blue cross blue shield kansas prostate biomarkers Policy Update | OpenPayer
Modifiedblue cross blue shield - kansasPolicy N/A
Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer
This policy addresses the use of genetic and protein biomarker tests to inform decisions about initial or repeat prostate biopsy in men, including which specific commercial tests are considered experimental/investigational for diagnosis or cancer risk assessment.
Policy Summary
Payerblue cross blue shield - kansas
PolicyGenetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer
Key ActionIf prior authorization is required, indicate the specific marketed test and intended-use population and document PSA/DRE and prior biopsy status.
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bibliographic citations
A.11new test added
Coverage Criteria and Evidence Summary
inv-01: Experimental/Investigational Tests
The following tests are considered experimental / investigational (not covered):
Tests considered experimental/investigational: Kallikrein markers (e.g., 4Kscore), Prostate Health Index (phi), HOXC6 and DLX1 testing (e.g., SelectMDx), PCA3/ERG/SPDEF exosome assays (e.g., ExoDx Prostate IntelliScore), autoantibody panels (e.g., Apifiny), PCA3 testing (e.g., Progensa PCA3 Assay), TMPRSS2:ERG fusion assays (e.g., MyProstate Score), gene hypermethylation testing (e.g., ConfirmMDx), mitochondrial DNA mutation testing (e.g., Prostate Core Mitomics Test), PanGIA Prostate, MiCheck Prostate, and candidate gene panels are considered experimental/investigational and not medically necessary for diagnosis or cancer risk assessment of prostate cancer.
inv-02: Evidence and intended-use considerations
Summary of evidence-based considerations for using kallikrein/protein biomarker tests to inform biopsy decisions
Evidence prerequisites: Use the marketed/validated version of the test and apply it to a population reflective of the intended use (typically men with indeterminate PSA levels); studies should include an appropriate reference standard and describe patient selection and clinical characteristics.
Supported by study selection criteria and concerns about out-of-range PSA or positive DRE in validations.
Performance expectations: Expect heterogeneous sensitivity, specificity, and predictive values across studies; pooled or study-level estimates vary (eg, reported pooled sensitivity for some kallikrein tests ~87% with NPV up to 96% in biopsy‑naïve subgroups), and AUCs commonly reported in the 0.81–0.88 range in some comparisons.
Performance metrics are heterogeneous and study-dependent.
Clinical utility evidence: No randomized controlled trials demonstrating improved patient health outcomes were identified; clinical utility must rely on a chain-of-evidence built from clinical validity and management-effect studies, which is incomplete for many tests.
Direct RCT evidence lacking; see discussion on chain of evidence.
inv-03: Evidence summaries influencing coverage
Summary of evidence-based interpretation and implications for coverage decisions
PHI/proPSA clinical validity summary: PHI (proPSA-based) is associated with prostate cancer detection; reported sensitivities around 85–93% with specificity wide-ranging (approximately 25–52%) and NPV varying widely across studies; observational data show reductions or delays in biopsy but clinical validity limitations prevent constructing a full chain of evidence for improved outcomes.
Derived from systematic reviews and observational studies.
MiPS/MyProstateScore clinical validity summary: Combined TMPRSS2-ERG and PCA3 algorithms (MiPS/MyProstateScore) have improved specificity or AUC versus some comparators in validation studies. A threshold of <10 was reported to rule out Gleason Group >2 with high sensitivity and NPV in Tosoian et al. (2021), but validation results vary and clinical utility (effect on outcomes) is unproven.MyProstateScore <10
Validation and potential conflicts of interest noted in source study.
Summary statements regarding clinical validity and utility
MiPS diagnostic performance: MiPS data suggest improved AUC and specificity versus some risk calculators or PSA alone in certain studies, but no prospective trials demonstrate that use of MiPS changes management to improve clinical outcomes; thus the chain of evidence is incomplete.
See Tomlins/Tosoian and Canary PASS analyses.
SelectMDx diagnostic performance: SelectMDx has pooled sensitivity around 82% and specificity around 56% in systematic reviews; some validation studies reported improved AUC versus clinical calculators, but clinical validity is insufficiently established to demonstrate clinical utility, and no trials compare outcomes with vs without the test.
Population applicability and comparison to %fPSA or PCPTRC are limited.
inv-05: SelectMDx — Insufficient Evidence
Evidence limitations and clinical validity considerations informing coverage stance
Chain of evidence incomplete for SelectMDx: Current evidence does not establish clinical validity of adding HOXC6 and DLX1 to clinical models across intended-use populations (eg, PSA 3–10 ng/mL, normal DRE); no trials of management or outcomes exist, so clinical utility cannot be inferred.
Clinical utility and validity evidence available for ExoDx Prostate (IntelliScore)
ExoDx clinical validity: Prospective multicenter validation reported improved discrimination (AUC ~0.73 vs standard of care 0.63 and PCPTRC 0.62) in intended-use men (≥50 years, PSA 2–10 ng/mL) with sensitivity ~97% and NPV ~96% for high-grade cancer.
Threshold for positive index test reported as 15.6 derived from training set.
