Modifiedblue cross blue shield - kansasPolicy N/A

Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

Policy governs coverage of comprehensive genomic profiling (expanded tumor genomic panels) to guide targeted therapy selection for individuals with advanced or recurrent cancer; applies to Blue Cross and Blue Shield of Kansas members.

Policy Summary

Payerblue cross blue shield - kansas

PolicyComprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

Policy CodePolicy N/A

Change TypeModified — criteria and coding updates

Effective DateMar 26, 2024

Next Review Date

Key ActionObtain prior authorization and document that the patient has not previously had genomic sequencing using the same assay for the same genomic location and that the test is FDA-approved or performed in a CLIA-certified laboratory.

SourceLink

POLICY UPDATE CHANGES

Section A1 changed the language to require that the individual has not previously had a genomic sequencing procedure using the same assay to investigate the same kind of alteration in the same genomic location.

Section A5 clarified that the genomic sequencing procedure must have FDA approval or be a validated diagnostic laboratory test performed in a CLIA-certified laboratory.

Gastroesophageal Cancer was added to the list of cancer types in Section A3.

Multiple new PLA/unique CPT codes (e.g., 0379U, 0391U, 0409U, 0473U, 0543U) were added to the coding section across updates.

A1-A5policy criteria structure (Sections)

Aug 13, 2024most recent literature update

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04-01-2025most recent coding update

50+CPT/PLA/MAAA codes enumerated

MultipleFDA-cleared panels/examples

Coverage criteria for comprehensive genomic profiling

Medically necessary — Comprehensive genomic profiling

Covered when ALL of the following are met:

Policy A medically necessary criteria: 1. The individual has not previously had a genomic sequencing procedure using the same assay to investigate the same kind of alteration in the same genomic location; 2. The individual has been diagnosed with recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; 3. The individual has one of the following cancer types: Breast cancer, Colorectal cancer, Gastroesophageal cancer, Melanoma, Non-small cell lung cancer, Ovarian cancer, Pancreatic cancer, or Prostate cancer; 4. The individual has decided to seek further treatment (e.g., therapeutic chemotherapy); 5. The genomic sequencing procedure has received FDA approval or is a validated diagnostic laboratory test performed in a CLIA-certified laboratory.

All conditions must be satisfied for coverage.

Evidence-based criteria and considerations

Clinical utility and validity considerations for comprehensive genomic profiling

Intended use: Test is performed on tumor tissue to identify somatic variants to guide targeted therapy in individuals with advanced cancer who have not previously received targeted therapy.

From PICO and populations

Test content: Comprehensive profiling must include major variant types (single nucleotide variants, small and large insertions/deletions, copy number variants, and gene fusions) and may include assessment of microsatellite instability and tumor mutational burden.

Defines scope of tests considered

Clinical validity must be demonstrated for specific variant–tumor pairings; panel-level clinical validity for expanded panels as a whole is not established because of heterogeneity of variants and tumor types.

Per-variant evidence required

Clinical utility evidence: High-quality evidence (randomized controlled trials) comparing variant-directed therapy with standard care is preferred; available RCT (SHIVA) using expanded panels showed no progression-free survival benefit in a refractory population.

RCT evidence is necessary to demonstrate net health outcome improvement

Supporting observational evidence: Systematic reviews and nonrandomized studies report higher response rates, PFS, and OS with variant-matched therapies within specific tumor types, but these do not establish that broad genomic profiling is superior to tumor-specific testing.

Observational evidence supports targeted approaches but not broad panel advantage

Evidence-based coverage considerations

Summary statements from evidence and guidelines relevant to coverage decisions:

Clinical utility summary: Randomized and nonrandomized trials yield mixed results: some studies and meta-analyses show improved response, PFS, and OS when therapy is matched to genetic variants, but the SHIVA randomized trial using expanded panels reported no PFS difference; overall, clinical utility of expanded panels to direct targeted therapy beyond tumor-specific testing has not been demonstrated.

See SHIVA and systematic reviews.

