Currentblue cross blue shield - kansasPolicy N/A

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

Defines BCBSKS coverage stance for circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) testing for cancer management, excluding indications addressed in separate policies; applies to BCBSKS members and providers determining medical necessity for these tests.

Policy Summary

Payerblue cross blue shield - kansas

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

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateOct 2, 2023

Next Review DateJan 5, 2026

Key ActionCheck member benefits with BCBSKS Customer Service to determine coverage or need for prior authorization.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Post-curativeTarget population for MRD monitoring

Stage II colonRandomized trial (DYNAMIC)

ExperimentalIndications not otherwise addressed

≤50%Sensitivity for MRD

Oct 24, 2025Literature update

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Criteria — ctDNA and CTC (Liquid Biopsy)

Not covered except where other policies apply

Covered only as specified in related, separate policy guidelines; all other uses:

Experimental/Investigational: The use of circulating tumor DNA and/or circulating tumor cells is considered experimental/investigational for all indications reviewed herein not otherwise addressed in policy guidelines.

See separate policies for certain tumor-specific, companion diagnostic, and tumor-informed ctDNA uses.

Coverage logic for CTC/ctDNA uses

Policy conclusions and criteria logic summarized from this section of the evidence review:

Selecting targeted treatment in advanced cancer: No direct evidence that selecting targeted treatment using CTCs improves net health outcome compared with tumor tissue testing; clinical validity of each commercially available CTC test has not been established, therefore clinical utility cannot be inferred.

Trials are ongoing; see supplemental materials referenced in the full review.

Monitoring treatment response: ctDNA and CTC kinetics may correlate with treatment response and ctDNA can show early drops within weeks of therapy; however, evidence linking use of these tests to improved PFS or OS is insufficient in reviewed indications.

Best unit for quantifying ctDNA burden not established.

Surveillance after curative therapy: Liquid biopsy is proposed to monitor for residual tumor after curative treatment to enable early intervention, but PICO and outcomes (PFS, OS) evidence is variable and timing depends on cancer type; evidence in this review segment is insufficient to confirm clinical utility.

Further details in subsequent sections of the evidence review.

Coverage for post-curative surveillance using ctDNA/CTCs

Covered when ALL of the following are met

Population: Individual has received curative-intent treatment for cancer

see source RCT populations

Intended use: Test is ordered to monitor for molecular/minimal residual disease (MRD) or molecular relapse after curative therapy

Liquid biopsy using ctDNA or CTCs

Assay performance: Assay demonstrates ability to detect ultra-low ctDNA concentrations to minimize false-negative results

Sensitivity critical to ensure benefit of early treatment

Comparator consideration: Use complements standard monitoring methods (imaging and clinical examination) and outcomes should include OS, disease-specific survival, and test validity

Contexts with randomized direct evidence

Evidence-based contexts where ctDNA testing demonstrated clinical outcomes or strong prognostic validity

ctDNA-guided adjuvant chemotherapy in stage II colon cancer: Use of ctDNA to guide adjuvant chemotherapy in stage II colon cancer was shown in the randomized DYNAMIC trial to reduce ACT use without compromising 2-year recurrence-free survival; updated 5-year results showed comparable RFS and OS between ctDNA-guided and standard management.trial-specific ctDNA positivity definitions (not consistently reported)

Trial limitations include undefined concentration thresholds and other design limitations; see study limitations tables.

Real-world monitoring / prognostic use

Observational/real-world evidence supporting prognostic use in lung cancers

ctDNA molecular response monitoring in lung cancer (PCG study): In real-world clinico-genomic cohorts, on-treatment ctDNA detection and predefined percent decreases (50%/90%) were associated with substantially different rwPFS and rwOS; molecular response complemented radiographic response in prognostication.>=90% or >=50% decrease used to define molecular response in cohort analyses

Study limitations include non-standardized timing (6-15 weeks) and variability in assays and specimen types.

Coverage conclusions and required evidentiary logic

Summary of coverage-relevant conclusions from evidence review

ctDNA monitoring for treatment response: Evidence is insufficient to determine that ctDNA monitoring for treatment response results in improved net health outcomes due to limitations in RCTs despite one RCT; therefore clinical utility is not established.

One RCT exists but limitations preclude conclusions (see chunk 76).

CTC monitoring for treatment response: No direct evidence that using CTCs to monitor treatment response improves net health outcomes; clinical validity of assays is not established and data are lacking.

