CurrentBlue Cross Blue Shield - Rhode IslandPolicy N/A

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

Defines medical necessity, coverage stance, and prior authorization requirements for specific genetic and protein biomarker tests used to diagnose prostate cancer or assess risk, affecting Medicare Advantage and commercial beneficiaries and ordering providers.

Policy Summary

PayerBlue Cross Blue Shield - Rhode Island

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

Policy CodePolicy N/A

Change TypeNo material change

Effective Date04/01/2023

Next Review DateN/A

Key ActionObtain prior authorization for 4Kscore, ConfirmMDx, ExoDx, and any unlisted molecular pathology codes for Medicare Advantage members; document medical necessity and shared decision-making in the medical record.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

8named tests listed

3prior-auth tests (MA)

9+not medically necessary (Commercial)

1FDA-approved test discussed

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Progensa PCA3 (CPT 81313) — Medicare Advantage criteria

Covered when ALL of the following are met

Ordering frequency and prescriber: The test is ordered only once per year by a physician or other qualified health care professional (e.g., NP, CNS, PA).

Clinical context: Used for men being considered for repeat biopsy who remain at higher risk despite a prior negative biopsy; PSA elevation should be confirmed under standardized conditions before testing.PSA thresholds as specified in policy (commonly >3 and <10 ng/mL; age-adjusted thresholds may apply).

No other absolute indication or contraindication for biopsy: No other relative indication for immediate prostate biopsy (examples include positive mpMRI PI-RADS 2–3 if available, suspicious DRE, prior positive biopsy findings such as Grade Group ≥1, intraductal carcinoma, or atypical intraductal proliferation, high‑risk ethnicity, or first‑degree relative with prostate cancer).

Biopsy contraindications (exclude if present): Test should not be performed if relative contraindications to biopsy are present such as life expectancy <10 years (not a candidate for treatment), active prostatitis or current antibiotic therapy, recent invasive treatment for benign prostatic disease, or use of medications that influence PSA within prior 6 months.

4Kscore (CPT 81539) — Medicare Advantage criteria

Covered when ALL of the following are met

Age and PSA: Testing for men 45 years of age and older with a confirmed moderately elevated PSA (commonly >3 and <10 ng/mL; greater than or equal to 4 and <10 ng/mL in men >75 years of age).PSA >3 and <10 ng/mL (age-adjusted as noted).

PSA elevation should be verified after a few weeks under standardized conditions (e.g., no ejaculation, no recent manipulations or UTI) in the same laboratory before considering biopsy.

Clinical risk context: No other relative indication for immediate prostate biopsy; presence of other risk factors (for example positive mpMRI, suspicious DRE, high‑risk ethnicity, first‑degree relative with prostate cancer, or known high‑penetrance gene per NCCN) may support testing.

Relative indications/contraindications are not absolute; medical record must support medical necessity if present.

Shared decision making: Documented shared decision making between the ordering provider and the beneficiary regarding 4Kscore testing must be present in the medical record and provided to the laboratory at time of order.

ConfirmMDx (CPT 81551) — Medicare Advantage criteria

Covered when ALL of the following are met

No established prostate cancer: The patient must not have an established diagnosis of prostate cancer.

Candidate for biopsy per guidelines: Beneficiary is a candidate for initial or repeat prostate biopsy according to consensus guidelines (e.g., NCCN, ASCO, AUA); PSA/DRE thresholds are applied by age and clinical context.PSA thresholds vary by age and context per policy; exception allowed for validated biomarkers with PSA >10 ng/mL when mpMRI is negative if appropriate.

Biopsy history: Beneficiary has had a previous negative biopsy or non‑malignant but abnormal histopathology (e.g., ASAP or HGPIN) or is under consideration for repeat biopsy.

Clinical utility and laboratory standards:

ExoDx Prostate IntelliScore (EPI) — criteria

Covered when ALL of the following are met

Frequency and prescriber: The test is ordered only once per year by a physician or other qualified health care professional (e.g., NP, CNS, PA).

Age and PSA: Men aged ≥50 years with a PSA >4 ng/mL when being evaluated for initial or repeat biopsy consideration.PSA >4 ng/mL; age ≥50 years.

Coding-linked coverage (Medicare Advantage)

Covered when medical criteria are met for Medicare Advantage Plans

Medicare Advantage coverage: The following CPT/temporary codes are covered for Medicare Advantage Plans when the medical criteria above are met: 81313 (PCA3), 81539 (4Kscore), 81551 (ConfirmMDx), 0005U/000SU/000SU‑style temporary codes (ExoDx EPI and other proprietary/temporary codes listed in policy), 0113U, 0228U, 0339U, and related codes noted in the policy.

