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

POLICY NUMBER

A.2.04.141

DESCRIPTION

Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in peripheral blood, referred to as “liquid biopsy,” have several potential uses for guiding therapeutic decisions in patients with cancer or being screened for cancer. This policy evaluates uses for liquid biopsies not addressed in a separate policy. If a separate policy exists, then conclusions reached there supersede conclusions here.

Liquid Biopsy

Liquid biopsy refers to the analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) as methods of noninvasively characterizing tumors and tumor genome from the peripheral blood.

Circulating Tumor DNA

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or CTCs. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor.

Circulating Tumor Cells

Intact CTCs are released from a primary tumor and/or a metastatic site into the bloodstream. The half-life of a CTC in the bloodstream is short (1 to 2 hours), and CTCs are cleared through extravasation into secondary organs. Most assays detect CTCs through the use of surface epithelial markers such as epithelial cell adhesion molecules (EpCAM) and cytokeratins. The primary reason for detecting CTCs is prognostic, through quantification of circulating levels.

Detecting Circulating Tumor DNA and Circulating Tumor Cells

Detection of ctDNA is challenging because ctDNA is diluted by nonmalignant circulating DNA and usually represents a small fraction (<1%) of total cell-free DNA. Therefore, more sensitive methods than the standard sequencing approaches (eg, Sanger sequencing) are needed.

Highly sensitive and specific methods have been developed to detect ctDNA, for both single nucleotide variants (eg BEAMing [which combines emulsion polymerase chain reaction with magnetic beads and flow cytometry] and digital polymerase chain reaction) and copy-number variants. Digital genomic technologies allow for enumeration of rare variants in complex mixtures of DNA.

Approaches to detecting ctDNA can be considered targeted, which includes the analysis of known genetic mutations from the primary tumor in a small set of frequently occurring driver mutations, which can impact therapy decisions or untargeted without knowledge of specific variants present in the primary tumor, and include array comparative genomic hybridization, next-generation sequencing, and whole exome and genome sequencing.

Circulating tumor cell assays usually start with an enrichment step that increases the concentration of CTCs, either by biologic properties (expression of protein markers) or physical properties (size, density, electric charge). Circulating tumor cells can then be detected using immunologic, molecular, or functional assays.

Note that targeted therapy in non-small-cell lung cancer and metastatic colorectal cancer, use of liquid biopsy for detection or risk assessment of prostate cancer, and use of AR-V7 CTC liquid biopsy for metastatic prostate cancer are addressed in separate policies.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

Certain liquid biopsy-based assays have been cleared or approved by the FDA as companion diagnostic tests (see the table below). These indications are addressed in other policies and are listed here for information only. Refer to the associated policy (Column 5) for details.

FDA Cleared or Approved Liquid Biopsy Companion Diagnostic Tests

FDA: US Food and Drug Administration; NSCLC: non-small cell lung cancer

POLICY

The use of circulating tumor DNA and/or circulating tumor cells is considered investigational for all indications reviewed in this policy (see Policy Guidelines).

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

This policy does not address the use of blood-based testing (liquid biopsy) to select targeted treatment for breast cancer, non-small-cell lung cancer, melanoma/glioma, ovarian cancer, pancreatic cancer, and prostate cancer, the use of liquid biopsy to select immune checkpoint inhibitor therapy, tumor-Informed circulating tumor DNA testing for cancer management, comprehensive genomic profiling for selecting targeted cancer therapies, the use of blood-based testing for detection or risk assessment of prostate cancer, or the use of AR-V7 circulating tumor cells for metastatic prostate cancer. Refer to the following related policies for indications not covered here:

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

• Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)

• Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, MMR/MSI, HER2, and TMB)

• Gene Expression Profile Testing and Circulating Tumor DNA Testing for Predicting Recurrence in Colon Cancer

• Somatic Genetic Testing to Select Individuals with Melanoma or Glioma or Targeted Therapy (BRAF)

• Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management

• Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

• Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Breast Cancer (BRCA1, BRCA2, PIK3CA, Ki-67, RET, BRAF, ESR1)

• Tumor-Informed Circulating Tumor DNA Testing for Cancer Management

• Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations)

• Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency)

• Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

11/17/2016: Approved by Medical Policy Advisory Committee.

06/13/2018: Policy description updated regarding examples of liquid biopsy tests. Policy statement updated to add "or" and state that the use of circulating tumor DNA and/or circulating tumor cells is considered investigational for all indications. Policy Guidelines updated.

01/24/2019: Policy description updated to state that this policy evaluates uses for liquid biopsies not addressed in a separate policy. Removed list of biopsy tests. Policy statement updated to clarify that other indications may be reviewed in a separate policy. Policy guidelines updated.

08/13/2019: Policy description updated regarding devices. Policy statement unchanged.

09/09/2020: Policy description updated regarding devices. Policy statement unchanged. Policy Guidelines updated.

12/08/2021: Policy description updated regarding companion diagnostic tests. Policy statement unchanged. Policy Guidelines updated to add related policies and to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

04/01/2023: Policy description updated regarding related medical policies. Policy statement unchanged. Code Reference section updated to add CPT codes 0091U, 0242U, 0337U, and 0338U.

09/12/2023: Policy description updated regarding FDA cleared or approved liquid biopsy companion diagnostic tests. Policy statement unchanged. Policy Guidelines updated.

12/21/2023: Code Reference section updated to add new 2024 CPT codes 0422U and 0428U, effective 01/01/2024.

09/11/2024: Policy description updated. Policy statement unchanged. Medical policy links updated in Policy Guidelines.

10/01/2024: Code Reference section updated to add new CPT codes 0490U and 0492U.

12/31/2024: Code Reference section updated to make note of deleted CPT code 0428U.

07/18/2025: Code Reference section updated to add new CPT code 0569U. Effective 07/01/2025.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.141

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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