated for PSA >10 and mpMRI is negative if performed; patients under consideration for repeat biopsy must have had repeat PSA and/or DRE per guidelines; medical record documents medical necessity; beneficiary would benefit from treatment and patient management would be impacted as demonstrated in peer‑reviewed literature; testing performed in intended validated population with validated algorithm; testing performed in CLIA/FDA‑accredited laboratory; only one molecular biomarker per clinical indication unless a second adjunct test meeting all criteria is justified; algorithm validation in an independent cohort required when applicable; test ordered by a physician specialist in prostate management (exception for remote locations).

Documentation and validation requirements emphasized; analytes must demonstrate clinical validity and utility.

inv-03: MyProstateScore (MPS) — Covered when ALL of the following are met

MPS may be considered medically necessary when numbers 1–3 below are met:

MPS criteria: Test is ordered no more than once per year by a qualified clinician; patient meets age and PSA criteria consistent with other biomarker tests (eg, confirmed moderately elevated PSA >3 and <10 ng/mL, with adjusted thresholds for older men) and PSA elevation is confirmed under standardized conditions in the same laboratory (eg, no ejaculation, no recent manipulations or urinary infection) before considering biopsy; no other absolute indication for biopsy is present and relative indications/contraindications (eg, suspicious DRE, positive mpMRI PI‑RADS 2–3 if available, prior positive biopsy findings, high‑risk ethnicity, family history, known high‑penetrance gene, life expectancy <10 years, prostatitis, recent procedures or medications affecting PSA) are considered and documented; testing performed in a CLIA‑certified laboratory.

Detailed list of relative indications and contraindications must be considered and documented.

inv-04: General evidence-based coverage stance

Overall policy stance (evidence synthesis)

Evidence summary: For initial and repeat biopsy decision contexts, the evidence is primarily observational (systematic reviews, meta‑analyses, and cohort studies); comparative studies and direct evidence showing improved long‑term clinical outcomes or impact on physician rebiopsy decisions are lacking for many tests. The evidence is insufficient to determine that these technologies improve net health outcomes in several contexts.

The following genetic and protein biomarker assays are considered not covered / not medically necessary due to insufficient evidence: PanGIA Prostate, Apifiny, mitochondrial DNA variant testing (eg, Prostate Core Mitomics Test), candidate gene panels, and single nucleotide variant testing for prostate cancer risk assessment. These tests lack adequate evidence to demonstrate improvement in net health outcomes for diagnosis or risk assessment of prostate cancer.

For Medicare Advantage Plans these CPT codes are designated as not covered and are considered not medically necessary for Commercial Products when used for prostate testing: 0021U (detection of 8 autoantibodies), 0228U (PanGIA Prostate multianalyte molecular profile), and 86316 (immunoassay for tumor antigen, other antigen, quantitative). Providers should avoid billing these codes for prostate indications under the listed ICD-10-CM diagnoses.

Coverage and payment for services are determined by the member’s subscriber agreement, member certificate, or employer agreement, which will supersede this medical policy. For member-specific benefit or eligibility questions, providers must contact the payer’s provider call center.

The evidence base for many genetic and protein biomarker tests used to inform initial or repeat prostate biopsy decisions is primarily observational, with systematic reviews and meta-analyses but few comparative studies. For several assays the published literature does not show that testing leads to improved long-term clinical outcomes or overall net health benefit; therefore evidence is rated as insufficient to determine improved net health outcome for these tests.

For multiple proprietary assays and newer tests, clinical validity and demonstration of an effect on physician rebiopsy decisions or longer-term outcomes have not been established. The policy notes limited data comparing biomarker performance with standard risk models and an absence of direct evidence showing that test results change rebiopsy management or improve survival, quality of life, or resource utilization; such tests are therefore considered to have insufficient evidence of clinical utility.

Coding and Billing for Prostate Biomarker Tests

CPT/PLA/Unlisted codes referencedmixed

81539	Oncology (high-grade prostate cancer), biochemical assay of four proteins (total PSA, free PSA, intact PSA and hK2) plus age, DRE status, and no history of positive prostate biopsy, prognostic algorithm reported as probability score
81313	PCA3/KLK3 ratio (Progensa PCA3)
81551	Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), FFPE tissue, algorithm reported as likelihood of prostate cancer detection on repeat biopsy
0113U	Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum; algorithm reported as risk score (MyProstateScore/MPS)
0228U	PanGIA Prostate (PLA) - multianalyte molecular profile by photometric detection of macromolecules on nanosponge array slides with machine learning, first morning voided urine, algorithm reported as likelihood of prostate cancer
0339U	SelectMDx - Oncology (prostate), mRNA expression profiling of HOXC6 and DLX1, first-void urine following DRE, algorithm reported as probability of high-grade cancer
81479	Unlisted molecular pathology procedure (used for Prostate Health Index [phi] and Prostate Core Mitomics Test)
OOOSU	ExoDx Prostate (EPI) - Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, SPDEF), urine, algorithm reported as risk score
86316	Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each