ExoDx clinical utility trial results: An RCT (Tutrone et al 2020) did not meet its primary endpoint of reducing initial biopsies; ExoDx increased biopsy rates and detected more high-grade cancers but also increased biopsies with no-cancer/low-grade findings, raising concerns about potential overtreatment; follow-up analyses showed differences in time-to-biopsy and detection rates at 2.5 years.
RCT limitations include inclusion of low PSA values and unclear pre-enrollment standard-of-care testing.
inv-07: Apifiny & MiCheck — Preliminary Evidence
Other emerging assays
Apifiny: Evidence for Apifiny is preliminary; a case-control validation set reported an AUC of 0.69, but thresholds and full diagnostic performance metrics versus standard tests have not been established.
Further diagnostic-validation studies are needed.
MiCheck Prostate has preliminary development and validation data: initial study reported AUC ~0.83 with sensitivity ~95% and NPV ~92%; independent/ prospective outcome data are limited and no RCTs of clinical utility were identified.
Validation cohorts limited and some analyses used internal cross-validation.
inv-08: Evidence-based coverage considerations
Coverage tied to demonstration of clinical utility and appropriate clinical context
Clinical utility evidence: Direct evidence from RCTs demonstrating that use of biomarker tests changes management to improve health outcomes is lacking for most assays; absence of such trials is a key limitation for coverage decisions.
Preferred evidence are intervention studies; none identified for many tests.
Appropriate test context for PCA3 and other assays: Intended use populations differ by assay (eg, PCA3 performance varies for initial vs repeat biopsy; many urine/serum assays target men in PSA 'gray zone'); document clinical setting and ensure test application matches validated populations.
Decision analyses model potential biopsy reductions but also predicted missed cancers; context matters for interpretation.
Evidence status for emerging tests: Tests with only preliminary analytic/clinical validity data (eg, MiCheck, Apifiny, candidate gene panels) lack an evidence chain to support clinical utility and thus are not supported for coverage absent stronger validation or outcome studies.
Validation and clinical outcome data required for coverage consideration.
inv-09: Coverage criteria for biomarker tests to guide repeat biopsy
Covered when ALL of the following are met
Intended use population: Patient is a man being considered for repeat prostate biopsy because an initial prostate biopsy was negative or equivocal and clinical suspicion for missed cancer persists.
Policy identifies this population as the relevant group for rebiopsy-directed biomarker testing.
Comparator and prior evaluation: Standard clinical evaluation (eg, DRE, PSA trend, % free PSA, risk calculators) has been performed and documented; consider high-quality prostate MRI when available prior to biomarker testing.
Policy recommends standard assessment prior to using biomarkers to replace or augment decisions.
Test-specific evidence requirement: The ordered biomarker must have demonstrated clinical validity using an appropriate reference standard (eg, repeat biopsy) and analytic validation of the marketed test version; if direct clinical utility evidence is absent, a complete chain of evidence linking test performance to management changes and outcomes is required to support coverage.
Policy emphasizes need for marketed-version validation and chain-of-evidence when RCTs are lacking.
inv-10: ConfirmMDx: Insufficient evidence
Coverage is contingent on established clinical validity and demonstrable clinical utility; for the tests reviewed, such evidence is incomplete.
ConfirmMDx coverage rationale: Clinical validity for ConfirmMDx has not been established to the degree necessary to infer clinical utility; retrospective validation studies report moderate sensitivity and NPV in some cohorts but no direct outcome studies demonstrating improved patient health from test-directed management.
Policy notes sensitivity 62–74% and NPV up to 96% in subgroups but lack of outcome data prevents inferring utility.
inv-11: PCMT: Preliminary evidence only
PCMT has preliminary validation data but lacks independent confirmation and outcome evidence.
PCMT coverage rationale: A small validation study reported sensitivity ~84% and NPV ~91% for the mitochondrial DNA deletion test (PCMT), but independent confirmation and studies showing that use of the test improves clinical outcomes are lacking; selection bias and small sample size limit interpretation.
No studies of long-term outcomes; clinical utility unproven.
Candidate gene panels show initial associations but lack validated clinical performance and outcome data.
Candidate gene panels coverage rationale: Several multigene candidate panels (eg, an 8-gene panel) have reported promising sensitivity in development studies, but clinical validity is unestablished and outcome data are absent; these multigene panels are considered experimental until independently validated.
Validation and comparisons to standard risk models are needed before coverage.
inv-13: Evidence-based coverage rationale
Coverage considerations tied to clinical validity and utility evidence:
Evidence requirements for clinical utility: Clinical utility should be demonstrated by direct comparative studies of outcomes (preferably RCTs). If direct evidence is lacking, a complete chain of evidence founded on robust clinical validity in the intended-use population is required to support coverage decisions.
Policy specifies need for direct outcome data or an intact chain-of-evidence.
inv-14: Experimental / Investigational
The policy lists specific genetic and protein biomarkers that are considered experimental/investigational.
Experimental/Investigational tests: Biomarkers enumerated in Item A of the policy (as revised) are classified as experimental/investigational for the diagnosis of prostate cancer; tests listed may be denied as not medically necessary when used for diagnosis or cancer risk assessment.
See policy Item A revisions and coding history.