No trials demonstrating improved outcomes based on CTC-guided treatment (chunks 75, 76).

ctDNA for predicting relapse (MRD): No direct evidence that ctDNA testing to predict risk of relapse improves net health outcomes; additional studies needed to establish individual-level threshold metrics.

RCTs show correlation with worse outcomes but thresholds for individual prediction are not established (chunk 77).

This policy does not address the use of blood-based testing (liquid biopsy) to select targeted treatment for certain tumor types, including breast cancer, non-small cell lung cancer (NSCLC), melanoma/glioma, ovarian cancer, pancreatic cancer, and prostate cancer. It also excludes use of liquid biopsy to select immune checkpoint inhibitor therapy, tumor‑informed ctDNA testing for cancer management, comprehensive genomic profiling for selecting targeted cancer therapies, blood‑based testing for detection or risk assessment of prostate cancer, and AR‑V7 circulating tumor cell (CTC) testing for metastatic prostate cancer. Refer to the member's contract benefits at the time of service to determine coverage for these services.

Alternate listing: the policy specifically excludes liquid biopsy to select targeted therapies for breast, non‑small cell lung, melanoma/glioma, ovarian, pancreatic, and prostate cancers; selection of immune checkpoint inhibitor therapy based on blood testing; tumor‑informed ctDNA testing for management; comprehensive genomic profiling via blood; blood‑based prostate cancer detection/risk assessment; and AR‑V7 CTC testing for metastatic prostate cancer. Coverage determinations depend on the member's contract benefits.

Use of ctDNA or CTC assays for purposes other than monitoring for residual tumor or molecular relapse (for example, unrelated population screening) is not described as an intended use in this policy. When tissue biopsy is feasible, tissue‑based molecular characterization remains the expected comparator and individuals with negative liquid biopsy results should be reflexed to tumor biopsy testing if able to undergo tissue sampling.

Because assays, timing, and definitions of molecular response vary substantially across studies, heterogeneity and lack of standardized definitions reduce the ability to generalize results and may confound clinical validity. Assay variability and inconsistent timepoints limit comparability across tests and studies and should be considered when interpreting results or requesting coverage.

ASCO guidance states that, in early‑stage breast cancer (node‑negative or node‑positive ER‑positive, HER2‑positive, or triple‑negative disease), clinicians should not use ctDNA or circulating tumor cells to guide decisions about adjuvant endocrine therapy or adjuvant chemotherapy (evidence‑based recommendation; strength: strong).

Administrative note: this policy does not address use of liquid biopsy to select targeted treatments for the tumor types listed above, nor does it address tumor‑informed ctDNA testing or AR‑V7 CTC testing for metastatic prostate cancer; such uses are outside the scope of this policy and require review under the applicable tumor‑specific policy or the member's contract.

Coverage stance: circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) testing for indications not otherwise addressed in this policy or in separate, tumor‑specific policies is considered experimental/investigational and not medically necessary.

Currently available commercially marketed CTC assays lack independently established clinical validity for the management decisions reviewed here; therefore, using CTC test results to select or guide treatment is not supported by sufficient evidence of clinical utility.

Assay sensitivity is critical for clinical utility in the MRD/molecular relapse setting. Tests that cannot detect ultra‑low ctDNA concentrations risk high false‑negative rates and would not meet the necessary clinical validity for MRD surveillance or for informing early intervention decisions.

Performance limitation: clinical sensitivity of ctDNA assays for postoperative MRD detection is often suboptimal, with sensitivity shortly after completion of therapy frequently reported at or below 50% (≤50%), while clinical specificity is generally high (often ≥90%). Variable performance across assays and timepoints limits reliability for routine MRD use.

ASCO recommendation: clinicians should not use ctDNA or CTC to guide adjuvant endocrine or chemotherapy decisions in node‑negative or node‑positive ER‑positive, HER2‑positive, or triple‑negative early‑stage breast cancer (strong, evidence‑based recommendation).

Covered Indications and Accepted Uses

FDA-cleared companion diagnostic liquid biopsy assays for specific tumor types are recognized and are addressed in their respective policy opinions.

These FDA-cleared or approved companion diagnostic liquid biopsy assays are recognized and handled in their tumor-specific policies; listed here for information:

FDA-cleared companion diagnostics: FDA-cleared/approved liquid biopsy companion diagnostic assays (examples include assays such as Agilent Resolution ctDx FIRST and Roche cobas EGFR Mutation Test v2) are acknowledged; coverage determinations for these assays are addressed in the associated tumor-specific medical policies.

