Centene ctDNA/CTC Policy Update Coverage

Coverage Criteria for ctDNA and CTC Testing

Broad Molecular Profiling Panel Tests via ctDNA - Medically Necessary

Considered medically necessary when ALL of the following conditions are met:

Broad ctDNA panel medical necessity: Member has a diagnosis, progression, or recurrence of one of the listed tumor types (see enumerated list); AND if the broad ctDNA panel is performed simultaneously with solid tumor tissue testing, the member must have one of the specified lung diagnoses (lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or NSCLC NOS).See enumerated diagnoses

Enumerated diagnoses include stage IV/metastatic lung cancers, locally advanced/metastatic pancreatic adenocarcinoma, metastatic/advanced gastric and esophagogastric cancers, metastatic prostate cancer, stage III+ cutaneous melanoma, metastatic colorectal cancer, locally advanced/metastatic ampullary adenocarcinoma, persistent or recurrent cervical cancer, unresectable or metastatic biliary tract cancer, suspected/confirmed histiocytic neoplasm, locoregional unresectable/metastatic poorly differentiated neuroendocrine carcinoma, locoregional unresectable/metastatic large or small cell carcinoma, mixed neuroendocrine-nonneuroendocrine neoplasm, suspected metastatic malignancy of unknown primary with initial histology determination, recurrent ovarian/fallopian tube/primary peritoneal cancer, and recurrent or stage IV breast cancer (see policy for full list).

Broad Molecular Profiling Panel Tests via ctDNA - Investigational

Investigational when:

Broad ctDNA panels investigational: Performed for indications other than the enumerated tumor types, including when performed simultaneously with solid tumor tissue testing for tumor types other than the specified lung cancers.N/A

Policy explicitly states investigational for all other indications.

Lung Cancer Focused Panel Tests via ctDNA - Medically Necessary

Considered medically necessary when ALL of the following are met:

Lung ctDNA panel medical necessity: Member has a diagnosis or progression of advanced or metastatic lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or NSCLC not otherwise specified (NOS).Advanced or metastatic disease

Lung-focused ctDNA panels are investigational for all other indications.

EGFR Variant Analysis via ctDNA - Medically Necessary

Considered medically necessary when ALL of the following are met:

EGFR ctDNA medical necessity: Member has advanced or metastatic lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or NSCLC NOS; AND treatment with an EGFR tyrosine kinase inhibitor (eg, erlotinib, gefitinib, afatinib, osimertinib) is being considered.Consideration of EGFR TKI therapy

EGFR ctDNA (81235) as a standalone test is investigational for other indications.

BRAF Variant Analysis via ctDNA - Medically Necessary

Considered medically necessary when ANY one of the following diagnostic scenarios is met:

BRAF ctDNA medical necessity: 1) Metastatic colorectal cancer AND testing for NRAS and KRAS is also being performed (separately or as part of a panel); OR 2) Stage III or higher cutaneous melanoma AND being considered for adjuvant or other systemic therapy; OR 3) Locally advanced or metastatic pancreatic adenocarcinoma AND being considered for anticancer therapy.See scenarios

BRAF ctDNA (81210) is investigational for all other indications.

KRAS Variant Analysis via ctDNA - Medically Necessary

Considered medically necessary when ANY of the specific scenarios are met:

KRAS ctDNA medical necessity: A) Metastatic colorectal cancer AND testing for NRAS and BRAF is also being performed (as separate tests or as part of an NGS panel); OR B) Locally advanced or metastatic pancreatic adenocarcinoma AND is being considered for anticancer therapy.See scenarios

KRAS ctDNA (81275, 81276) is investigational for other indications.

PIK3CA Variant Analysis via ctDNA - Medically Necessary

Considered medically necessary when ALL of the following are met:

PIK3CA ctDNA medical necessity: Member has recurrent, unresectable, or stage IV hormone receptor-positive/HER2-negative breast cancer; AND is considering treatment with alpelisib plus fulvestrant or capivasertib plus fulvestrant; AND has had progression on at least one line of therapy.Progression on ≥1 prior line of therapy

If ctDNA testing is negative, tumor tissue testing is recommended per NCCN guidance (testing can be performed on tissue or ctDNA).