Single-nucleotide variant testing to assess inherited or somatic prostate cancer risk is listed in the policy as experimental/investigational and is therefore considered not covered for diagnosis or cancer risk assessment of prostate cancer.
Studies that do not report results for the marketed/validated version of a test or that include patient populations outside the intended-use range (for example, men with PSA >10 ng/mL or with a positive DRE when the intended population is men with indeterminate PSA) were excluded from validity evaluations and limit applicability of findings to clinical practice.
Many primary studies and systematic reviews evaluated cohorts with mixed PSA levels and DRE findings; lack of standardization of diagnostic cutoffs and inclusion of men with low (<4 ng/mL) or high (>10 ng/mL) PSA or positive DREs reduce generalizability of reported test performance to the typical intended-use population.
No coverage justification can be supported for a test if clinical validity is not established. Tests lacking adequate validation against an appropriate reference standard (for example, repeat biopsy when intended to guide rebiopsy) cannot be justified for coverage.
When a test increases overall biopsy rates without demonstrating an associated improvement in net health outcomes (for example, reduced morbidity or improved survival), its use may be considered not medically necessary because of the potential for overtreatment.
Use of novel biomarker assays as standalone replacements for established diagnostic pathways (standard clinical evaluation, risk calculators, or imaging) is unsupported unless studies demonstrate improved clinical outcomes when the test replaces or meaningfully augments those pathways.
Studies that did not use the marketed version of a test, lacked an appropriate reference standard, or failed to report necessary patient or performance data were excluded from clinical validity assessments and therefore do not support coverage considerations.
Tests for which clinical validity is unestablished, or for which no chain of evidence demonstrates clinical utility, are excluded from coverage consideration until adequate analytic and clinical validation and outcome evidence are available.
There are no direct clinical utility studies reported for the MyProstate Score that demonstrate improved patient outcomes; because clinical validity has not been fully established in the contexts needed for decision making, clinical utility cannot be inferred and coverage is not supported.
The policy explicitly lists multiple genetic and protein biomarkers (Item A) that are considered experimental / investigational for the diagnosis of prostate cancer and therefore not eligible for coverage as medically necessary tests.
Use of the listed genetic and protein biomarker tests for diagnosis or cancer risk assessment is regarded as not medically necessary / experimental-investigational in the absence of established clinical validity and demonstrated clinical utility.
Claims that these biomarker tests provide a direct clinical outcome benefit (for example, improved survival or demonstrated management benefit from RCTs) are not supported by the existing evidence base, since randomized controlled trials demonstrating improved health outcomes were not identified.
Because randomized controlled trial evidence demonstrating improved patient outcomes is lacking and clinical validity findings are variable, a reliable chain of evidence linking test results to better clinical outcomes cannot be constructed for many assays.
Use of MiPS (MyProstateScore) or SelectMDx to guide management decisions lacks direct evidence showing improvements in patient outcomes; therefore their routine use for decision-making cannot be supported on the basis of available data.
SelectMDx and ExoDx Prostate (IntelliScore) have demonstrated aspects of clinical validity in some studies, but limitations exist: SelectMDx evidence is insufficient to establish clinical utility, and an RCT of ExoDx did not reduce unnecessary biopsies and instead increased overall biopsy rates, raising concern about net benefit.
Ordering biomarker assays to guide initial biopsy, treatment selection, or other management decisions is unsupported when no evidence shows that such decisions lead to improved health outcomes; in those situations, the tests should not be considered medically necessary.
Use of biomarker results to guide the decision to perform an initial biopsy or to select treatments should be reserved for contexts where clinical utility has been demonstrated; absent such evidence, using biomarkers to make these decisions is considered unsupported.
ConfirmMDx, PCMT, and candidate multigene panels lack direct evidence that their use improves clinical outcomes. Until clinical validity is established and an evidence chain demonstrating clinical utility is available, these assays are not supported for routine management decisions.
MyProstate Score has not been shown in studies to improve outcomes when used to inform repeat biopsy or treatment decisions; because direct outcome evidence is lacking and clinical validity is incomplete, the test is not supported for these purposes.
Tests classified in this policy as experimental/investigational are regarded as not medically necessary for the diagnosis of prostate cancer and may be denied coverage when billed for that purpose.
Billing Codes, Thresholds, and Key Values
Documentation Required
Provider Actions and Billing Guidance
Include the specific PLA/CPT code on the claim and document medical necessity. Confirm the test ordered matches the marketed/validated version and intended-use population (eg, PSA range, DRE status, biopsy-naive vs repeat biopsy). Verify benefit eligibility and that standard evaluation (history of PSA values, % free PSA, DRE, consideration of age/race/family history, and, where appropriate, high-quality prostate MRI or repeat PSA/%fPSA) has been performed or considered before ordering a novel biomarker. Document specimen timing and collection method (eg, first-catch/first-morning urine, post-DRE urine, serum/plasma prior to biopsy) and the algorithm threshold used (eg, PHI 4–10 ng/mL intended-use; ExoDx threshold 15.6; MiPS <10 to rule out GG>2; SelectMDx first-void post-DRE). Provide clinical context in the record: indication for testing, prior standard-of-care tests and results, patient age, DRE findings, PSA level and %fPSA, and whether the test result will change management (eg, defer vs proceed to biopsy). For PCA3 interpretation, document initial vs repeat biopsy intent and the PCA3 threshold applied (eg, >60 for initial biopsy PPV; <20 for repeat biopsy NPV). When ordering methylation- or panel-based tests, document tissue source (eg, FFPE tumor tissue vs urine), assay version, and that the marketed assay methodology was used. Be aware tests without demonstrated net health benefit or outside their intended-use populations carry a high risk of denial as experimental/investigational. No blanket preauthorization or billing denial is stated here, but benefit verification is required and payers may deny payment if documentation does not show medical necessity, appropriate pre-testing, or use of the validated marketed test version.