Refer to the related somatic biomarker and tumor-specific policy opinions for coverage details.

Patient populations and intended use categories (selection, monitoring, surveillance)

Patient populations and intended-use categories include the following:

Advanced disease - selection: Individuals with advanced cancer when genomic characterization may inform selection of targeted therapy (tissue testing preferred when feasible).

Not Covered / Experimental Uses

All ctDNA and/or CTC testing indications that are not specifically addressed in other policy guidelines are considered experimental/investigational and not medically necessary, and claims for such testing may be denied unless coverage is established under a separate tumor‑specific policy or member contract.

Specific tests and contexts not addressed by this policy include tumor‑informed ctDNA testing for cancer management and AR‑V7 circulating tumor cell assays for metastatic prostate cancer; these uses lack established policy coverage within this document.

Tests that are unable to reliably detect ultra‑low ctDNA concentrations, or tests not used in the context of MRD/molecular relapse monitoring, lack demonstrated clinical utility for the uses evaluated in this policy.

Circulating tumor cell assays that lack independent demonstration of clinical validity are not established as clinically useful for guiding management decisions and therefore are considered not proven for treatment selection or monitoring.

ctDNA or CTC testing to guide adjuvant therapy decisions in early‑stage breast cancer is not supported; ASCO explicitly recommends against using these assays to guide adjuvant endocrine or chemotherapy in node‑negative or node‑positive early breast cancer subtypes.

Use of liquid biopsy to select targeted therapies, to select immune checkpoint inhibitor therapy, or tumor‑informed MRD approaches outside the specified indications are not covered under this policy and are treated as experimental/investigational.

Eligibility Requirements and Ordering Conditions

Eligibility excerpts: when a tissue biopsy is feasible, tissue‑based molecular characterization is the standard comparator; liquid biopsy is generally considered when tissue is unavailable or biopsy is not feasible. Individuals with negative liquid biopsy results who can undergo tissue biopsy should be reflexed to tissue testing.

Eligibility excerpts: prior authorization for MRD surveillance should confirm the individual has received curative‑intent therapy and that the intended use is monitoring for molecular/minimal residual disease or molecular relapse using an assay capable of detecting ultra‑low ctDNA concentrations; documentation should include the specific assay and intended management action.

Eligibility excerpt (ASCO‑related): ordering clinicians should document the intended management action (for example, a plan to omit or administer adjuvant chemotherapy based on ctDNA results) and specify the assay/version used because trial results and recommendations are assay‑ and protocol‑specific; ASCO also notes cfDNA testing is most helpful when tissue results are unavailable.

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Verify member benefits and contract language

Verify member benefits and contract language prior to ordering liquid biopsy. State and federal mandates and member contract provisions take precedence over this medical policy. Contact Blue Cross and Blue Shield of Kansas Customer Service to confirm benefits, prior authorization requirements, and any applicable exclusions.

State/federal mandates and member contract language take precedence
Contact BCBSKS Customer Service to verify benefits/prior authorization

Documentation Required

Provide indication and assay information

Provide the clinical indication for testing and specific assay information when submitting requests or claims for circulating tumor DNA (ctDNA) or circulating tumor cell (CTC) testing. Document the assay type (tumor‑informed vs tumor‑agnostic, PCR vs NGS), intended timing relative to curative-intent therapy, and the intended use (surveillance for MRD, guidance for adjuvant chemotherapy, or other management decisions).

Coding and Procedure Codes (Informational)

FDA-cleared/approved assays (examples listed in text)mixed

No codes listed

Notesmixed

See table

Certain liquid biopsy-based assays have been cleared or approved by the FDA as companion diagnostic tests; these are listed in the source document and addressed in tumor-specific policies (informational only).