Society guideline relevance: ASCO (provisional clinical opinion) recommends genomic testing for metastatic/advanced solid tumors when (1) genomic biomarker–linked therapies are approved for that cancer, or (2) when biomarker status (eg, dMMR/MSI, TMB) influences immunotherapy decisions; NCCN provides tumor-specific gene testing recommendations (eg, breast, colon, NSCLC, ovarian, pancreatic, prostate).

See ASCO and NCCN guidance.

Evidence limitations: Many studies are nonrandomized or have design limitations (selection bias, lack of blinding, heterogeneous populations), which limits applicability of results to broad genomic profiling coverage decisions.

Initial coverage criteria (Section A)

Covered when ALL of the following are met

Policy A coverage criteria: 1) The individual has not previously had a genomic sequencing procedure using the same assay to investigate the same kind of alteration in the same genomic location; AND 2) The individual has been diagnosed with recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; AND 3) The individual has one of the following cancer types: breast, colorectal, melanoma, non-small cell lung cancer, ovarian, pancreatic, prostate, or gastroesophageal cancer; AND 4) The individual has decided to seek further treatment (e.g., therapeutic chemotherapy); AND 5) The genomic sequencing procedure has received FDA approval or is a validated diagnostic laboratory test performed in a CLIA-certified laboratory.

Exact section language summarized from policy A (see coding/revision history).

The policy states that the use of comprehensive genomic profiling panels is considered experimental/investigational when the medical necessity criteria in Policy A are not met. This means coverage is limited to cases that satisfy all listed conditions (see Policy A); testing that does not meet those requirements is treated as investigational and not covered.

The document notes that panel-level clinical validity is not established. Because expanded panels include hundreds of variants across many cancer types, the clinical validity of a panel as a whole cannot be determined; validity must be demonstrated for specific variant–tumor pairings rather than for the entire panel.

Evidence summaries conclude that the clinical utility of expanded molecular panels to direct targeted cancer treatment has not been demonstrated compared with limited, tumor-specific testing. While trials and nonrandomized studies show benefit when therapy is matched to specific variants, randomized data using broad panels (eg, the SHIVA trial) did not show a PFS advantage, and therefore routine use of broad profiling to guide targeted therapy remains of unproven utility.

One of the Policy A requirements explicitly excludes individuals who have already undergone the same genomic interrogation: coverage requires that the individual has not previously had a genomic sequencing procedure using the same assay to investigate the same kind of alteration in the same genomic location. Prior identical testing with the same assay for the same target therefore precludes coverage under the policy.

Within the referenced sections and committee notes, no additional explicit exclusions (beyond the policy criteria and prior-testing restriction) are listed. The document states that no other explicit exclusions appear in these sections.

Indications covered by this policy

Individuals with recurrent, relapsed, refractory, metastatic, or advanced (stage III/IV) solid tumors of specified types being considered for targeted therapy; purpose is to identify somatic variants in tumor tissue to guide targeted treatment decisions.

Covered indications for comprehensive genomic profiling — key clinical scenarios where testing is intended to inform targeted treatment or trial enrollment:

Advanced/recurrent solid tumors considered for targeted therapy: The individual has recurrent, relapsed, refractory, metastatic, or advanced (stage III/IV) solid tumor and testing is performed to identify somatic variants in tumor tissue to guide targeted treatment decisions.

Policy focuses on somatic tumor profiling rather than germline testing; see clinical context.

Identification of somatic tumor variants to guide targeted therapy in individuals with advanced cancer who have not previously received targeted therapy.

Clinical context and population for intended use:

Advanced cancer without prior targeted therapy: Identification of somatic tumor variants to guide targeted therapy in individuals with advanced cancer who have not previously received targeted therapy.