Confirm intended use and prior standard-of-care testing (PSA history, %fPSA, DRE, MRI consideration).
Code list and medical necessity evaluation: include the specific PLA/CPT code billed and document medical necessity and how result will change management.
Prior Authorization, Documentation, and Ordering Guidance
Prior Authorization
Verify benefit coverage and prior authorization requirements
Prior authorization may be required per the member's contract and payer procedures; tests listed as experimental/investigational in Item A may not meet coverage criteria.
Verify member benefits and applicable mandates before ordering.
Services billed with listed codes will be evaluated for medical necessity according to the Policy section and member contract.
Prior Authorization
Identify marketed test and intended‑use population on authorization
If prior authorization is required, specify the exact marketed test and the intended‑use population (for example, MiCheck, 4Kscore, PHI, SelectMDx, MyProstateScore, or ExoDx and whether the patient is biopsy‑naïve or being considered for repeat biopsy).
Document the marketed/validated version of the test and patient clinical characteristics (PSA level, age, DRE status).
Background and Rationale
Prostate cancer includes a spectrum from indolent to aggressive disease. Conventional tools used to decide on biopsy include serum PSA measurement and digital rectal examination (DRE), but these tests have limited specificity and can lead to many low‑yield biopsies. Biomarker assays are proposed to improve risk stratification to reduce unnecessary biopsies and related morbidity.
Definitions and Test Descriptions
Gleason scoring — architectural grading system and score interpretation
Clinical implicationGleason grade (and Grade Group) is the reference standard for defining clinically significant prostate cancer in validation studies
Use in policyClinically significant or aggressive cancer definitions in the policy use Gleason ≥7 (or Grade Group ≥2) as target conditions
4Kscore / PHI / ExoDx (EPI) — Examples of blood- and urine-based biomarker assays
Key ActionIf prior authorization is required, indicate the specific marketed test and intended-use population and document PSA/DRE and prior biopsy status.
Experimental/Investigational denial risk: tests or uses lacking net health benefit or outside intended-use populations may be denied.
No explicit authorization or billing denial stated in policy: still verify benefits; payer may require documentation at claim review.
Tests not using marketed/validated version: document assay version and specimen source; use of unvalidated methods increases denial risk.
Preliminary evidence/PCMT: if ordering tests supported only by preliminary evidence, document rationale and patient-specific factors.
Experimental/Investigational tests: clearly document when a test is considered investigational and obtain prior authorization if required by the payer.
Benefit Verification: verify member coverage and any testing-specific requirements before ordering.
Test version and patient characteristics: record assay name, version, intended-use PSA range, DRE status, biopsy status (initial vs repeat), and age criteria.
Specimen timing and threshold documentation: document urine timing (first-catch, post-DRE) or serum collection timing and threshold used for interpretation.
Required clinical context: indication for test, how results will affect management (eg, avoid/perform biopsy), and prior test results.
Required clinical context documentation: include PSA value, %fPSA, DRE findings, age, race/family history, and prior imaging (MRI) if applicable.
Required documentation for PCA3 interpretation: initial vs repeat biopsy intent and PCA3 threshold applied (eg, >60 initial, <20 repeat).
When ordering methylation-based tests: document tissue source (FFPE), assay version, and that manufacturer's marketed assay was used.
Suggested documentation elements: clinical indication, prior standard testing and dates/results, specimen type/timing, assay/version, threshold used, and management plan tied to results.
Recommended pre-testing and use considerations: consider MRI, repeat PSA, and %fPSA before biomarker testing; use biomarkers after standard risk assessment.
Coding documentation: list billed CPT/PLA code on claim (eg, 0005U, 0113U, 0339U, 0403U, 0228U, 0591U, 81539, 81542, 81551, 81313) and ensure descriptor matches test.
Use after standard risk assessment: biomarkers intended to refine biopsy decisions in gray-zone PSA values (commonly ~2–10 ng/mL; PHI indicated 4–10 ng/mL).
No step therapy requirements described in policy; step therapy not specifically addressed — nonetheless follow local payer rules.
Consider MRI/repeat PSA/%fPSA before biomarker testing and document that these options were considered or performed.
Use standard evaluation before novel biomarker testing: perform DRE, review PSA trend, and assess patient risk factors prior to ordering.
Step therapy/sequencing: document rationale if biomarker testing is ordered before or instead of repeat PSA/MRI; be prepared to justify medical necessity.