Informational molecular pathology CPT/HCPCS codesCPT

81400	Molecular Pathology Procedure, Level 1 (Eg, Identification Of Single Germline Variant [Eg, Snp] By Techniques Such As Restriction Enzyme Digestion Or Melt Curve Analysis)
81401	Molecular Pathology Procedure, Level 2 (Eg, 2-10 Snps, 1 Methylated Variant, Or 1 Somatic Variant [Typically Using Nonsequencing Target Variant Analysis], Or Detection Of A Dynamic Mutation Disorder/Triplet Repeat)
81402	Molecular Pathology Procedure, Level 3 (Eg, >10 Snps, 2-10 Methylated Variants, Or 2-10 Somatic Variants [Typically Using Non-Sequencing Target Variant Analysis], Immunoglobulin And T-Cell Receptor Gene Rearrangements, Duplication/Deletion Variants Of 1 Exon)
81403	Molecular pathology procedure, level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex pcr in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons)
81404	Molecular Pathology Procedure, Level 5 (Eg, Analysis Of 2-5 Exons By DNA Sequence Analysis, Mutation Scanning Or Duplication/Deletion Variants Of 6-10 Exons, Or Characterization Of A Dynamic Mutation Disorder/Triplet Repeat By Southern Blot Analysis)
81405	Molecular Pathology Procedure, Level 6 (Eg, Analysis Of 6-10 Exons By DNA Sequence Analysis, Mutation Scanning Or Duplication/Deletion Variants Of 11-25 Exons, Regionally Targeted Cytogenomic Array Analysis)
81406	Molecular Pathology Procedure, Level 7 (Eg, Analysis Of 11-25 Exons By DNA Sequence Analysis)

Listed CPT/HCPCS codes in policymixed

81400	Molecular Pathology Procedure, Level 1
81401	Molecular Pathology Procedure, Level 2
81402	Molecular Pathology Procedure, Level 3
81403	Molecular pathology procedure, level 4
81404	Molecular Pathology Procedure, Level 5
81405	Molecular Pathology Procedure, Level 6
81406	Molecular Pathology Procedure, Level 7
81407	Molecular Pathology Procedure, Level 8
81408	Molecular Pathology Procedure, Level 9
81479	Unlisted Molecular Pathology Procedure

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ctDNA level cut-off (trial example)

ctDNA median cut-offMedian ctDNA level across all samples = 5268.2 parts per million (ppm); used to define high (>= median) versus low (< median) ctDNA

Cut-off contextReported as the median value used in trial analyses to dichotomize ctDNA levels for outcome comparisons

Implication for interpretationValues >=5268.2 ppm classified as ‘high’ ctDNA and <5268.2 ppm as ‘low’ for trial-specific subgroup analyses

Molecular response definition (PCG study)

Primary molecular response thresholdsPre-specified cutoffs of 90% and 50% decrease in ctDNA from baseline were used to define molecular response in the PCG real-world study

Definitions and Background

Background: Liquid biopsy refers to analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) from peripheral blood. ctDNA are small fragments of tumor‑derived cell‑free DNA used to quantify tumor DNA burden and assess treatment dynamics; CTCs are intact tumor cells shed into the circulation and are primarily used for prognostic enumeration or characterization. Detection is technically challenging because tumor‑derived material can be present at very low concentrations and requires sensitive targeted or broad genomic methods.

Liquid biopsy — definition

DefinitionLiquid biopsy: analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) from peripheral blood for noninvasive tumor characterization

Primary purposesUsed to characterize tumor genomics and quantify circulating tumor material

SpecimenPeripheral blood (plasma/whole blood) specimens are used for testing

Circulating tumor DNA (ctDNA) — definition

Revision History and Document Dates

2026-01-05document_revisionLatest

Rationale and references sections updated (document revision noted).

2023-10-02effective_date

Current effective date of the policy set to October 2, 2023.

2021-02-27original_effective_date

Policy Summary

Payerblue cross blue shield - kansas

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

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateOct 2, 2023

Next Review DateJan 5, 2026

Key ActionCheck member benefits with BCBSKS Customer Service to determine coverage or need for prior authorization.

SourceLink

On This Page

Clinical benefit must be demonstrated versus standard surveillance

Chain of evidence requirement: Clinical utility inference requires clinical validity plus an evidence-based management pathway; for CTCs such a pathway is not explicated and for many ctDNA indications it is not yet established.

Absent validated management pathways, no inference on clinical utility (chunk 74).

ASCO notes cfDNA may be used when tissue is unavailable.

On-treatment monitoring: Patients receiving systemic therapy where ctDNA or CTC kinetics are used to monitor treatment response.

Evidence for improved outcomes from monitoring is insufficient but kinetics can be prognostic.