Coding and billing codes

No explicit CPT/HCPCS/ICD-10 codes listed in this part of the documentmixed

No codes listed

Covered CPT Codes (selected list)CPTCovered

81445	Solid organ neoplasm, genomic sequence analysis panel 5-50 genes, DNA analysis or combined DNA and RNA analysis.
81449	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, RNA analysis.
81450	Hematolymphoid neoplasm, genomic sequence analysis panel, 5-50 genes, DNA analysis or combined DNA and RNA analysis.
81451	Hematolymphoid neoplasm, genomic sequence analysis panel, 5-50 genes, RNA analysis.
81455	Solid organ or hematolymphoid neoplasm, 51 or greater genes, DNA analysis or combined DNA and RNA analysis.
81456	Solid organ or hematolymphoid neoplasm, 51 or greater genes, RNA analysis.
88342	Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure.
88381	Microdissection (sample preparation of microscopically identified target); manual.

PLA and other specific assay codesmixedCovered

0019U	Oncology, RNA, gene expression by whole transcriptome sequencing, FFPE or fresh frozen tissue, predictive algorithm reported as potential targets.
0022U	Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes.
0036U	Exome (somatic mutations); paired FFPE tumor tissue and normal specimen, sequence analyses.
0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes (FoundationOne CDx PLA).
0048U	Oncology (solid organ neoplasia), DNA, targeted sequencing of 468 cancer-associated genes (MSK-IMPACT).
0101U	Hereditary colon cancer disorders, genomic sequence analysis panel (ColoNext).
0102U	Hereditary breast cancer-related disorders, genomic sequence analysis panel (BreastNext).
0103U	Hereditary ovarian cancer panel (OvaNext).
0111U	Oncology (colon), targeted KRAS and NRAS gene analysis (Praxis Extended RAS Panel).
0174U	Oncology (solid tumor), mass spectrometric 30-protein targets, prognostic/predictive algorithm (OncoOnimisDx).

1–10 of 21

1/3

Tumor mutational burden (TMB) — threshold

TMB threshold> 10 mutations per megabase

Use case for TMBReferenced as a biomarker for immunotherapy eligibility (Keytruda) in solid tumors when TMB >10 mut/Mb

Measurement contextReported as tumor mutational burden determined from multigene panels or whole-exome analysis

Panel gene count thresholds

Small panels (5–50 genes)CPT codes 81445/81449/81450/81451 describe panels interrogating 5–50 genes for sequence variants, copy number variants, or rearrangements

Larger panels (51+ genes)

Provider requirements, prior authorization, and documentation

Prior Authorization

Prior authorization / Medical necessity verification — Prior authorization required when medical necessity criteria must be verified before coverage

Prior authorization may be required when medical necessity must be verified before coverage. The policy's medical necessity criteria require that the individual has not previously had a genomic sequencing procedure using the same assay to investigate the same kind of alteration in the same genomic location; has recurrent, relapsed, refractory, metastatic, or advanced stage III/IV cancer; has one of the listed cancer types; has decided to seek further treatment; and that the sequencing procedure is FDA-approved or a validated diagnostic test performed in a CLIA-certified laboratory.

Prior authorizationrecommended when medical necessity verification is required
Medically necessary criteria must be documented (see policy A1–A5)
Tests must be FDA-approved or CLIA-validated diagnostic laboratory tests

Prior Authorization

Confirm clinical validity for indicated variant–tumor pairings

Prior authorization should confirm the test is intended to detect somatic tumor variants (SNVs, indels, CNVs, fusions, with optional MSI and TMB) and is clinically appropriate for the tumor/variant pairing being investigated. The evidence base indicates clinical validity is variant- and tumor-specific; ensure the requested assay reports the relevant variants for the indicated cancer type.

Situations not covered by this policy

The policy focuses on comprehensive genomic profiling (CGP), which tests a large number of somatic tumor markers to identify potential targeted therapies. It distinguishes CGP and expanded panels from single-gene tests or small tumor-specific panels, and notes that single-gene or focused panels with established clinical utility are addressed in other policies rather than in this coverage statement.

The policy indicates that claims that an expanded panel has clinical validity as a whole for many cancers are unsupported. Because expanded panels include many variants across diverse tumor types, clinical validity must be established for each specific variant–tumor pairing rather than for panel-level claims, and broad panel-level validity is not established.