Document the clinical indication when ordering tests; clinical utility is uncertain and payers may require indication and limits (PSA range, DRE status, prior biopsy history).
Clinical reports should include PSA level, DRE status, prior biopsy history, and whether the patient is in the PSA 'gray zone' (approximately 3–10 ng/mL).
Prior Authorization
Follow local payer prior authorization procedures
No explicit prior authorization codes or universal PA rules are specified in this policy; follow local payer rules and member contract regarding PA requirements.
Clinical use and prior authorization depend on documented indication and local policy given insufficient evidence for broad coverage.
Prior Authorization
Confirm intended use and prior standard‑of‑care testing
When requesting prior authorization, confirm the intended use population and that standard‑of‑care testing (repeat PSA, %fPSA, DRE) was considered or performed.
Examples: men being considered for initial biopsy with PSA in the specified range or men with prior negative biopsy being evaluated for repeat biopsy.
Prior Authorization
Recommend prior authorization if test directs biopsy management
Prior authorization is advised when biomarker test results will be used to change biopsy decisions in place of established standard‑of‑care approaches, because direct RCT evidence of clinical utility is lacking.
Authorization reviewers should consider whether use of the test would replace or augment repeat PSA/%fPSA, DRE, or MRI.
Document how the test result will alter management.
Prior Authorization
Obtain prior authorization for repeat‑biopsy biomarker tests
When ordering commercial biomarker tests to inform repeat biopsy selection (e.g., PCA3/Progensa, ConfirmMDx, PCMT, MyProstate Score, gene panels), prior authorization may be required.
Tests intended for repeat‑biopsy selection are evaluated against clinical validity evidence that used repeat biopsy as the reference standard.
Prior Authorization
PA recommended for ConfirmMDx, PCMT, and gene panels
Prior authorization may be required for ConfirmMDx, PCMT, or multigene panel tests due to limited or insufficient evidence of clinical validity and utility; reviewers should assess available validation studies and whether results will change management.
Confirm that the marketed/validated version was used and that the result would alter clinical decision making before approving.
Note
Codes listed are informational — medical necessity will be evaluated
The CPT/PLA codes listed are informational; services billed with these codes will be reviewed for medical necessity according to the Policy section and the member's contract.
Inclusion of a code in the coding section does not imply coverage.
Verify member benefits for coverage determinations.
Billing Rule
Report the specific PLA/CPT/HCPCS code for each test
Claims must report the specific PLA/CPT/HCPCS code referenced in the coding section that corresponds to the biomarker test performed (examples include 0113U, 0339U, 0228U, 0403U, 0591U).
Accurate coding supports the medical necessity review tied to the Policy.
Step Therapy
Perform standard clinical evaluation before biomarker testing
Standard clinical evaluation (DRE, PSA trend, %fPSA, risk calculators, and prostate MRI when recommended) should precede biomarker testing; biomarkers are adjuncts to standard assessment.
Repeat PSA and DRE are recommended prior to using a secondary biomarker.
Consider high‑quality prostate MRI when available for patients with prior negative biopsy and persistent suspicion.
Step Therapy
Use biomarkers after standard risk assessment
Consider biomarker testing only after standard risk assessment (DRE, PSA history, risk calculators and MRI when available) has been completed; biomarkers are intended to be used in the comparator context of standard clinical evaluation.
Document prior standard assessments in the medical record when ordering biomarkers.
Step Therapy
No step therapy mandated
No step therapy requirements or sequencing are specified in this policy for biomarker tests.
Clinical guidelines recommend selective use of biomarkers when results would influence biopsy decisions, but no required sequence is defined.
Step Therapy
Step therapy not specified
Step therapy sequencing is not addressed; there are no policy directives specifying required prior use of other tests before biomarker ordering.
Apply clinical judgment and follow payer‑specific rules where applicable.
Step Therapy
Consider MRI or repeat PSA/%fPSA before biomarker testing
Consider repeat PSA, percent‑free PSA, or prostate MRI before ordering certain biomarker tests, since MRI had the highest net benefit in one comparison and some evidence questions whether biomarkers should replace these evaluations.
Guidelines recommend repeating PSA prior to secondary biomarker or imaging.
Document rationale if proceeding to biomarker testing without these steps.
Prior Authorization
Require standard evaluation before approving biomarker as replacement
Require standard clinical assessment (PSA, %fPSA, DRE, risk calculators) before approving biomarker testing intended to replace those assessments, because evidence is insufficient that biomarkers alone improve patient outcomes.
Document how the test result will change management compared with standard evaluation.
Documentation Required
Document standard clinical evaluation elements in the record
Document PSA trend, DRE findings, risk factors, % free PSA, and prostate MRI results (when applicable) in the clinical record when ordering a biomarker test.
Clinical reports should note whether the patient falls within the PSA 'gray zone' (approximately 3–10 ng/mL) and prior biopsy history.
Note
Note
Documentation Required
Verify member benefits before ordering test
Verify member benefits and applicable state/federal mandates prior to testing; member contract language takes precedence over Policy statements.
Contact BCBSKS Customer Service to confirm benefit coverage for the specific test.