Post-curative surveillance (MRD): Individuals who have completed curative-intent therapy and are monitored for molecular/minimal residual disease or molecular relapse using ctDNA or CTCs.

Assay sensitivity and timing are critical for MRD use.

Guiding adjuvant chemotherapy in select stage II colon cancer patients (DYNAMIC trial evidence)

Guiding adjuvant chemotherapy in select stage II colon cancer patients — randomized trial evidence:

DYNAMIC trial evidence: Randomized evidence (DYNAMIC) showed that a ctDNA-guided strategy in stage II colon cancer reduced adjuvant chemotherapy use without compromising 2-year RFS; updated analyses with longer follow-up reported comparable 5-year RFS and OS between arms.trial-specific ctDNA positivity definitions

Ordering clinicians should document intended management action and assay used because results are assay- and protocol-specific.

On-treatment ctDNA monitoring in lung cancer (molecular response definitions and prognostic associations)

On-treatment ctDNA monitoring in lung cancer — molecular response definitions and prognostic associations:

Molecular response thresholds used in cohort analyses: Pre-specified cutoffs of 90% and 50% decreases in ctDNA were used to define molecular response in the PCG real-world analyses and were associated with differences in rwPFS and rwOS.>=90% or >=50% decrease in ctDNA

Specimens were collected 6–15 weeks after therapy initiation; assay heterogeneity limits generalizability.

Use of cfDNA when tissue-based testing unavailable to identify actionable alterations for treatment selection (ASCO noted)

When tissue-based testing is unavailable and genomic testing is indicated:

cfDNA as alternative to tissue testing: ASCO notes that in patients without tissue-based genomic results, treatment may be based on actionable alterations identified in cfDNA; testing is most helpful when archival tissue is unavailable or new biopsies are not feasible.

Use should follow tumor-specific guidance and laboratory standards.

Document assay methodology (tumor‑informed vs tumor‑agnostic; PCR vs NGS)
Specify timing (post-curative treatment surveillance timepoint)
State intended management use (e.g., ctDNA-guided adjuvant chemotherapy)

Denial Risk

Claims for ctDNA and/or CTC testing for unaddressed indications

Claims for ctDNA and/or CTC testing for indications not addressed in this policy are considered experimental/investigational and may be denied. Inclusion of codes in the coding section is informational and does not imply coverage — coverage depends on medical necessity and member contract.

Tests/uses not addressed by policy are experimental/investigational
Coverage contingent on member contract and medical necessity

Note

Tests and uses explicitly not addressed by this policy

This policy does not address certain blood-based testing uses. Tests and uses explicitly not addressed include: selection of targeted therapy for breast cancer, non-small cell lung cancer, melanoma/glioma, ovarian cancer, pancreatic cancer, and prostate cancer; use of liquid biopsy to select immune checkpoint inhibitor therapy; tumor‑informed ctDNA testing for cancer management; comprehensive genomic profiling for therapy selection; blood-based detection or risk assessment of prostate cancer; and AR-V7 CTC testing for metastatic prostate cancer. Refer to the member's contract benefits for coverage decisions.

Breast, NSCLC, melanoma/glioma, ovarian, pancreatic, prostate targeted therapy selection
Liquid biopsy to select immune checkpoint inhibitor therapy
Tumor‑informed ctDNA testing for cancer management
Comprehensive genomic profiling for selecting targeted therapies
Blood-based testing for prostate cancer detection/risk assessment
AR‑V7 CTC testing for metastatic prostate cancer

Denial Risk

Analytic and clinical variability risks

Assays vary widely in analytic sensitivity; inability to detect ultra-low ctDNA concentrations increases the risk of false-negative results and loss of clinical utility. The heterogeneity of assays, differing timepoints, and variable definitions for ctDNA reduction or clearance confound interpretation and clinical validity. Providers should document assay performance characteristics when relying on results for management.

Assays must detect ultra-low ctDNA concentrations to reduce false-negatives
Heterogeneity of assays and timepoints limits ability to standardize ctDNA response definitions
Clinical sensitivity for MRD detection shortly after therapy is often suboptimal (≤50%) despite high specificity (often ≥90%)

Prior Authorization

Reflex to tissue biopsy when liquid biopsy is negative

If a liquid biopsy (CTC or ctDNA) yields a negative result and the patient is able to undergo tissue biopsy, reflex testing of tumor tissue is expected. For patients who can undergo biopsy, tissue-based molecular testing is the comparator and generally expected to guide treatment decisions.