PIK3CA Variant Analysis via ctDNA - Medically Necessary (explicit codes)

PIK3CA variant analysis (0177U, 81309) via ctDNA is considered medically necessary when ALL of the following are met:

PIK3CA ctDNA medical necessity: A. Member has recurrent, unresectable, or stage IV hormone receptor-positive/HER2-negative breast cancer

PIK3CA ctDNA medical necessity: B. Member is considering treatment with alpelisib plus fulvestrant, or capivasertib plus fulvestrant

PIK3CA ctDNA medical necessity: C. Member has had progression on at least one line of therapy

PIK3CA Variant Analysis via ctDNA - Investigational

PIK3CA variant analysis via ctDNA is considered investigational for:

PIK3CA ctDNA investigational: All other indications not listed as medically necessary.

PIK3CA testing outside the HR+/HER2- recurrent/unresectable/stage IV setting for the specified therapy considerations is investigational.

KRAS Variant Analysis via ctDNA

KRAS variant analysis (81275, 81276) via ctDNA is considered medically necessary when ANY of the following apply (per fragment present):

KRAS colorectal: A. Member has metastatic colorectal cancer AND testing for NRAS and BRAF is also being performed, either as separate tests or as part of an NGS panel.

KRAS pancreatic: B. Member has locally advanced or metastatic pancreatic adenocarcinoma AND is being considered for anticancer therapy.

KRAS Variant Analysis via ctDNA - Investigational

KRAS variant analysis via ctDNA is considered investigational for:

KRAS investigational: All other indications not specified as medically necessary.

AR-V7 CTC Analysis - Medically Necessary

AR-V7 CTC analysis (81479) is considered medically necessary when ALL of the following are met:

AR-V7 criterion A: A. Member has metastatic castration-resistant prostate cancer.

AR-V7 criterion B: B. Tissue-based testing is not feasible for the member.

AR-V7 criterion C: C. The test is ordered only once during the current cancer diagnosis.

CMS LCD allows a second test only if it meets all criteria and is reasonable and necessary.

AR-V7 criterion D: D. Member has at least one of: newly metastatic cancer OR signs of clinical, radiological or pathologic disease progression.

AR-V7 CTC Analysis - Investigational

AR-V7 CTC analysis is considered investigational for:

AR-V7 investigational: All other indications not listed as medically necessary.

CTC Enumeration - Not Medically Necessary / Investigational

Circulating Tumor Cell enumeration (86152):

CTC enumeration stance: CTC enumeration is considered investigational; evidence does not show change in outcomes resulting from management changes based on enumeration.

NCCN and CMS LCD note limited clinical utility and lack of evidence for impact on outcomes.

Updated coverage criteria (summary)

Coverage criteria were revised to align with current clinical guidelines (NCCN) and CMS LCDs. Notable policy-level criteria changes include:

Broad Molecular Profiling Panel Tests via ctDNA: Replaced 'Comprehensive' with 'Broad'; added CPT codes 81462-81464; minor expansion to include additional tumor types; concurrent ctDNA and tissue testing allowed for advanced/metastatic NSCLC.

Chunks 38,39,44

EGFR Variant Analysis via ctDNA: Coverage limited to patients with advanced or metastatic disease; criteria wording changed to 'advanced' lung cancer rather than stage IV.

Chunk 44

BRAF/KRAS/PIK3CA Variant Analyses via ctDNA: Criteria updated to align with guidelines; removal of requirement that tissue testing be unavailable, and PIK3CA criteria updated to include consideration of capivasertib in addition to alpelisib.

Chunks 38-40,44

Cell-free circulating tumor DNA (ctDNA) testing, including broad molecular profiling panels, is intended to complement—not replace—histologic tissue diagnosis. The policy explicitly states that ctDNA analysis should not be used in lieu of a histologic tissue diagnosis and that when ctDNA results are negative, follow-up tissue-based analysis is recommended. Broad molecular profiling ctDNA panels are considered investigational for indications not specifically listed in the policy (see enumerated tumor types for medically necessary use).

If a broad ctDNA panel is performed simultaneously with tissue testing, simultaneous testing is allowed only for specified lung cancer diagnoses (lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or NSCLC NOS); simultaneous testing for other tumor types is considered investigational.

