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

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 01|01|2024 POLICY LAST REVIEWED: 01|07|2026 OVERVIEW 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 does not address the use of blood-based testing (liquid biopsy) to select targeted treatment for breast cancer, metastatic colorectal 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. MEDICAL CRITERIA Not applicable PRIOR AUTHORIZATION
Not applicable Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal or other administrative processes related to prior authorization/medical necessity.
In no circumstance shall a laboratory or a physician/provider use a representative of a laboratory or anyone with a relationship to a laboratory and/or a third party to obtain authorization on behalf of the ordering physician, to facilitate any portion of the authorization process or any subsequent appeal of a claim where the authorization process was not followed and/or a denial for clinical appropriateness was issued, including any element of the preparation of necessary documentation of clinical appropriateness. If a laboratory or a third party is found to be supporting any portion of the authorization process, BCBSRI will deem the action a violation of this policy and severe action will be taken up to and including termination from the BCBSRI provider network. If a laboratory provides a laboratory service that has not been authorized, the service will be denied as the financial liability of the participating laboratory and may not be billed to the member. POLICY STATEMENT Medicare Advantage Plans The use of circulating tumor DNA and/or circulating tumor cells is not covered for all indications as the evidence is insufficient to determine the effects of the technology on health outcomes.
Commercial Products The use of circulating tumor DNA and/or circulating tumor cells is considered not medically necessary for all indications as the evidence is insufficient to determine the effects of the technology on health outcomes. Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19-81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a Medical Coverage Policy | Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information.

COVERAGE Benefits may vary between groups/contracts. Please refer to the appropriate section of the Benefit Booklet, Evidence of Coverage or Subscriber Agreement for services not medically necessary.

BACKGROUND Liquid biopsy refers to 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 an 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 (1-2 hours), and CTCs are cleared through extravasation into secondary organs. Most assays detect CTCs through the use of surface epithelial markers such as 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 (e.g., Sanger sequencing) are needed.

Highly sensitive and specific methods have been developed to detect ctDNA, for both single nucleotide mutations e.g. BEAMing [which combines emulsion polymerase chain reaction with magnetic beads and flow cytometry] and digital polymerase chain reaction and copy-number changes. Digital genomic technologies allow for enumeration of rare mutant 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 mutations present in the primary tumor, and include array comparative genomic hybridization, next-generation sequencing, and whole exome and genome sequencing.

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

For individuals who have advanced cancer who receive testing of CTCs to select targeted treatment, the evidence includes observational studies. The relevant outcomes are overall survival, progression-free survival, recurrence-free survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs can replace variant analysis of tissue. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who receive testing of ctDNA to monitor treatment response, the evidence includes randomized clinical trials, systematic reviews with meta-analysis, and observational studies. Relevant outcomes are overall survival, progression-free survival, recurrence-free survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Numerous randomized clinical trials and systematic reviews identified an association with the detection of ctDNA or the kinetics of ctDNA and worse clinical outcomes for individuals with cancer, thus illustrating the clinical validity of testing for ctDNA. However, studies reporting clinical utility are lacking. Further studies are needed to establish a standardized definition for ctDNA molecular response and to illustrate how ctDNA testing can lead to different treatment regimens for cancer management. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of ctDNA should be used to monitor treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who receive testing of CTCs to monitor treatment response, the evidence includes a randomized controlled trial, observational studies, and systematic reviews of observational studies. Relevant outcomes are overall survival, progression-free survival, recurrence-free survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. The available randomized controlled trial found no effect on overall survival when patients with persistently increased CTC levels after first-line chemotherapy were switched to an alternative cytotoxic therapy. Other studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs should be used to monitor treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have received curative treatment for cancer who receive testing of ctDNA to predict risk of relapse, the evidence includes randomized clinical trials, systematic reviews with meta-analysis, and observational studies. Relevant outcomes are overall survival, progression-free survival, recurrence-free survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Numerous randomized clinical trials and systematic reviews identified an association with the detection of ctDNA or the kinetics of ctDNA and worse clinical outcomes for individuals with cancer, thus illustrating the clinical validity of testing for ctDNA. However, there were no studies assessing clinical utility. Further studies are needed to distinguish the timing to assess ctDNA to accurately prognosticate the clinical outcomes for individuals with cancer and establish thresholds that lead to meaningful predictions for clinical outcomes. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of ctDNA should be used to predict relapse response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have received curative treatment for cancer who receive testing of CTCs to predict risk of relapse, the evidence includes observational studies. Relevant outcomes are overall survival, disease- specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs should be used to predict relapse response. The evidence is insufficient to determine the effects of the technology on health outcomes.

CODING The following codes are not covered for Medicare Advantage Plans and not medically necessary for Commercial products:

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

86152 Cell enumeration using immunologic selection and identification in fluid specimen

         (eg, circulating tumor cells in blood)

86153 Cell enumeration using immunologic selection and identification in fluid specimen

         (eg, circulating tumor cells in blood); physician interpretation and report, when required

This CPT code can be used for FirstSightCRC™ (CellMax Life) 0091U Oncology (colorectal) screening, cell enumeration of circulating tumor cells, utilizing whole blood, algorithm, for the presence of adenoma or cancer, reported as a positive or negative result

RELATED POLICIES Biomarker Testing Mandate
Genetic Testing Services
Proprietary Laboratory Analyses (PLA)

PUBLISHED Provider Update, January/March 2026 Provider Update, November 2024 Provider Update, January/November 2023 Provider Update, May 2021 Provider Update, June 2019

REFERENCES

1. Centers for Medicare & Medicaid Services (CMS) National Coverage Determination (NCD): Next Generation Sequencing (90.2)
2. Centers for Medicare & Medicaid Services (CMS) Local Coverage Determination (LCD): MolDX: Molecular Diagnostic Tests (MDT) (L35160)
3. Centers for Medicare & Medicaid Services (CMS) Local Coverage Determination (LCD) article: Billing and Coding: MolDX: Molecular Diagnostic Tests (MDT) (A57526)
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500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

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