Reflex to tumor tissue testing when liquid biopsy is negative and tissue is available
Tissue-based molecular characterization is preferred for patients able to undergo biopsy

Documentation Required

Documentation requirements — indication and intent

Documentation submitted for prior authorization or claims should include that testing is being performed in the setting of curative‑intent therapy and for surveillance (MRD) purposes when applicable. Include clinical history, dates of definitive therapy, indication for surveillance, and how results will influence management.

State that testing is for surveillance after curative‑intent treatment when applicable
Provide clinical history and dates of definitive therapy
Explain how test results will change management

Note

Trial documentation and limitations

Trials assessing ctDNA-guided management (for example, the DYNAMIC randomized trial in stage II colon cancer) provide direct evidence that ctDNA-guided adjuvant chemotherapy can reduce chemotherapy use without compromising short‑term recurrence-free survival; updated longer-term results have shown comparable 5-year RFS and OS in trial cohorts. Trial limitations (population diversity, undefined positivity thresholds, assay/version clarity, and test interpretation procedures) should be acknowledged in clinical decision-making and documentation.

DYNAMIC trial: ctDNA-guided ACT reduced chemotherapy use and was noninferior for 2-year RFS; 5-year RFS/OS later reported as comparable
Acknowledge trial limitations: population diversity, undefined ctDNA positivity thresholds, assay/version and test interpretation issues

Billing Rule

Coding and medical necessity linkage

Codes listed in the coding section are informational. Medical necessity must be established and documented for coverage. Inclusion of a procedure or diagnosis code does not guarantee reimbursement. The codes are medically necessary only when the procedure is performed according to the Policy section.

Coding lists are informational only — confirm medical necessity and member contract
Procedure codes are considered medically necessary only if performed per Policy

Note

Consider standard monitoring as comparator

Consider standard monitoring approaches (imaging and clinical examination) as the comparator or baseline surveillance strategy when evaluating the clinical utility of liquid biopsy. For patients unable to undergo tissue biopsy, standard therapy and standard monitoring are the typical management pathways.

Standard monitoring = imaging methods and clinical exam
Patients unable to undergo biopsy generally receive standard therapy

Documentation Required

When tissue biopsy is available, prefer tissue-based testing

When patients are able to undergo tissue biopsy, tissue-based molecular testing is generally expected and is the standard comparator for molecular characterization; liquid biopsy should not replace tissue testing when tissue is available for evaluation.

Tissue-based testing is preferred when biopsy is feasible
Liquid biopsy is primarily an alternative when tissue cannot be obtained

Step Therapy

ctDNA-guided adjuvant chemotherapy as a management step

ctDNA-guided adjuvant chemotherapy (ACT) can be considered a step in management for select patients (e.g., stage II colon cancer) where trial evidence supports reducing ACT use without compromising recurrence outcomes. Prior authorization may be required and should confirm curative intent and how test results will be used to guide therapy.

ctDNA-guided ACT supported by trial evidence for select stage II colon cancer patients
Prior authorization should confirm curative intent and intended management use

Timing of measurement

On-treatment liquid biopsies were collected 6–15 weeks after start of therapy for response classification

Clinical associationMolecular response by these cutoffs was associated with substantially different rwPFS and rwOS in cohort analyses

Example ctDNA panel gene count

Example panel size (0242U)CPT 0242U: targeted genomic sequence analysis panel of cell‑free circulating DNA covering 55–74 genes

Analytes interrogatedInterrogates sequence variants, gene copy number amplifications, and gene rearrangements

Code context0242U listed in policy coding section as an example cfDNA panel for solid organ neoplasms

Circulating tumor DNA (ctDNA): small fragments of tumor‑derived cell‑free DNA in blood, originating from apoptotic/necrotic tumor cells or CTCs and used for genomic tumor characterization

Biologic notectDNA fragments vary in length; necrosis tends to produce larger fragments unlike apoptosis

Use casesUsed to quantify DNA burden, assess dynamics of treatment response, MRD, prognosis, and to identify somatic genomic alterations when tissue is unavailable

Circulating tumor cells (CTCs) — definition

DefinitionCirculating tumor cells (CTCs): intact tumor cells shed into the bloodstream from primary or metastatic sites, detectable and quantifiable for prognostic purposes