The routine use of expanded molecular panels to direct targeted therapy is considered not covered when it is not tied to guideline-recommended or regulatory-approved biomarker–linked treatments. Randomized evidence (for example, the SHIVA trial) did not show benefit for off-label targeted therapy based on broad profiling in a refractory population, supporting the exclusion of routine, untargeted use of large panels outside guideline-supported indications.

Historically, CGP was described as experimental/investigational; the updated policy replaces that blanket statement with defined medically necessary criteria. Aside from the clarified prior-testing restriction and policy criteria, the excerpt does not list other specific test-level exclusions within these sections.

Across the referenced sections, the document does not enumerate additional explicitly excluded tests or indications beyond those captured by the policy criteria and the prior-testing restriction.

Definitions and background information

Comprehensive genomic profiling (CGP) evaluates large numbers of somatic tumor markers to identify potential targeted therapies. The policy emphasizes that expanded panels may include many variants without established, tumor-specific therapeutic benefit and that clinical validity and utility must be demonstrated for specific variant–tumor pairings. CGP differs from single-gene tests or focused tumor-specific panels, which may have established clinical utility and are handled in separate policies.

Expanded panel (definition)

DefinitionA molecular panel that tests a wide variety of genetic markers in cancers without regard for whether a specific targeted treatment has demonstrated benefit for that cancer.

ScopeFocuses on many potential variants rather than tumor-specific, limited panels; may lead to treatment choices different from usual cancer-type–based selections.

Policy focusThis policy evaluates 'expanded' panels rather than single-gene or small tumor-specific panels with established utility.

Laboratory-developed test (LDT)

Eligibility requirements and related notes

(No top-level eligibility requirements are specified in the inventory for this section.)

Additional provider-facing notes

Note

Genetic counseling requirements

No explicit pre- or post-test genetic counseling requirements are stated in the policy sections referenced.

Counseling is not mandated by this policy; follow local practice guidelines as appropriate.

Note

Follow intended-use statements for FDA-cleared tests

Some FDA-cleared tests indicate intended use by 'qualified health care professionals'; ordering clinicians should follow the test's intended-use statements.

Check the assay's labeling for any restrictions on who may order the test.

Note

Billing rules and common denial triggers

Note

Policy Summary

Payerblue cross blue shield - kansas

PolicyComprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

Policy CodePolicy N/A

Change TypeModified — criteria and coding updates

Effective DateMar 26, 2024

Next Review Date

SourceLink

On This Page

Study design limitations reduce generalizability.

From PICO/populations in evidence review.

Metastatic or advanced solid tumors when patients are candidates for genomic biomarker–linked therapies approved by regulatory agencies, or when biomarker status (dMMR/MSI, TMB) influences immunotherapy decisions.

When multigene testing is recommended by professional societies:

Biomarker-linked therapy or immunotherapy decision: Metastatic or advanced solid tumors when patients are candidates for genomic biomarker–linked therapies approved by regulatory agencies, or when biomarker status (dMMR/MSI, TMB) influences immunotherapy decisions; ASCO recommends multigene panels when multiple biomarkers may guide therapy and for assessing TMB/MSI when relevant.

ASCO provisional opinion supports these scenarios; NCCN lists tumor-specific gene panels.

Recurrent, relapsed, refractory, metastatic, or advanced stage III/IV cancer of specified tumor types (breast, colorectal, melanoma, non-small cell lung, ovarian, pancreatic, prostate, gastroesophageal).

Covered cancer types under Policy A (applicability requires meeting all Section A criteria):

Specified tumor types: Recurrent, relapsed, refractory, metastatic, or advanced stage III/IV cancer of the following tumor types: breast; colorectal; melanoma; non-small cell lung; ovarian; pancreatic; prostate; or gastroesophageal cancer.

Patient must be considering further treatment and not have prior same-assay sequencing of the same alteration/location; assay must be FDA-approved or CLIA-validated.

