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CurrentBlue Cross Blue Shield - North DakotaPolicy 83

Expanded Molecular Testing of Cancers to Select Targeted Therapies

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Coverage of tumor-tissue molecular panel testing to identify genetic variants that may guide FDA-approved targeted treatment for advanced or metastatic solid tumors, distinguishing medically necessary testing from investigational and excluded testing.

Policy Summary

PayerBlue Cross Blue Shield - North Dakota

PolicyExpanded Molecular Testing of Cancers to Select Targeted Therapies

Policy CodePolicy N/A

Change TypeNo material change

Effective DateOct 1, 2026

Last ReviewSep 1, 2026

Next Review DateApr 1, 2027

Key ActionSubmit documentation identifying the test, laboratory, genes or variants tested, billing codes, clinical rationale, and related medical records.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

3Medical-necessity criteria

3Investigational sequencing categories

5Non-covered test groups

7Documentation elements

8NCCN cancer types with example support

Coverage Criteria

Medically Necessary Expanded Tumor Panel Testing

Covered when ALL of the following criteria are met:

ALL of the following

The individual has an advanced or metastatic (e.g., stage III or IV) solid tumor (nonhematologic) cancer.
The tumor tissue molecular panel includes one or more genes for which an FDA-approved therapy is available for the cancer indication.
The individual has not decided to forgo targeted cancer treatment.

Investigational Broad Profiling When Criteria Are Not Met

Broad profiling of tumor tissue for selection of targeted cancer treatment is investigational when the medical-necessity criteria are not met.

Policy Summary

PayerBlue Cross Blue Shield - North Dakota

PolicyExpanded Molecular Testing of Cancers to Select Targeted Therapies

Policy CodePolicy N/A

Change TypeNo material change

Effective DateOct 1, 2026

Last ReviewSep 1, 2026

Next Review DateApr 1, 2027

Key ActionSubmit documentation identifying the test, laboratory, genes or variants tested, billing codes, clinical rationale, and related medical records.

SourceLink

On This Page

The testing uses a broad tumor profiling panel and one or more medical-necessity criteria for expanded tumor tissue panel testing are not met.

This determination applies when the individual does not have advanced or metastatic solid tumor cancer, the panel does not include a gene with an available FDA-approved therapy for the cancer indication, or the individual has decided to forgo targeted cancer treatment.

Investigational Whole Genome, Exome, and Transcriptome Sequencing

The following tumor tissue sequencing approaches are considered investigational.

ANY of the following

Whole genome sequencing of tumor tissue.
Whole exome sequencing of tumor tissue.
Whole transcriptome sequencing of tumor tissue.

Medically Necessary

Tumor tissue testing using molecular panels, including expanded tumor profiling panels, may be medically necessary for patients with advanced or metastatic disease who meet the policy criteria.

ALL of the following

The cancer is an advanced or metastatic solid tumor, such as stage III or IV disease.
The molecular panel includes one or more genes for which an FDA-approved therapy is available for the cancer indication.
The individual has not decided to forgo targeted cancer treatment.

Advanced or Metastatic Cancer

Advanced or metastatic disease is required for medical necessity under this policy.

The individual has advanced or metastatic (e.g., stage III or IV) solid tumor (nonhematologic) cancer.Stage III or IV

Investigational Testing

Expanded tumor tissue panel testing is considered investigational when any of the following circumstances apply:

ANY of the following

The individual does not have advanced or metastatic (i.e., stage III or IV) cancer.
The testing is not associated with a gene for which an FDA-approved targeted treatment is available for the cancer indication.
The individual has already decided not to pursue targeted therapy.

This policy does not address testing for diagnostic purposes, such as diagnosis of central nervous system tumors; targeted variant testing; gene expression testing; testing for hematologic disorders, such as leukemia or lymphoma; or testing of circulating, cell-free tumor DNA (liquid biopsy) or circulating tumor cells.

Testing for individual variants with established utility is not covered in this evidence review. This review also does not address cancer-specific limited panels that include only a few variants, such as a panel specific to one cancer type. It addresses expanded panels that test for many potential variants that do not necessarily have established efficacy for the specific cancer in question.