Documentation Required
Document test version and patient characteristics
Document that the marketed/validated version of the test or algorithm was used and include patient clinical characteristics (PSA level, age, DRE status) because clinical validity studies required reporting of these features.
Studies excluded tests that did not use the marketed version; using non‑marketed versions may lead to denial.
Documentation Required
Record specimen timing and thresholds
Document specimen timing and any score thresholds applied (many studies collected urine after DRE and prior to biopsy and used defined positivity thresholds such as PSA >10 ng/mL, T2:ERG >8, or PCA3 >20).
Record timing of sample collection relative to DRE and biopsy and the threshold used to interpret the result.
Note
Note
Documentation Required
Document PCA3 use setting and threshold
When ordering or citing PCA3 results, document whether the test was used for initial versus repeat biopsy, the PCA3 threshold applied (examples: <20 or >60), and integration with clinical risk calculators, because performance differs by setting and threshold.
PCA3 (Progensa) is FDA‑approved to assist decisions among men with prior negative biopsies; thresholds affect PPV/NPV.
Documentation Required
Document prior negative biopsy specimen and indication for methylation tests
When ordering methylation‑based tests (e.g., ConfirmMDx), include information about the prior negative prostate biopsy specimen and the indication for repeat biopsy, since clinical validity data are based on testing archived negative biopsy tissue with repeat biopsy as the reference standard.
ConfirmMDx validation studies used prior negative biopsy cores and repeat biopsy outcomes as the reference standard.
Documentation Required
Provide comprehensive documentation of indication and management impact
Include indication (initial vs repeat biopsy), prior biopsy results, PSA/DRE status, and how test results will change management when ordering biomarker tests, because direct evidence of clinical utility is lacking and reviewers will evaluate whether results will alter care.
Provide a clear management plan tied to the test result to support medical necessity review.
Documentation Required
Adhere to guideline‑based pretesting workflow
Follow guideline‑based pretesting: repeat PSA and DRE prior to secondary biomarker testing; clinicians may use adjunctive urine or serum markers when results would influence the biopsy decision.
After a negative biopsy, biomarkers may be used selectively for further risk stratification if results will influence repeat biopsy decisions.
Denial Risk
Risk of denial: experimental/investigational classification
Use of the listed genetic and protein biomarker tests for diagnosis or cancer risk assessment is considered experimental/investigational and may be denied as not medically necessary.
Tests listed in Item A are regarded as not medically necessary for prostate cancer diagnosis per the Policy.
Inclusion of a code does not imply coverage; refer to the member's contract.
Denial Risk
Risk of denial for unvalidated test versions or out‑of‑population use
Use of tests outside their marketed/validated version or in populations not reflective of intended use (for example, PSA >10 ng/mL or positive DRE when not intended) may trigger coverage denial.
Studies that did not use the marketed version or included out‑of‑range PSA/DRE were excluded from validity evaluation and may not support coverage.
Denial Risk
Denial risk: SelectMDx evidence limitations
Insufficient clinical validity evidence for SelectMDx may lead to denial of coverage when the chain of evidence for clinical utility cannot be constructed.
SelectMDx clinical validity is currently insufficient to establish a chain of evidence for clinical utility; document intended population and supporting data.
Denial Risk
Denial risk: lack of demonstrated net health benefit
Tests (including ExoDx) that increase biopsy rates or lack demonstrated net health benefit risk being considered not medically necessary if their use leads to increased biopsies and potential overtreatment without improved outcomes.
One RCT of ExoDx increased biopsy rates and did not meet its primary endpoint of reducing unnecessary biopsies; document rationale if using such tests.
Denial Risk
Denial risk: absent RCT evidence of clinical utility
Lack of randomized controlled trial evidence demonstrating clinical utility may lead to denial when tests are proposed to change management without outcome data.
Direct evidence from RCTs is preferred; absence of such trials weakens support for medical necessity determinations.
Note
Denial Risk
Denial risk: insufficient ConfirmMDx evidence
Lack of established clinical validity and an incomplete chain of evidence for ConfirmMDx may lead to noncoverage or denial.
While ConfirmMDx showed sensitivity 62–74% and NPV 79–90% in validation studies, no data demonstrate effects on clinical outcomes.
Denial Risk
Denial risk: preliminary PCMT evidence
Preliminary and unconfirmed performance of PCMT, and absence of direct clinical outcome data, may trigger coverage denial.
PCMT validation was small and independent confirmation of clinical validity is lacking.
Denial Risk
Denial risk: unvalidated multigene panels
Candidate multigene panels without established clinical validity or independent confirmation lack a chain of evidence to support clinical utility and may be denied.
Provide validation data using marketed versions and appropriate reference standards to mitigate denial risk.
Note
Coding does not guarantee coverage — verify benefits and medical necessity
Inclusion or exclusion of procedure, diagnosis, or device codes in the coding section does not imply member coverage; services billed with these codes will be evaluated for medical necessity according to the Policy and member contract.
Verify benefit coverage and document medical necessity per policy criteria.
Denial Risk
Tests in Item A are considered not medically necessary — expect denials without justification
Tests classified as experimental/investigational in Item A are considered not medically necessary and may be denied; prior authorization may be required to document intended use and evidence.
