CurrentCapital BluecrossPolicy MP 2.267

Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

Defines Capital BlueCross coverage stance on use of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) for cancer management across indications not covered by separate policies; applies to products administered by Capital BlueCross with benefit variations. Affects providers ordering or interpreting liquid biopsy tests for members.

Policy Summary

PayerCapital Bluecross

PolicyCirculating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

Policy CodePolicy MP 2.267

Change TypeNo material clinical or coverage changes

Effective DateOct 1, 2024

Next Review Date

Key ActionConsult the member's health benefit plan and obtain preauthorization if required by the plan before ordering liquid biopsy testing.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

InvestigationalCoverage stance

10/01/2024Effective

Insufficient evidenceRationale

9 listedInvestigational codes

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Coverage Criteria — Liquid Biopsy (ctDNA/CTCs)

Investigational — general

The use of ctDNA and/or CTCs is considered investigational for the indications reviewed in this policy unless a separate policy covers the indication.

Investigational for reviewed indications: Use of circulating tumor DNA (ctDNA) and/or circulating tumor cells (CTCs) is considered investigational for all indications reviewed herein

Separate policies (for example: breast cancer, non-small cell lung cancer, melanoma/glioma, ovarian, pancreatic, and prostate cancers; tumor‑informed ctDNA testing; comprehensive genomic profiling to select targeted therapies; AR‑V7 CTC testing) supersede this policy where applicable.

This policy does not address liquid biopsy uses that are covered under separate Capital BlueCross policies. Examples of excluded uses include liquid biopsy to select targeted treatment for breast cancer, non-small cell lung cancer, melanoma/glioma, ovarian cancer, pancreatic cancer, and prostate cancer; selection of immune checkpoint inhibitor therapy; tumor‑informed circulating tumor DNA testing for cancer management; comprehensive genomic profiling to select targeted cancer therapies; blood‑based testing for prostate cancer detection or risk assessment; and AR‑V7 circulating tumor cell testing for metastatic prostate cancer. Where a separate policy exists for a specific indication, that policy supersedes the conclusions in this document.

The following procedure codes are designated investigational and therefore not covered: 0091U, 0337U, 0338U, 0368U, 0491U, 0492U, 0453U, 86152, and 86153.

The rationale for the investigational designation is that published evidence is insufficient to establish clinical validity and clinical utility of ctDNA or CTC testing for the reviewed indications. Across uses to select targeted therapy, monitor treatment response, predict risk of relapse after curative treatment, or screen asymptomatic high‑risk individuals, studies are limited, methodology varies widely between commercially available tests, and data demonstrating improved clinical outcomes or change in patient management are lacking. Therefore, available evidence does not demonstrate that these assays improve net health outcomes.

Coding — Investigational / Not Covered Codes

Investigational / therefore not coveredCPTNot Covered

0091U	Investigational (listed in document)
0337U	Procedure Code listed as investigational
0338U	Procedure Code listed as investigational
0368U	Procedure Code listed as investigational
0491U	Procedure Code listed as investigational
0492U	Procedure Code listed as investigational
0453U	Procedure Code listed as investigational
86152	Procedure Code listed as investigational
86153	Procedure Code listed as investigational

Provider Actions, Prior Authorization, and Benefit Determination

Note

Policy Applicability and Product Variations

This policy applies only to certain programs and products administered by Capital Blue Cross and is subject to benefit variations. Refer to the member's specific health benefit plan for applicability; FEP PPO members should refer to the FEP Medical Policy Manual at: https://www.fepblue.org/benefit-plans/medical-policies-and-utilization-managementguidelines/medical-policies.

Applicable to certain Capital Blue Cross programs/products
FEP PPO: see FEP Medical Policy Manual (link above)

Documentation Required

Benefit Determination

The existence of this medical policy does not imply the service is a covered benefit. Benefit determinations are made based on the member's applicable health benefit plan language; medical policies are not a description of benefits.

Background — Liquid Biopsy Overview

Liquid biopsy refers to analysis of tumor‑derived material in peripheral blood — most commonly circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) — to noninvasively characterize tumors and tumor genomes. ctDNA consists of small fragments of cell‑free DNA released from apoptotic or necrotic tumor cells and typically represents a small fraction of total cell‑free DNA, requiring highly sensitive detection methods. CTCs are intact tumor cells shed into the bloodstream and are most frequently used in prognostic applications through quantification.