These codes are not medically necessary for Commercial Products as noted elsewhere in the policy; unlisted molecular pathology (81479) requires prior authorization.

The following genetic and protein biomarker tests are identified in the policy as not covered because available evidence is insufficient to demonstrate improvement in net health outcomes: Apifiny, MyProstateScore (MPS), PanGIA Prostate, HOXC6 and DLX1 testing (e.g., SelectMDx), mitochondrial DNA variant testing (e.g., Prostate Core Mitomics Test), candidate gene panels, and single nucleotide variant testing for prostate cancer risk assessment. (These items are listed under Medicare Advantage exclusions and the Commercial Products section as lacking sufficient evidence.)

The policy lists several CPT and temporary codes that are designated as not medically necessary for Commercial Products while noting these same codes may be covered for Medicare Advantage when their specific medical criteria are met. Examples include codes representing PCA3 (CPT 81313), 4Kscore (CPT 81539), ConfirmMDx (CPT 81551), and proprietary/temporary codes (e.g., 0005U, 0021U, 0113U, 0228U, 0339U) referenced in the coding section.

Coverage and payment are ultimately governed by each member's plan documents. The member's subscriber agreement, member certificate, or employer agreement determines benefit applicability and supersedes this medical policy; providers should confirm member-specific benefits by calling the provider call center.

For Commercial Products the policy explicitly considers several commonly referenced prostate biomarker tests to be not medically necessary because evidence is insufficient to show improved net health outcomes. Tests listed include PCA3 (Progensa PCA3), kallikrein-based markers (e.g., 4Kscore), ExoDx Prostate IntelliScore (PCA3/ERG/SPDEF exosomal RNA), and ConfirmMDx (gene hypermethylation), as well as other proprietary assays enumerated in the document.

The evidence summary states that for many biomarker tests the literature is limited to observational studies, systematic reviews, and meta-analyses with inconsistent or incomplete validation. Important gaps include lack of standardized cutoffs, limited comparative studies versus standard risk models, absence of direct evidence that test use changes long-term clinical outcomes, and no clear demonstrations that testing improves net health outcomes such as survival, disease-specific outcomes, or quality of life.

Services determined to be not medically necessary are not guaranteed payment. Providers should confirm benefits and obtain any required prior authorization; if a service is non-covered, providers generally may not bill the member unless there is a prior written agreement with the member acknowledging financial responsibility.

Coding, CPT and Proprietary Codes

Named tests and associated CPTsCPT

81539	4Kscore (OPKO Health)
81313	Progensa PCA3 (Hologic)
81551	ConfirmMDx (MDx Health)
000SU	ExoDx Prostate IntelliScore (EPI) CPT listed in doc as 000SU/OOOSU/0OOSU
0021U	Apifiny (Exact Sciences)
0113U	MyProstateScore (MPS) (Lynx Dx)
0228U	PanGIA Prostate (Genetics Institute of America)
Unlisted	Prostate Core Mitomics Test (Mitomics) — Unlisted CPT

Unlisted CPT guidanceCPT

Unlisted

All services without specific CPT should use Unlisted CPT; require authorization

Covered CPT Codes (Medicare Advantage when criteria met)CPTCovered

81313	PCA3/KLK3 ratio (prostate specific antigen 3 / kallikrein-related peptidase 3)
81539	Oncology (high-grade prostate cancer), biochemical assay of four proteins (total PSA, free PSA, intact PSA and hK2) plus patient age, DRE status, algorithm reported as probability score
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

Proprietary/Temporary Codes and Unlisted CodeCPT

0005U	Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, SPDEF), urine, algorithm reported as risk score
0021U	Oncology (prostate), detection of 8 autoantibodies, multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score
0113U	Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage; RNA amplification and fluorescence-based detection, algorithm reported as risk score
0228U	Oncology (prostate), multianalyte molecular profile by photometric detection on nanosponge array slides, first morning voided urine, algorithm reported as likelihood of prostate cancer
0339U	Oncology (prostate), mRNA expression profiling of HOXC6 and DLX1, RT-PCR, first-void urine following DRE, algorithm reported as probability of high-grade cancer (New Code Effective 10/1/2022)
81479	Unlisted molecular pathology procedure (requires prior authorization for Medicare Advantage and Commercial products)

PSA thresholds referenced

Common PSA range (general criteria)PSA greater than 3 ng/mL and less than 10 ng/mL is used as a common threshold in eligibility criteria for biomarker testing