The following CPT code(s) are coveredCPTCovered

81313

PCA3/KLK3 (prostate antigen 3 [non-protein coding] /kallikrein-related peptidase 3 [prostate specific antigen]) ratio

The following CPT code(s) are covered when medical criteria above are metCPTCovered

81539	Oncology (high-grade prostate cancer), biochemical assay of four proteins plus age, DRE status, and no history of positive prostate biopsy, algorithm reported as probability score
81551	Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing FFPE tissue, algorithm reported as likelihood of prostate cancer detection on repeat biopsy
0113U	Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage; algorithm reported as risk score

Additional CPT code (new code)CPTCovered

0339U

Oncology (prostate), mRNA expression profiling of HOXC6 and DLX1 by RT-PCR, first-void urine following DRE, algorithm reported as probability of high-grade cancer (New code effective 10/1/2022)

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

0021U	Oncology (prostate), detection of 8 autoantibodies, multiplexed immunoassay and flow cytometry, serum, algorithm reported as risk score
0228U	Oncology (prostate), multianalyte molecular profile by photometric detection of macromolecules on nanosponge array slides with machine learning, first morning voided urine, algorithm reported as likelihood of prostate cancer
86316	Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each

Unlisted CPT code authorizationCPT

81479

Unlisted molecular pathology procedure (requires prior specific authorization for tests without an assigned CPT code, can be used for Prostate Health Index [phi] and other tests lacking a CPT code)

PSA level — thresholds

Typical PSA thresholdGenerally greater than 3 and less than 10 ng/mL for men considered for 4Kscore-guided biopsy decisions

Adjusted threshold for older menFor men >75 years the policy uses ≥4 and <10 ng/mL as the PSA window

Age requirement referencedTesting of men 45 years of age and older is specified for 4Kscore use

Requirement to confirm PSA elevationPSA elevation should be confirmed under standardized conditions (eg, no ejaculation, no UTI) in the same laboratory before considering biopsy or testing

4Kscore cut-off references

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for certain prostate biomarker tests and recommended for others. For Medicare Advantage plans, prior authorization is required for 4Kscore. Prior authorization is also required for tests without a specific CPT (Unlisted molecular pathology 81479) — a prior specific authorization is needed to determine coverage and medical necessity. For participating providers, prior authorization for ConfirmMDx, MyProstateScore (MPS), and SelectMDx is obtained via the payer's online tool. Laboratories are not permitted to obtain authorization on behalf of ordering physicians; only the ordering physician may participate in authorization, appeals, or related administrative processes.

4Kscore: Prior authorization required for Medicare Advantage; recommended for Commercial Products.
ConfirmMDx, MyProstateScore (MPS), SelectMDx: Prior authorization obtained via online tool for participating providers.
Unlisted molecular pathology (e.g., 81479): Prior specific authorization required to determine what service is rendered and whether it is covered.
Laboratories and their representatives may NOT obtain authorization on behalf of ordering physicians; violations may result in severe action up to network termination.

Note

Background and Intended Use

Prostate cancer exhibits a wide spectrum of behavior from indolent to aggressive disease. Biomarker assays are intended to refine risk estimates and help guide the decision to perform an initial or repeat prostate biopsy with the goal of reducing unnecessary procedures. However, individual tests vary in the strength of evidence for clinical validity and utility; some (eg, select urine- and blood-based assays) have supporting studies and regulatory clearances, while others lack comparative or outcome data to support routine clinical use.

Definitions of Tests and Guideline Sources

4Kscore — definition

DefinitionA blood test measuring four kallikrein proteins (total PSA, free PSA, intact PSA, and hK2) combined with clinical information (age, DRE, biopsy history) and processed through a proprietary algorithm to produce a percent risk for high-grade (Gleason ≥7) prostate cancer

Intended useDesigned to refine patient selection for prostate biopsy and reduce unnecessary biopsies

Algorithm inputsBiomarker levels plus clinical variables (age, digital rectal exam findings, and prior biopsy history) are incorporated into the reported probability score

Progensa PCA3 — definition / intended use

Test name and approval contextProgensa PCA3 (Hologic/Gen-Probe) — FDA-approved urine assay to aid repeat biopsy decisions

Indicated population

Policy Revision History

2025-03-01Effective dateLatest

Policy effective date updated to 2025-03-01.

2024-11-06Last review

Policy last reviewed on 2024-11-06.

Policy Summary

PayerBlue Cross Blue Shield - Rhode Island

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

Policy CodePolicy N/A

Change TypeNo material change

Effective DateMar 1, 2025

Next Review DateMar 1, 2025

Key ActionObtain prior authorization for 4Kscore and certain listed tests (and for unlisted molecular pathology 81479) as required before ordering.