Detection methodsMost assays detect CTCs using surface epithelial markers such as EpCAM and cytokeratins; enumeration assays (e.g., CellSearch) are described in coding entries

Clinical rolePrimarily used for prognostic quantification; clinical validity must be independently established for each commercial CTC test

CTC detection and clinical validity

Detection and validity noteCTC levels are strongly prognostic in multiple studies, but currently available CTC tests lack independent clinical validity evidence for many uses; no RCTs show CTC‑guided early treatment improves outcomes

Analytic methodsCTC detection commonly uses EpCAM/cytokeratin‑based enrichment with immunologic selection and identification

ImplicationBecause clinical validity is not established for many commercial CTC assays, clinical utility cannot be inferred without an evidence‑based management pathway

ctDNA quantification note

Quantification notectDNA quantification methods and optimal units are not standardized; kinetics (percent change) correlate with treatment response

Sensitivity requirementAssays must detect ultra‑low ctDNA concentrations to minimize false‑negative MRD results and enable benefit from early intervention

Clinical usectDNA dynamics can identify responses earlier than radiographic methods and are used for MRD, prognosis, and genomic profiling when tissue is unavailable

MRD / Molecular relapse — definition

DefinitionMRD / MR: minimal or molecular residual disease and molecular relapse — presence of persistent or recurrent tumor burden detected by sensitive assays (often ctDNA) after potentially curative therapy

Clinical implicationDetection of MRD by ctDNA after curative treatment is associated with high risk of future relapse

Assay requirementAccurate MRD assessment requires assays capable of detecting ultra‑low ctDNA concentrations to reduce false negatives

Clinically valid — definition

DefinitionClinically valid test: a test that detects presence/absence of a condition, risk of developing a condition, or treatment response (beneficial or adverse)

Evidence implicationClinical validity is required before inferring clinical utility; absent validated test performance, no inference on clinical benefit can be made

Application to CTCs/ctDNAEach commercially available CTC or ctDNA assay must demonstrate clinical validity for the intended use and population

ctDNA — alternate definition wording

Definition (alternate)ctDNA: circulating tumor DNA — tumor‑derived DNA fragments detectable in plasma used to assess MRD, prognosis, and treatment response

Specimen and assaysInterrogated via targeted cfDNA panels (examples such as CPT 0242U) and other sequencing approaches

Clinical noteBest unit for quantifying burden is not established; kinetics are informative for response assessment

CTC — alternate definition wording

Definition (alternate)CTC: circulating tumor cells — intact tumor cells detected and enumerated in blood, associated with prognosis in several cancers

Coding examplesCTC enumeration codes include CPT 86152 and 86153; assays such as CellSearch are referenced in coding entries

Clinical noteCTC half‑life in bloodstream is short (1–2 hours); detection commonly relies on epithelial markers

MRD — alternate definition wording

Definition (alternate)MRD: molecular/minimal residual disease — residual tumor burden detectable by sensitive assays (often ctDNA) after definitive therapy; used to predict relapse risk

Evidence requirementMRD detection should be linked to an evidence‑based management pathway to infer clinical utility

Assay considerationsTiming and assay sensitivity vary across studies; standardized thresholds are lacking

Chain of evidence — definition

DefinitionChain of evidence: approach where clinical utility is inferred from validated clinical validity data plus an evidence‑based management pathway that links test results to improved outcomes

RequirementDirect evidence from RCTs is preferred; absent direct evidence, strong clinical validity plus a validated management pathway can support utility inference

ApplicationNo explicated evidence‑based management pathway exists for CTC‑guided early treatment; therefore chain of evidence is incomplete for many CTC uses

CTC coding examples & references

CTC coding examplesCPT 86152 and 86153: cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood)

Additional CTC codes0091U and 0338U are included for specific CTC applications (cell enumeration/screening and CTC selection/identification with biomarker quantification)

Assay exampleCellSearch® referenced in coding entries as an example assay for CTC enumeration and HER2‑expressing cell quantification

ctDNA coding examples & references

ctDNA coding examplesCPT 0242U: targeted genomic sequence analysis panel of 55–74 genes for cell‑free circulating DNA; listed as an example cfDNA panel

Molecular pathology codesProcedure codes 81400–81408 and 81479 are listed for molecular pathology services including cfDNA sequencing panels

ContextctDNA panels and molecular pathology CPT/HCPCS codes are provided for informational purposes in the policy coding section

Original effective date recorded as February 27, 2021.