Use of the ctDNA and CTC tests listed in this policy for clinical indications that are not enumerated as medically necessary is considered investigational or not covered. Examples include ordering PIK3CA ctDNA testing outside the specified hormone receptor‑positive/HER2‑negative breast cancer scenario tied to specified therapies and progression criteria, KRAS ctDNA testing outside the listed colorectal or pancreatic indications, or AR‑V7 CTC analysis outside the defined metastatic castration‑resistant prostate cancer context.

Providers should ensure the requested test and clinical scenario match the policy’s listed medically necessary indications; requests for these tests for other indications may be denied as investigational.

Certain clinical criteria related to colorectal and melanoma‑focused ctDNA panel tests were removed from the policy because currently available, validated tests for those focused indications are lacking. The policy language was updated to reflect those removals and to align coverage language with current guideline and coverage evidence.

When criteria for a focused panel indication are removed due to lack of available tests, the policy treats those indications as not covered/investigational until appropriate tests and evidence are available.

Use of the listed broad ctDNA panels or single‑gene/variant analyses for tumor types or clinical scenarios other than those explicitly enumerated as medically necessary in this policy is considered investigational and not medically necessary. The policy provides specific medically necessary indications (for example: EGFR testing only in advanced/metastatic non‑small cell lung cancer when EGFR TKI therapy is being considered; BRAF testing for metastatic colorectal cancer with concurrent NRAS/KRAS testing, stage III+ melanoma under consideration for systemic/adjuvant therapy, or advanced pancreatic adenocarcinoma; KRAS testing for metastatic colorectal cancer with NRAS/BRAF testing or for advanced pancreatic disease; and PIK3CA testing only for recurrent/unresectable/stage IV HR+/HER2‑ breast cancer when considering specified targeted therapies after progression).

Requests for these assays outside the listed tumor types or scenarios should be considered investigational per the policy and may be denied.

Circulating tumor cell (CTC) enumeration (CPT code 86152) is considered investigational / not medically necessary. The policy states that CTC enumeration has not demonstrated an impact on patient management sufficient to support coverage.

Evidence reviewed and guideline statements cited in the policy indicate that enumeration alone does not reliably guide therapeutic decisions and lacks demonstrated outcome benefit.

The policy notes that although CTC enumeration may provide prognostic information, available evidence does not show that enumeration alters clinical outcomes by changing management. This lack of conclusive evidence is a key reason enumeration is categorized as investigational.

That CMS local coverage determination language and NCCN guidance cited in the policy emphasize that CTC enumeration has not been shown to produce clear outcome changes resulting from management changes, and this may influence coverage determinations for CTC enumeration analyses.

Covered Indications and Tumor Types

Coding and Test Codes

Broad Molecular Profiling Panel Tests via ctDNAmixedCovered

0239U	Broad molecular profiling panel via ctDNA (FoundationOne Liquid CDx example)
0242U	Broad molecular profiling panel via ctDNA (Guardant360 CDx example)
0326U	Broad molecular profiling panel via ctDNA (Guardant360 83+ genes example)
0409U	Broad molecular profiling panel via ctDNA (LiquidHALLMARK/other example)
81445	NGS panel-related code referenced for ctDNA
81455	NGS panel-related code referenced for ctDNA
81462	NGS panel-related code added to broad molecular profiling criteria
81463	NGS panel-related code added to broad molecular profiling criteria
81464	NGS panel-related code added to broad molecular profiling criteria

Lung Cancer Focused Panel Tests via ctDNAmixedCovered

0179U	Lung cancer focused ctDNA panel (example)
0388U	Lung cancer focused ctDNA panel (InVisionFirst-Lung example)
81210	BRAF variant analysis (listed for some lung-focused panels)
81235	EGFR variant analysis
81275	KRAS variant analysis
81462	CPT code referenced for lung-focused ctDNA panels (also listed under broad panels)

Single-Gene / Variant Analyses via ctDNAmixedCovered

81235	EGFR variant analysis via ctDNA
81210	BRAF variant analysis via ctDNA
81275	KRAS variant analysis via ctDNA
81276	KRAS additional variant analysis via ctDNA
0177U	PIK3CA variant analysis via ctDNA (proprietary/test-specific PLA example)
81309	PIK3CA variant analysis (molecular pathology procedure)