Definitions

Liquid biopsy — definition

DefinitionAnalysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) from peripheral blood to noninvasively characterize tumors and tumor genomes.

Sample sourcePeripheral blood (cell-free DNA or intact tumor cells).

PurposeNoninvasive tumor characterization for genomic profiling or prognostic assessment.

SynonymLiquid biopsy.

ctDNA — definition

DefinitionTumor-derived fragments of cell-free DNA in the blood originating largely from apoptotic and/or necrotic tumor cells; used for genomic characterization of the tumor.

Variant Analysis and Biomarker Requirements

Variant analysis — biomarkers and methods

Scope of variant analysisIncludes detection of single-nucleotide variants, copy-number variants, and other genomic alterations for tumor characterization.

Methods referencedBoth targeted (analysis of known driver mutations) and untargeted approaches (array CGH, next-generation sequencing, whole exome/genome sequencing) are described.

Analytical capabilityDigital genomic technologies (eg, digital PCR, BEAMing, high-sensitivity NGS) enable enumeration of rare variants in complex DNA mixtures.

ImplicationHigh analytical sensitivity is required because ctDNA is often a small fraction of total cfDNA; methods can detect mutations and copy-number changes and support measures such as tumor mutational burden (TMB) depending on platform.

Policy Summary

PayerCapital Bluecross

PolicyCirculating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

Policy CodePolicy MP 2.267

Change TypeNo material clinical or coverage changes

Effective DateOct 1, 2024

Next Review Date

Key ActionConsult the member's health benefit plan and obtain preauthorization if required by the plan before ordering liquid biopsy testing.

SourceLink

On This Page

Prior Authorization

Preauthorization and Coverage Determinations

The member's health benefit plan governs coverage, exclusions, benefit limits, and preauthorization requirements. Providers and members must consult the member's benefit plan or contact Capital Blue Cross for benefit information prior to ordering services.

Coverage, exclusions, limits, and preauthorization determined by the member's plan
Contact Capital Blue Cross or review member benefit plan for details

Denial Risk

Investigational Designation

Use of circulating tumor DNA (ctDNA) and/or circulating tumor cells (CTCs) is considered investigational for all indications reviewed in this policy. Investigational services may be denied.

Billing Rule

Investigational Coding and Denial Risk

Tests and procedure codes designated investigational in the coding section may be denied; identification of a code here does not imply coverage. Providers should verify coverage and billing eligibility with the member's benefit plan prior to submission.

Investigational / not covered codes include: 0091U, 0337U, 0338U, 0368U, 0491U, 0492U, 0453U, 86152, 86153

Prior Authorization

Provider Action — Verify Preauthorization

Providers may need to obtain preauthorization per the member's health benefit plan before performing liquid biopsy testing. Verify preauthorization requirements and required documentation with the member's plan.

Obtain preauthorization when required by the member's plan
Ensure documentation aligns with the member's benefit plan language

ctDNA is a subset of cell-free DNA (cfDNA) released by normal and tumor cells; tumor-derived fragments are typically a small fraction of total cfDNA.

Analytical challengectDNA often represents <1% of total cfDNA, requiring highly sensitive detection methods (eg, digital PCR, BEAMing, advanced NGS).

Clinical use noteCan be analyzed using targeted or untargeted approaches (eg, targeted mutation panels, NGS, whole exome/genome sequencing).

CTCs — definition

DefinitionIntact tumor cells released into the bloodstream from a primary tumor or metastatic site, detectable after enrichment and by immunologic, molecular, or functional assays.

BiologyCTCs have a short half-life in blood (approximately 1–2 hours) and are cleared by extravasation into secondary organs.

Detection methodsAssays typically begin with an enrichment step (based on surface markers like EpCAM/cytokeratins or physical properties) followed by detection via immunologic or molecular assays.

Primary applicationMost commonly used prognostically via quantification of circulating levels.

Definitions — placeholder / missing excerpt

Status of definitions sectionDefinitions section present in the policy document but marked 'N/A' in this excerpt; core definitions for liquid biopsy, ctDNA, and CTCs are provided elsewhere in the policy.

Action for readersRefer to the policy's Definitions and Description/Background sections for full terminology and context when needed.

Document noteThis placeholder indicates no additional or alternate definitions were supplied in the 'V. DEFINITIONS' excerpt.