Whole-genome, whole-exome, and whole-transcriptome sequencing of tumor tissue are not included among the targeted or expanded molecular panel approaches addressed as medically necessary under this policy.

Expanded tumor tissue panel testing is not medically necessary when the individual does not have advanced or metastatic disease, when the testing is not associated with an FDA-approved targeted treatment for the cancer indication, or when the individual has decided not to pursue targeted therapy.

Covered Cancer Indications

Advanced or Metastatic Solid Tumor With FDA-Associated Gene

Coverage may be considered when all of the following conditions are met:

Advanced or metastatic solid tumor with an FDA-associated gene

Disease status: The individual has advanced or metastatic solid tumor (nonhematologic) cancer.For example, stage III or IV
Molecular panel: Tumor tissue is tested using a molecular panel, including a broad tumor profiling panel.
FDA-approved therapy association: The test includes at least one gene for which an FDA-approved therapy is available for the cancer indication.
No decision to forgo treatment: The individual has not decided to forgo targeted cancer treatment.

FDA-Targeted-Treatment Examples

The policy provides the following examples of cancer indications, biomarkers, and associated targeted therapies. This list is not exhaustive; current FDA or National Cancer Institute information should be consulted.

Applicable cancer and biomarker example

Any advanced or metastatic solid tumor: Biomarker: BRAF, NTRK1/2/3, or RET.
Examples of associated therapies include Tafinlar, Mekinist, Retevmo, Rozlytrek, and Vitrakvi.
HER2-negative tumor: Biomarker: BRCA1/2.
Examples of associated therapies include Lynparza and Talzenna.
HR-positive, HER2-negative advanced or metastatic breast cancer: Biomarker: ESR1, PIK3CA, PTEN, or ERBB2/HER2.
Examples of associated therapies include Truqap, Orserdu, and Piqray.

Advanced or Metastatic Cancer Coverage Pathway

Tumor molecular panel testing may be considered medically necessary when all of the following are present:

Advanced or metastatic cancer pathway

Disease status: The patient has advanced or metastatic cancer.Generally stage III or IV
Testing purpose: Molecular profiling is being used to identify a targeted treatment or clinical trial for which the patient may be eligible.
Policy criteria: The patient meets the policy criteria for tumor molecular panel testing.

NCCN-Supported Cancer Types

For advanced or metastatic disease, NCCN guidelines include recommendations for somatic multigene panel testing for the following cancer types:

ONE or more supported cancer types

Breast cancer: Advanced or metastatic breast cancer.
Colon cancer: Advanced or metastatic colon cancer.
Non-small-cell lung cancer: Advanced or metastatic non-small-cell lung cancer.
Chondrosarcoma: Advanced or metastatic chondrosarcoma.

Molecular Profiling for Targeted Treatment or Clinical Trials

Molecular profiling may be considered medically necessary when it can inform management in advanced or metastatic disease:

Clinical rationale for molecular profiling

Targeted-treatment opportunity: Testing may identify a targeted treatment for which the patient may be eligible.
Clinical-trial opportunity: Testing may identify a clinical trial for which the patient may be eligible.
Policy criteria: The tumor molecular panel, including an expanded tumor profiling panel, meets the applicable policy criteria.

Eligibility Requirements

Submit medical record documentation of the conventional testing performed and its outcomes, along with any additional treatment already provided. Supporting documentation should identify the genetic or panel test, performing laboratory or testing organization, exact genes or variants tested, relevant billing codes, and how the results will guide clinical decisions that would not otherwise be made. Include the tumor-tissue sample collection date and the relevant history and physical examination.

Provider Submission and Review Actions

Documentation Required

Required Test and Clinical Documentation

Submit documentation sufficient to determine the clinical utility of the requested genetic test or panel and how the results will guide a clinical decision that would not otherwise be made. Include the test or panel name, performing laboratory or testing organization, exact genes or variants, and relevant billing codes.

Documentation Required

Required Medical Records

Include the medical records related to the genetic test for review, including the tumor tissue sample collection date, history and physical examination, conventional testing and outcomes, and any additional treatment provided.