Alternate PSA range (age >75)Some criteria specify PSA greater than 4 ng/mL and less than 10 ng/mL for men older than 75 years

ExoDx (EPI) thresholdExoDx Prostate IntelliScore (EPI) criteria specify PSA greater than 4 ng/mL and age ≥50 years

Age adjustment notePSA thresholds are adjusted by age in several criteria sets (eg, higher lower bound for men >75 years) and PSA elevation should be confirmed under standardized conditions before biopsy

phi and PCA3 test age and PSA thresholds

PCA3 age and biopsy historyProgensa PCA3 is indicated for men age ≥50 years with one or more prior negative prostate biopsies

phi age and PSA rangeProstate Health Index (phi) is indicated for men 50 years and older with total PSA between 4.0 and 10.0 ng/mL and a negative DRE

phi clinical contextphi is used to help distinguish prostate cancer from benign conditions in men meeting the age and PSA criteria

Prior Authorization, Documentation, and Billing Actions

Prior Authorization

Prior Authorization Required

Prior authorization is required for certain molecular prostate tests for Medicare Advantage Plans; Unlisted CPT (81479) and specified tests require authorization to determine coverage. Laboratories may not obtain authorizations on behalf of ordering providers; only the ordering physician may initiate and participate in the authorization and related appeals.

Prior authorization required for: 4Kscore, ConfirmMDx, ExoDx Prostate IntelliScore (Medicare Advantage).
Unlisted molecular pathology (CPT 81479) requires authorization for Medicare Advantage and Commercial Products.
Laboratories are prohibited from obtaining authorizations or participating in the authorization process on behalf of the ordering physician.

Denial Risk

Laboratory Authorization Prohibition and Denial Risk

When a service is provided without required authorization, the service may be denied. If a laboratory obtains or facilitates an authorization in violation of policy, BCBSRI may take severe action (including termination) and deny payment; the financial liability for unauthorized laboratory services will rest with the participating laboratory and may not be billed to the member.

Services provided without required authorization may be denied.
Unauthorized lab-obtained authorizations or third-party participation is prohibited and may result in denial and provider/network sanctions.
Providers should not rely on laboratories or third parties to secure authorizations.

Note

Confirm Benefits via Provider Call Center

Confirm member-specific benefits and eligibility before ordering. Benefits and eligibility are determined by the member's subscriber agreement or employer agreement and may supersede this policy. Contact the provider call center for member-specific determinations.

Call the BCBSRI provider call center to verify member coverage and eligibility prior to ordering tests.
Do not assume coverage based on policy alone; benefit design may vary by member plan.

Documentation Required

Medical Necessity and Shared Decision-Making Documentation

Medical necessity must be documented in the medical record and shared decision-making between the ordering provider and patient should be recorded. The record must support that testing will impact patient management and is consistent with the test's intended use and validated population.

Document clinical indications, PSA/DRE findings, prior biopsy history, and rationale for testing.
Record shared decision-making discussion and that results would affect management.
Testing must follow CLIA/FDA requirements and validated algorithms where applicable.

Billing Rule

Use of Specific CPT/Temporary HCPCS Codes

Use the specific CPT and temporary HCPCS codes that correspond to the test performed and the covered indications. Billing must match the service rendered and the code requested during authorization.

Bill using the specific CPT or temporary HCPCS code that represents the test performed (e.g., 81313, 81539, 81551, 0113U, 0228U, 0339U, 0021U where applicable).
If no specific CPT exists, use 81479 and obtain prior authorization to describe the service.
Authorization must reflect the code billed and the clinical indication; discrepancies may lead to denial.

Note

Some CPT Codes Covered for Medicare Advantage

Some CPT codes are covered for Medicare Advantage when medical criteria are met but are not medically necessary for Commercial Products. Verify plan type and apply criteria accordingly.

Medicare Advantage: codes 81313, 81539, 81551 may be covered when criteria met.
Commercial Products: the same codes may be considered not medically necessary per policy; confirm with benefits.

Denial Risk

Member Billing and Denial Risk

If services are not medically necessary or are non-covered benefits, the provider may not bill the member unless the member has been informed and provided written agreement to be financially responsible prior to receiving services.

Obtain written member agreement before billing the member for non-covered or not medically necessary services.
Refer to your participation agreement(s) for applicable billing provisions.