SourceLink

On This Page

Reported 4Kscore cut-offs in literatureStudies report 4Kscore diagnostic cut-offs in the ~7.5% to 10% range for decision-making regarding biopsy

Evidence type supporting cut-offsMeta-analyses and systematic reviews (eg, Mi et al. 2021; Russo et al. 2017) describe diagnostic value at these thresholds

Prospective validationMulti-institutional prospective trials confirm 4Kscore identifies men with high-grade prostate cancer, supporting use of reported cut-offs in decision-making

Providers must verify member benefits and eligibility prior to ordering testing. Benefits and eligibility are determined by the member's subscriber agreement, certificate, and/or employer agreement and may supersede this policy. Contact the provider call center or member services to confirm coverage, prior authorization requirements, and any plan-specific limitations.

Denial Risk

Not Covered Codes May Be Denied

Some CPT codes are not covered or are considered not medically necessary for certain products. If these codes are billed for Medicare Advantage Plans they may be denied; commercial plans may also consider them not medically necessary. Examples include 0021U and 0228U (not covered) and 86316 when filed for prostate-related testing with the listed ICD-10 code(s).

Not covered / not medically necessary codes (examples): 0021U, 0228U.
86316 may be denied when filed for prostate testing with the policy-specified ICD-10-CM code(s).
Covered vs not-covered coding determinations are contingent on meeting the medical criteria in this policy.

Billing Rule

Member Financial Liability When Service Is Not Covered

If a service is determined to be not medically necessary or is a non-covered benefit, the provider may not bill the member for the service unless the member has been informed in advance and has agreed in writing to accept financial responsibility. If a laboratory provides a 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.

Do not charge members for services determined not medically necessary unless written advance agreement is obtained.
Unauthorized laboratory services are the financial responsibility of the laboratory and may not be billed to the member.

Documentation Required

Shared Decision-Making and Documentation

When molecular biomarker testing is clinically appropriate, there must be documented shared decision-making between the ordering provider and the patient. The medical record must include documentation that the patient and provider discussed the rationale for testing, potential benefits and risks, and how the test results would affect management. This documentation must support medical necessity and be available upon request.

Medical record must document shared decision-making and rationale for testing.
Documentation should explain how test results will impact patient management and support medical necessity.

Prior Authorization

Unlisted CPT Handling

For tests that lack a specific CPT code, submit an Unlisted CPT (e.g., 81479) with prior specific authorization as required. When an unlisted code is submitted, the medical necessity criteria in the Genetic Services policy will be used to evaluate the request.

Unlisted CPT usage (e.g., 81479) requires prior specific authorization.
Medical necessity review will follow the Genetic Services policy criteria for unlisted codes.

Denial Risk

Coverage Contingent on Meeting Medical Criteria

Coverage and payment are contingent on meeting the medical criteria outlined in this policy. If the criteria are not met, claims may be denied. Always ensure documentation supports that the testing meets the policy's medical necessity requirements.

Payments are conditional on meeting policy medical criteria.
Ensure clinical documentation supports all required criteria before ordering/testing.

ExoDx Prostate (EPI) — definition

Test name and assay targetsExoDx Prostate (EPI) — urine-based assay measuring PCA3, ERG, and SPDEF gene expression

OutputProprietary algorithm translates expression levels into a risk score for high-grade prostate cancer

Note on PSA incorporationEPI score does not incorporate PSA into the score and is intended to be used alongside standard clinical factors (eg, age, PSA, DRE)

Testing to inform decision for initial prostate biopsy — definition / context

Purpose (initial biopsy)Testing intended to inform the decision to perform an initial prostate biopsy by refining risk assessment beyond PSA and DRE to select patients for biopsy

Evidence contextEvidence for initial-biopsy use is primarily observational with systematic reviews and meta-analyses; comparative studies showing improved long-term outcomes are limited

Clinical application notesBiomarker results are intended to be integrated with clinical findings (eg, PSA level, DRE, mpMRI) and shared decision-making documented in the medical record

Testing to inform decision for repeat prostate biopsy — definition / context

Purpose (repeat biopsy)Testing intended to inform decision to perform a repeat prostate biopsy after a prior negative biopsy by identifying men at higher or lower risk of clinically significant cancer

Progensa PCA3 specific useProgensa PCA3 is FDA-approved to aid repeat biopsy decisions in men ≥50 with prior negative biopsies

Evidence limitationsEvidence supporting rebiopsy-directed biomarker testing is primarily observational and insufficient to demonstrate improvement in long-term clinical outcomes or physician rebiopsy decisions in many cases

Guideline sources referenced

NCCNNational Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection

AUA/SUOAmerican Urological Association / Society of Urologic Oncology (AUA/SUO) Early Detection of Prostate Cancer guideline

NICENational Institute for Health and Care Excellence (NICE): Prostate cancer: diagnosis and management (NG131)