Denial Risk

Investigational Tumor Sequencing

Broad tumor profiling panels used to select targeted cancer treatment are investigational when the policy’s coverage criteria are not met. Whole-genome, whole-exome, and whole-transcriptome sequencing of tumor tissue are also considered investigational.

Billing Rule

Contract Exclusions

Contract language takes precedence over this Medical Policy. Contracts exclude services or procedures considered investigational or cosmetic; providers may bill members for those services and should inform members in advance that they may be financially responsible.

Note

Testing Outside the Policy Scope

This policy does not address testing for individual genetic markers with established utility for a specific cancer type or limited cancer-specific panels that include a few variants. These testing categories may require separate review under applicable coverage policies.

Denial Risk

Targeted-Treatment Criteria Not Met

Expanded tumor tissue panel testing is considered investigational when the patient does not have advanced or metastatic cancer, the testing is not associated with an FDA-approved targeted treatment, or the patient has decided not to pursue targeted therapy.

Denial Risk

Broad Sequencing Types Considered Investigational

Whole-genome, whole-exome, and whole-transcriptome tumor testing are considered investigational because evidence-based clinical guidelines do not currently recommend these approaches over more targeted testing.

Note

Review Test Performance

Before ordering testing, review the test’s performance characteristics and discuss the potential for false-positive and false-negative results with the patient.

Molecular and Genomic Testing Codes

Listed molecular and genomic testing codesCPT

0022U	Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence/or absence of variants and associated therapy(ies) to consider.
0036U	Exome (ie, somatic mutations), paired formalin-fixed paraffin-embedded tumor tissue and normal specimen, sequence analyses.
0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden.
0048U	Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s).
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.

Oncology molecular and genomic testing codesCPT

0048U	Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide ...)

Oncology molecular and genomic testing codesCPT

0048U	Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s).
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue.
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden.

Molecular oncology testing codesCPT

0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden
0048U	Exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)

Oncology molecular testing codesHCPCS

0048U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden.
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue.
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutational burden.
0048U	Exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s).

Molecular oncology genomic testing codesCPT

0048U	Exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s).
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue.
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden.

Additional molecular oncology codeCPT

0297U

Oncology (pan tumor), whole genome sequencing of paired malignant and [description continues beyond the available text].

CODESCPT

0048U	Oncology (pan-tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue.
0211U	Oncology (pan-tumor), exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s).
0244U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.
0250U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue.
0297U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden.

Oncology molecular and genomic testing codesCPT

0048U	Exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden
0297U	Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE)

Molecular oncology testing codesHCPCS

0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden
0297U	Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE)

Oncology molecular and genomic testing codesHCPCS

0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden
0297U	Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE)
0048U

Molecular oncology and genomic profiling codesHCPCS

0048U	significant mutation(s)
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden
0297U	Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and variant identification

Oncology molecular and genomic testing codesHCPCS

0211U	Mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s).
0244U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.
0250U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue.
0297U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations including single-nucleotide variants, small insertions and deletions, one amplification, and four translocations, microsatellite instability, and tumor-mutation burden; also described for pan-tumor whole genome sequencing of paired malignant and normal DNA specimens from fresh or formalin-fixed paraffin-embedded tissue, blood, or bone marrow, with comparative sequence analyses and variant identification.