Test Definitions and Biomarker Descriptions

Biomarker tests referenced

Included biomarker familiesKallikrein-based tests (eg, 4Kscore), PCA3, ExoDx (exosomal RNA assays), ConfirmMDx (methylation profiling), phi (Prostate Health Index), TMPRSS2:ERG/MyProstateScore and other urine- or exosome-based molecular assays

4Kscore (kallikrein panel)Blood-based panel measuring total PSA, free PSA, intact PSA and hK2 plus clinical data reported as a percent risk for high-grade (Gleason ≥7) cancer

ExoDx and other urine assaysUrine-based exosomal RNA assays (eg, ExoDx EPI, MyProstateScore) that measure PCA3, ERG and other transcripts to provide a risk score for high-grade disease

ConfirmMDx (methylation)Tissue-based promoter methylation profiling (GSTP1, APC, RASSF1) reported as likelihood of cancer detection on repeat biopsy

Proprietary and unlisted testsIncludes proprietary assays and temporary/unlisted CPT-coded tests (eg, Apifiny, PanGIA, HOXC6/DLX1, Prostate Core Mitomics) referenced in exclusions and coding sections

PCA3 (Progensa PCA3 Assay)

Assay name (Progensa)Progensa PCA3 Assay (PCA3) - an mRNA expression assay performed on post‑DRE urine

Indication notedFDA‑approved to help decide whether a repeat biopsy is necessary in men ≥50 years with one or more prior negative prostate biopsies

Typical cutoffA PCA3 score cutoff of 25 was used in validation studies (sensitivity ~77.5%, specificity ~57.1%)

4Kscore (definition)

Biomarkers measured4Kscore measures four kallikrein protein biomarkers: total PSA (tPSA), free PSA (fPSA), intact PSA (iPSA), and human kallikrein‑related peptidase 2 (hK2)

Clinical inputsAlgorithm incorporates clinical data (age, DRE status, and history) to produce a percent risk for Gleason score ≥7 prostate cancer

Purpose and useUsed to refine selection for biopsy and reduce unnecessary biopsies by predicting risk of high‑grade disease; referenced in multiple CMS LCDs and clinical studies

ExoDx Prostate IntelliScore (EPI) definition

Assay platform and analytesExoDx Prostate IntelliScore (EPI) is a urine‑based 3‑gene exosomal RNA assay measuring PCA3, ERG and SPDEF

OutputProprietary algorithm translates expression levels into an individualized risk score for high‑grade prostate cancer

Intended useDesigned to be used in conjunction with standard‑of‑care factors (age, family history, PSA and DRE) but does not include PSA in the score itself

phi (Prostate Health Index) definition

ComponentsProstate Health Index (phi) combines total PSA, free PSA and [-2]proPSA into a numerical phi score

Indicated populationIndicated for men 50 and older with total PSA 4.0–10.0 ng/mL and negative DRE to help distinguish cancer from benign conditions

Clinical valueComposite index shown in validation studies to improve specificity for clinically significant prostate cancer compared with PSA alone

4Kscore additional context

Regulatory/coverage context4Kscore is referenced in multiple CMS Local Coverage Determinations and clinical guidance documents

Evidence baseMultiple prospective and validation studies cited in the policy support 4Kscore's use to predict high‑grade prostate cancer

CodingCPT 81539 is listed for 4Kscore in the coding sections and is covered for Medicare Advantage when medical criteria are met

Prostate Health Index (PHI) additional context

Composite index definitionProstate Health Index (PHI) is a composite index incorporating [-2]proPSA, free PSA and total PSA to improve specificity for clinically significant prostate cancer

ValidationMultiple validation studies and a manufacturer PMA are cited supporting PHI's performance in risk prediction of aggressive disease

Clinical roleUsed to improve multivariable risk prediction and aid biopsy decision‑making versus PSA alone

Urine/exosome‑based molecular assays

Assay typesUrine‑ or exosome‑based molecular assays (eg, PCA3, TMPRSS2:ERG/MyProstateScore, ExoDx EPI) evaluate urinary or exosomal RNA markers to predict presence or risk of clinically significant prostate cancer

Common targetsThese assays commonly measure transcripts such as PCA3 and TMPRSS2:ERG, sometimes combined with serum PSA measurements in algorithmic scores (eg, MyProstateScore)

Clinical applicationIntended for detection and risk stratification prior to initial or repeat biopsy; performance and utility vary across tests and studies

OpenPayer

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

Coverage Criteria and Medical Necessity

Coding, CPT and Proprietary Codes

Prior Authorization, Documentation, and Billing Actions

Test Definitions and Biomarker Descriptions

Background and Clinical Context

Policy Revision History