Use of somatic genomic testing/CGP in metastatic or advanced cancer to direct targeted therapy selection or enrollment in precision oncology trials

Intended uses for directing therapy or clinical trial enrollment:

Direct targeted therapy or trial enrollment: Use of somatic genomic testing/comprehensive genomic profiling in metastatic or advanced cancer to direct selection of targeted therapies or enrollment in precision oncology trials.

Supported by multiple precision-medicine studies and ASCO provisional opinion; documentation of actionable variants and their use in management is expected.

CPT codes 81455/81456 cover panels of 51 or greater genes (DNA and/or RNA analysis)

Very large/expanded panels (80–648 genes)PLA codes and specific assay codes list panels ranging up to 648 genes (examples include 84+, 257, 324, 437, 468, 517, 523, and 648 gene panels)

Assay scope: SNVs, indels, CNVs, fusions; may include MSI and TMB
Confirm assay reports the variant/tumor pairing relevant to treatment decisions

Prior Authorization

Prior authorization recommendation — When testing is performed to identify biomarker-linked therapies that are regulatory-agency approved or to inform use of tumor-agnostic therapies

When testing is performed to identify biomarker-linked therapies that are regulatory-agency approved or to inform use of tumor-agnostic treatments, prior authorization is recommended to verify that testing aligns with guideline recommendations (eg, ASCO, NCCN) and that results will inform an approved therapy or appropriate clinical decision.

Use multigene testing when patients are eligible for regulatory-approved biomarker-linked therapies
Consider multigene panels when multiple biomarkers could affect therapy choice

Prior Authorization

PA requirement for listed genomic assay codes — Prior authorization may be required for comprehensive genomic profiling/targeted genomic sequence assays identified by the CPT/PLA codes

Prior authorization may be required for comprehensive genomic profiling assays identified by CPT/PLA codes listed in the Coding section. Confirm payer-specific code-level requirements and effective dates when submitting authorizations.

Verify coverage/PA requirements for specific CPT/PLA/HCPCS codes prior to billing
Refer to most recent coding updates for effective dates and added codes

Note

Prior authorization — No explicit prior authorization requirements are specified in these sections.

No explicit prior authorization process, step therapy requirements, or detailed documentation checklist is provided in the policy text. Providers should follow payer-specific administrative procedures and local prior authorization portals for submission requirements.

No explicit step therapy program is described in this policy
No explicit denial triggers are listed in the policy text beyond failure to meet medical necessity criteria
No comprehensive documentation checklist is provided in the policy; document clinical indication, prior testing history (same assay/alteration/location), tumor stage/status, and that the test is FDA-approved or CLIA-validated

Denial Risk

Denial triggers — Failure to meet the medical necessity criteria (see Policy A)

Providers should be aware that denials may result if the medical necessity criteria are not met (for example, prior identical genomic sequencing using the same assay for the same alteration/location) even though the policy does not list an explicit denial triggers section. To reduce denial risk, include documentation showing the assay has not been previously used for the same alteration/location and that the patient meets the policy clinical criteria.

Potential denial rationale: clinical utility not demonstrated for expanded panels when criteria not met
Denial risk if prior same-assay sequencing for same alteration/location is documented

Documentation Required

Required documentation — Document that the individual has not previously had genomic sequencing with the same assay for the same genomic location, has recurrent/advanced disease, and that the assay is FDA-approved or CLIA-validated

Documentation supporting authorization requests should include sufficient clinical information even though the policy does not provide a formal checklist. At minimum, submit: cancer diagnosis and stage, prior treatment history, intent to pursue further treatment, prior genomic testing history (including assay and genomic locations tested), and laboratory validation (FDA approval or CLIA certification).

Minimum recommended documentation: diagnosis/stage, treatment plan, prior testing history (same assay/alteration/location), assay regulatory/validation status
Include genomic profiling results when available (identified actionable alterations and genes tested) to support medical necessity

Note

Single-gene testing alternative — Consideration of single-gene testing versus comprehensive profiling is relevant

Consider whether single-gene testing is appropriate per tumor-specific guidelines before authorizing broad panels when guideline-directed single-gene tests exist (eg, EGFR/ALK/ROS1 in NSCLC). The policy recognizes single-gene testing as a current comparator practice.