If a test in Item A is requested, expect coverage review and potential denial unless adequate supporting evidence and appropriate clinical context are provided.
Assays may use plasma/serum (4Kscore, PHI), urine after DRE or without DRE (SelectMDx, ExoDx), or tissue for methylation tests (ConfirmMDx)
PurposeThese tests produce algorithmic risk scores intended to improve selection for initial or repeat prostate biopsy versus standard clinical evaluation
MiCheck %Risk of csPCa — Algorithmic percentage risk score combining tPSA, fPSA, HE4, and age
MiCheck %Risk of csPCa (definition)Algorithmic percentage risk score combining tPSA, fPSA, HE4, and age to estimate probability of clinically significant prostate cancer
Target conditionPredicts aggressive prostate cancer (Gleason >3+4) as reported in development/validation studies
Evidence statusMiCheck has preliminary development and validation data but lacks RCTs demonstrating clinical utility
Clinically significant prostate cancer (csPCa) — Typically Gleason ≥7
Clinically significant prostate cancer (csPCa) definition usedTypically defined as Gleason score ≥7 (Grade Group ≥2) in this policy and validations
Role in evaluationsMost clinical validity studies report performance for detection of csPCa (Gleason ≥7) as the primary outcome
Implication for thresholdsTest thresholds and decision models are selected to optimize detection of csPCa while reducing unnecessary biopsies
PHI / proPSA — Prostate Health Index integrates proPSA with PSA measures
PHI / proPSA definitionProstate Health Index integrates [-2]proPSA with total and free PSA to calculate a PHI score used to aid diagnosis
Reported performance rangeSystematic reviews report sensitivities ~85–93% with variable specificity and NPV across studies
FDA approval notePHI (proPSA) received FDA approval for men ≥50 with PSA 4–10 ng/mL and non-suspicious DRE
MiPS / MyProstateScore componentsCombines urine TMPRSS2-ERG and PCA3 scores (and serum PSA) to generate an algorithmic risk score
Versions notedMyProstateScore (MiPS) and MyProstateScore 2.0 are urine-based assays measuring PCA3 and TMPRSS2-ERG with algorithmic risk outputs
Validated threshold exampleTosoian et al. (2021) identified MyProstateScore <10 as a rule-out threshold for Grade Group ≥2
MiPS (MyProstate Score) — TMPRSS2-ERG, PCA3, and PSA algorithm
MiPS (MyProstate Score) components and purposeTMPRSS2-ERG, PCA3, and PSA algorithm to estimate prostate cancer risk and improve specificity over PSA alone
Study contextsValidated in cohorts undergoing initial and repeat biopsy; samples typically collected after DRE and prior to biopsy
Performance notesReported to improve AUC vs some risk calculators in certain studies though results vary across analyses
SelectMDx — Urine-based HOXC6 and DLX1 expression with clinical factors
SelectMDx descriptionUrine-based HOXC6 and DLX1 mRNA expression combined with clinical factors to predict clinically significant prostate cancer
Sampling methodFirst-void urine collected after DRE is used for SelectMDx testing in validated protocols
Reported AUCsStudies report improved AUC versus clinical risk models in some cohorts, especially within PSA gray-zone populations
ExoDx Prostate (IntelliScore) descriptionUrine exosome RNA assay (PCA3, ERG, SPDEF) producing an IntelliScore that predicts high-grade (Gleason ≥7) prostate cancer
DRE requirementExoDx does not require DRE prior to collection in its marketed procedure
Validation performanceReported sensitivity ~97% and NPV ~96% for high-grade cancer in intended-use cohorts
SelectMDx — urine mRNA-based test incorporating HOXC6 and DLX1 expression plus clinical factors
SelectMDx (test summary)Urine mRNA-based test incorporating HOXC6 and DLX1 expression plus clinical factors to estimate risk of high-grade prostate cancer
Evidence summarySystematic reviews show pooled sensitivity ~82% and specificity ~56% with NPV ~90% in some analyses
Population noteMost applicable to men in PSA gray zone (3–10 ng/mL) with normal DRE
Apifiny — autoantibody-based assay in preliminary development
Apifiny summaryAutoantibody-based assay in preliminary development with AUC ~0.69 in a validation set
Evidence statusPerformance thresholds and full diagnostic metrics not established; further validation required
MiCheck Prostate — serum-based algorithmic test developed to predict aggressive prostate cancer (GS ≥3+4)
MiCheck Prostate summarySerum-based algorithmic test combining tPSA, fPSA, HE4, and age to predict aggressive prostate cancer (GS ≥3+4)
Reported performanceDevelopment/validation studies reported AUC ~0.83 (training) and AUC ~0.79 in subsequent validation; sensitivity and NPV for aggressive cancer reported high in initial cohorts
Aggressive prostate cancer — defined as Gleason ≥3+4 in this policy
Aggressive prostate cancer definition used in policyDefined as Gleason ≥3+4 (Grade Group ≥2) for target condition in performance reporting
Use in validationsMany tests report sensitivity/NPV specifically for detection of aggressive (Gleason ≥3+4) disease
ImplicationThresholds and clinical decision rules are often chosen to prioritize detection of aggressive disease while reducing unnecessary biopsy
PCA3 thresholds — <20 and >60 thresholds cited
PCA3 thresholds citedExamples cited include PCA3 <20 for repeat-biopsy NPV and PCA3 >60 for initial-biopsy PPV