Oncology molecular and genomic testing codesCPT

0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0244U	Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
0250U	Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations, including SNVs, small insertions and deletions, one amplification, and four translocations, microsatellite instability and tumor-mutation burden
0297U	Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens from fresh or formalin-fixed paraffin-embedded tissue, blood or bone marrow, with comparative sequence analyses and reporting of clinically significant mutations and microsatellite instability
0334U	Oncology (solid organ), targeted genomic sequence analysis, formalin-fixed paraffin-embedded tumor tissue, DNA analysis, 84 or more genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden, with report of clinically significant mutations and therapy associations
0379U	Targeted genomic sequence analysis panel, solid organ neoplasm, DNA (523 genes) and RNA (55 genes) by next-generation sequencing, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
0391U	Oncology (solid tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, 437 genes, interpretive report for single nucleotide variants, splice site variants, insertions/deletions, copy number alterations, gene fusions, tumor mutational burden, and microsatellite instability, with algorithm quantifying immunotherapy response score
0444U	Oncology (solid organ neoplasia), targeted genomic sequence analysis panel of 361 genes, interrogation for gene fusions, translocations, or other rearrangements, using DNA from formalin-fixed paraffin-embedded tumor tissue, report of clinically significant variant(s)
0473U	Oncology (solid tumor), next-generation sequencing of DNA from formalin-fixed paraffin-embedded tumor tissue with comparative sequence analysis from a matched normal specimen from blood or saliva, 648 genes, interrogation for sequence variants, insertion and deletion alterations, copy number variants, rearrangements, microsatellite instability, and tumor-mutation burden
0498U	Oncology (colorectal), next-generation sequencing for mutation detection in 43 genes

Policy Background

Expanded molecular tumor panels analyze many potential genetic variants in a cancer specimen to support treatment selection. Targeted cancer treatment uses genetic abnormalities identified in a patient’s cancer to select drugs directed at the specific abnormality; expanded panels may also help identify potential treatment options when multiple molecular pathways are being considered.

Definitions and Technical Terms

Expanded molecular panel testing

SpecimenTumor tissue

ScopeA large molecular panel testing many gene variants

PurposeAssists treatment selection or identification of clinical trials

Targeted cancer treatment

What it identifiesGenetic abnormalities present in a patient’s cancer

TreatmentDrugs directed at the specific genetic abnormality

Clinical conceptUses genetic markers to classify cancers by molecular pathways

Variant

DefinitionA change in a DNA or protein sequence

NomenclaturePreferred Human Genome Variation Society term

ReplacesTerms such as mutation

Pathogenic variant

DefinitionA variant associated with disease

ClassificationDisease-associated genetic change

ContextDistinguished from benign variants and variants of uncertain significance

Variant of uncertain significance

DefinitionA genetic change whose effect on human health is unknown

MeaningThe clinical significance of the change has not been established

ContextMost genetic changes have unknown effects on human health

Analytic validity

DefinitionThe technical accuracy of a test

DetectsA variant that is present

ExcludesA variant that is absent

Clinical validity

DefinitionThe diagnostic performance of a test in detecting clinical disease

Performance measuresSensitivity and specificity

Predictive valuesPositive and negative predictive values

Clinical utility

DefinitionHow test results are used to change patient management

Outcome assessmentWhether management changes produce clinically important improvements in health outcomes

Evidence focusThe evidence review focuses on clinical validity and utility

Advanced or metastatic disease

Policy definitionAdvanced or metastatic cancer

Stages includedStage III or stage IV cancer

Coverage contextA key disease-status criterion for expanded tumor panel testing

Targeted genomic sequence DNA analysis

Gene scope505 genes

Analytes and alterationsSomatic single-nucleotide variants, small insertions and deletions, one amplification, and four translocations

BiomarkersMicrosatellite instability and tumor-mutation burden

Targeted sequencing of 468 cancer-associated genes

Gene scopeProtein-coding exons of 468 cancer-associated genes

SpecimensMatched normal specimens and formalin-fixed paraffin-embedded tumor tissue

Assessed alterationsSomatic mutations and microsatellite instability

Comprehensive genomic profiling

Tumor typeSolid-organ tumors

Gene scope257 genes

Assessed findingsSingle-nucleotide variants, insertions and deletions, copy-number alterations, gene rearrangements, tumor-mutational burden, and microsatellite instability

Comprehensive genomic profiling

Assay typeMolecular oncology assay using DNA and/or RNA sequencing

PurposeIdentifies genomic alterations for therapy association

BiomarkersTumor mutational burden and microsatellite instability

Formalin-fixed paraffin-embedded tumor tissue

DefinitionTumor tissue preserved by fixation in formalin and embedding in paraffin

AbbreviationFFPE

UseSpecimen source for several listed oncology genomic assays

Single-nucleotide variant (SNV)