Order single-gene tests first when guideline recommendations specify them for the tumor type
If multiple biomarkers are relevant or tumor-agnostic therapy is considered, multigene panels may be preferred

DefinitionA test developed and validated in-house by a clinical laboratory that must meet CLIA high-complexity standards and laboratory licensing requirements.

Regulatory expectationLaboratories offering LDTs must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing.

Relation to coveragePolicy requires testing to be FDA-approved or a validated diagnostic laboratory test performed in a CLIA-certified laboratory; LDTs must meet CLIA high-complexity standards.

Comprehensive genomic profiling (term reference)

Term referencedComprehensive genomic profiling (CGP) — refers to tumor sequencing including major variant types (SNVs, indels, CNVs, fusions) and may include MSI and TMB.

MethodologiesTypically performed by next-generation sequencing technologies on tumor tissue; may include DNA and/or RNA analyses.

PurposeTo identify somatic variants in tumor tissue to guide targeted therapy decisions in advanced cancers.

Clinical outcomes (definitions)

Beneficial outcomesIncreased progression-free survival (PFS) and overall survival (OS), or avoidance of ineffective therapy.

Harmful outcomesReceiving ineffective therapy based on test results can cause adverse events without benefit.

Outcome monitoringFollow-up to monitor outcomes varies from several months to years depending on cancer type and stage.

Master basket trial (definition)

DefinitionA master basket trial sequences tumors of various types and assigns patients to targeted treatments based on molecular alterations.

ExampleNCI-MATCH enrolled 6,391 patients, sequenced 143 genes, and assigned patients to multiple treatment subprotocols.

PurposeProvides preliminary evidence on tumor-agnostic treatments and supports biomarker-selected subprotocols and combination trials.

Tumor-agnostic therapy (definition)

DefinitionTumor-agnostic therapy: treatments given based on a tumor’s molecular biomarker irrespective of the tumor’s tissue of origin.

Guideline contextASCO recommends considering genomic testing to determine candidacy for tumor-agnostic therapies in metastatic/advanced solid tumors without approved biomarker-linked therapies.

Use caseApplied when biomarker status (e.g., dMMR/MSI, TMB) or other actionable alterations indicate benefit from tumor-agnostic agents.

CGP (abbreviation)

AbbreviationCGP = Comprehensive Genomic Profiling

ComponentsCGP often includes DNA and/or RNA NGS panels interrogating sequence variants, copy number alterations, rearrangements, TMB, and MSI.

Context in policyPolicy uses CGP to refer to multigene tumor sequencing for identifying somatic variants to guide targeted therapy in advanced cancers.

Comprehensive genomic profiling (term referenced)

NoteComprehensive genomic profiling (CGP) is referenced throughout the policy; in some chunks the term is cited without an explicit standalone definition.

Clinical contentDescribed as multigene NGS panels assessing SNVs, indels, CNVs, fusions, and optionally MSI and TMB to inform targeted therapy decisions.

Coding linkageCGP is represented in coding by multiple CPT/PLA codes covering panels from small (5–50 genes) to very large (up to 648 genes).

Order testing within oncology care when results will guide treatment

Testing should be ordered in the context of advanced/metastatic solid tumors by oncology providers when results will inform selection of regulatory-approved biomarker-linked therapies or when recommended by tumor-specific guidelines.

Ordering clinician should be managing care for a patient seeking further treatment for advanced/recurrent cancer.

Documentation Required

Ordering clinician responsibility

The ordering clinician must be managing the patient’s care and the patient must be seeking further treatment for advanced or recurrent cancer; the policy does not list narrower provider-type requirements in the referenced excerpt.

Document that the ordering clinician is responsible for the patient’s ongoing cancer care and treatment decisions.