Progensa statusProgensa PCA3 Assay is FDA-approved to assist decisions among men with prior negative biopsies
Interpretation guidanceThreshold selection depends on clinical setting (initial vs repeat biopsy) and should be documented
PCA3 (Progensa PCA3 Assay) — Urine-based assay FDA-approved to assist decision making among men with prior negative prostate biopsy
Progensa PCA3 Assay (FDA-approved use)Urine-based PCA3 mRNA assay after prostate massage; FDA-approved to assist decision making among men with prior negative prostate biopsies
Typical applicationUsed to inform repeat-biopsy decisions in the context of persistent clinical suspicion
Documentation noteReport whether test used for initial vs repeat biopsy and the PCA3 threshold applied
ConfirmMDx — tissue-based methylation assay for prior negative biopsy cores
ConfirmMDx descriptionTissue-based methylation assay measuring GSTP1, APC, and RASSF1 methylation in prior negative biopsy cores to identify false-negative biopsies
Validation evidenceThree blinded multicenter validation studies reported sensitivity range ~62–74% and NPV range ~79–90% for negative second biopsy
Intended applicationIntended to inform repeat-biopsy decisions using archived negative biopsy tissue as the specimen
PCMT — Prostate Core Mitomics Test detecting mitochondrial DNA deletion in tissue
PCMT (Prostate Core Mitomics Test) descriptionTissue-based test detecting a 3.4-kb mitochondrial DNA deletion by PCR to identify tumor field effect in initial negative biopsy tissue
Evidence statusPreliminary validation data reported (sensitivity ~84%) but lacks independent confirmation and outcome evidence
Intended useProposed to help decide need for repeat biopsy after an initial negative biopsy
MyProstate Score 2.0 — urine test analyzing gene transcripts to predict Grade Group ≥2
MyProstate Score 2.0 descriptionUrine test analyzing an array of gene transcripts to predict Grade Group ≥2 (clinically significant prostate cancer)
PLA/CPT codingMyProstateScore is represented by PLA code 0113U in coding section
Intended useDesigned to improve prediction of clinically significant prostate cancer in men considered for biopsy
Clinically Useful — definition
Clinically Useful (definition)A test whose results inform management decisions that improve net health outcome (eg, guide correct or more effective therapy or avoid unnecessary procedures)
Implication for coverageClinical utility requires demonstrated change in management that yields better patient outcomes
Evidence requirementsRCTs or a convincing chain of evidence linking analytical validity, clinical validity, and improved outcomes are preferred
Clinically Valid — definition
Clinically Valid (definition)A test that detects presence/absence of a condition, future risk, or treatment response (beneficial or adverse)
Use in policy evaluationClinical validity (eg, sensitivity/specificity for Gleason ≥7) is necessary to build a chain of evidence for clinical utility
Documentation implicationStudies should use an appropriate reference standard (eg, repeat biopsy) and report thresholds and population details
Clinically Valid — A test must detect the presence/absence or risk or treatment response
Clinical validity requirement (restated)A test must detect the presence/absence of a condition, the risk of developing a condition, or treatment response
Policy relevanceAbsence of established clinical validity precludes inference of clinical utility in this policy
Reference standard noteMany reviewed studies used biopsy outcomes as the reference standard for clinical validity assessments
Clinically Useful — definition restated
Clinical usefulness requirement (restated)A test is clinically useful if results inform management decisions that improve net health outcomes (correct therapy or avoid unnecessary testing/therapy)
Coverage implicationTests lacking demonstrated effect on management and outcomes are considered experimental/investigational in this policy
Expectations for evidenceRandomized trials or validated chains of evidence linking test results to improved outcomes are preferred
GPS (Genomic Prostate Score) summarymRNA gene expression profiling of 17 genes from FFPE tissue reported as a risk score (PLA 0047U described in coding)
Use caseReported as a prognostic/risk score to inform management decisions in prostate cancer
MyProstateScore — measurement of PCA3 and TMPRSS2-ERG in urine after prostatic massage (PLA 0113U)
MyProstateScore measurement detailsMeasures PCA3 and TMPRSS2-ERG in urine after prostatic massage with PSA in serum; algorithm reported as a risk score (PLA 0113U)
Specimen timingUrine collected after DRE/prostatic massage and serum PSA obtained prior to biopsy in validation studies
Validation noteThresholds and cutoffs (eg, <10) were established in training cohorts and validated in combined datasets
SelectMDx — mRNA expression profiling of HOXC6 and DLX1 (PLA 0339U)
SelectMDx test detailsmRNA expression profiling of HOXC6 and DLX1 in first-void urine after DRE, reported as probability of high-grade cancer (PLA 0339U)
Sample handlingFirst-void urine after DRE is specified in validation studies for SelectMDx
Coding noteSelectMDx is represented by PLA code 0339U in the coding section