DefinitionA genomic alteration involving a change in a single nucleotide

AbbreviationSNV

Finding typeA sequence variant identified through genomic analysis

Tumor-mutational burden

DefinitionA biomarker reflecting the number of mutations present in a tumor

Reporting contextReported as part of several comprehensive oncology genomic assays

What it measuresThe mutation burden of tumor tissue

Microsatellite instability

DefinitionA biomarker assessing instability in short repeated DNA sequences

Reporting contextReported as part of several listed oncology assays

Assessment targetMicrosatellite DNA sequence stability

FFPE

Specimen typeFresh tissue or formalin-fixed, paraffin-embedded tissue

Testing designPaired malignant and normal DNA sequencing

ApplicationUsed for whole-genome sequencing

Whole genome sequencing

Specimen designPaired malignant and normal DNA specimens

Permitted tissueFresh or formalin-fixed paraffin-embedded tissue

AssessmentIncludes interrogation for somatic mutations and microsatellite instability

Tumor mutational burden

DefinitionA measure of the number of somatic mutations present in a tumor

Biologic sourceSomatic mutations in tumor tissue

UseReported or assessed in oncology genomic testing

Microsatellite instability

DefinitionA biomarker assessment performed as part of listed oncology genomic assays

Assessment targetInstability in microsatellite DNA sequences

Testing contextIncluded with genomic assay findings

FFPE

DefinitionFormalin-fixed paraffin-embedded tissue

Specimen roleTumor specimen used for oncology genomic testing

Testing contextUsed in listed molecular oncology assays

Microsatellite instability

DefinitionMicrosatellite instability

ReportingMay be reported alone or together with genomic findings

Clinical contextMay be reported with therapy association

Tumor mutational burden

DefinitionTumor mutational burden

Testing contextAssessed as part of comprehensive or targeted oncology genomic profiling

What it reflectsThe number of mutations present in a tumor

FFPE

DefinitionFormalin-fixed paraffin-embedded tissue

Specimen roleTumor specimen source for multiple molecular profiling assays

Testing contextUsed in oncology genomic profiling

NGS

Full termNext-generation sequencing

Analyzed materialTumor DNA, RNA, or matched tumor and normal specimens

PurposeIdentifies clinically significant genomic alterations

Not Covered Testing

The following tumor-tissue sequencing approaches are not covered as medically necessary under this policy: whole-genome sequencing, whole-exome sequencing, and whole-transcriptome sequencing. These services are considered investigational because sufficient evidence has not established improved health outcomes compared with more targeted testing.

Advanced cholangiocarcinoma: Biomarker: FGFR2.

Metastatic colorectal cancer: Biomarker: BRAF, KRAS, or NRAS.

Examples of associated therapies include Braftovi, Erbitux, Fruzaqla, Tukysa, and Vectibix.

Resected, unresectable, or metastatic GIST: Biomarker: KIT (c-KIT/CD117) or PDGFRA.

Examples of associated therapies include Ayvakit and Gleevec.

Unresectable or metastatic cutaneous melanoma: Biomarker: BRAF.

Examples of associated therapies include Braftovi, Cotellic, Mekinist, Opdivo, Tafinlar, Tecentriq, and Zelboraf.

Unresectable or metastatic uveal melanoma: Biomarker: HLA.

An associated therapy listed in the policy is Kimmtrak.

Advanced or metastatic NSCLC: Biomarker: BRAF, EGFR, ERBB2/HER2, KRAS, or ROS1.

The policy lists multiple associated therapies, including Keytruda, Krazati, Lumakras, Mekinist, Opdivo, Rozlytrek, Tafinlar, Tagrisso, Tecentriq, Xalkori, and Zykadia.

Advanced or metastatic urothelial carcinoma: Biomarker: FGFR2/3.

An associated therapy listed in the policy is Balversa.

Ovarian cancer: Advanced or metastatic ovarian cancer.

Biliary tract cancer: Advanced or metastatic biliary tract cancer.

Pancreatic adenocarcinoma: Advanced or metastatic pancreatic adenocarcinoma.

Rectal cancer: Advanced or metastatic rectal cancer.