Circulating Tumor Cell (CTC) Tests / Enumerationmixed

86152	Circulating tumor cell (CTC) enumeration (CELLSEARCH example)
0490U	CELLSEARCH Circulating Melanoma Cell (CMC) test
0491U	CELLSEARCH ER Circulating Tumor Cell (CTC-ER) test
0492U	CELLSEARCH PD-L1 Circulating Tumor Cell (CTC-PDL1) test

PIK3CA ctDNA codesCPTCovered

0177U	PIK3CA variant analysis via ctDNA (proprietary/test-specific PLA example)
81309	PIK3CA variant analysis (molecular pathology procedure)

KRAS ctDNA codesCPT

81275	KRAS variant analysis (specific exon/sequence testing)
81276	KRAS additional variant analysis

AR-V7 CTC analysis codesCPTCovered

81479

Unlisted/other molecular pathology procedure used for AR-V7 CTC analysis

CTC enumerationCPTNot Covered

86152

Circulating tumor cell (CTC) enumeration

Policy reference table: Added/updated CPT/HCPCS entriesCPT | HCPCS | mixed

81462	Added to criteria for Broad Molecular Profiling Panel Tests via ctDNA
81463	Added to criteria for Broad Molecular Profiling Panel Tests via ctDNA
81464	Added to criteria for Broad Molecular Profiling Panel Tests via ctDNA
0490U	CELLSEARCH Circulating Melanoma Cell test entry added
0491U	CELLSEARCH ER Circulating Tumor Cell test entry added
0492U	CELLSEARCH PD-L1 Circulating Tumor Cell test entry added
0485U	Caris Assure test entry added to Policy reference table
0487U	Northstar Select test entry added to Policy reference table
0499U	OptiSeq Dual Cancer Panel Kit test entry added to Policy reference table
86152	CELLSEARCH Circulating Tumor Cell (CTC) Test added to policy reference table

Disease stage thresholds

General thresholdMostly advanced or metastatic disease required for covered indications (examples in policy include Stage IV or metastatic disease; Stage III or higher for cutaneous melanoma).

Lung cancer examplesStage IV or metastatic lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or NSCLC NOS (policy allows concurrent ctDNA and tissue testing for advanced/metastatic NSCLC).

Melanoma thresholdStage III or higher cutaneous melanoma listed among covered tumor types for broad ctDNA panels.

Other tumor typesMetastatic or locally advanced cancers such as pancreatic adenocarcinoma, gastric cancer, colorectal cancer, prostate cancer, biliary tract cancer, and recurrent ovarian/fallopian tube/peritoneal cancer are listed as covered when advanced/metastatic criteria are met.

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization for Added/Updated Test Codes

Certain CPT/PLA entries for broad molecular profiling and new CTC tests have been added or updated. Providers should follow payer prior authorization policies and confirm PA is obtained when required prior to testing to avoid claim denials.

Added/updated CPT/PLA entries include broad molecular profiling panel and new CTC test codes (e.g., recently added CPT codes 81462, 81463, 81464 and new CTC PLA entries).
Prior authorization may be required per the Health Plan's prior authorization rules for these added/updated codes; verify plan-specific PA requirements before ordering.

Denial Risk

PIK3CA ctDNA Denial Trigger

PIK3CA ctDNA testing (0177U, 81309) is covered only when specific clinical criteria are met. Tests for PIK3CA via ctDNA that do not meet these listed conditions may be denied.

Medically necessary only when: recurrent, unresectable, or stage IV HR+/HER2- breast cancer; considering alpelisib plus fulvestrant or capivasertib plus fulvestrant; and progression on ≥1 line of therapy.

Not Covered and Investigational Uses

Use of broad ctDNA panels, lung‑focused panels, or single‑gene variant analyses for indications not enumerated in the policy is explicitly listed as not covered/investigational. The policy’s not‑covered section clarifies that tests performed outside the specified tumor types or clinical scenarios do not meet medical necessity criteria and are considered investigational.

Providers should confirm that the clinical indication matches the policy’s covered indications before ordering these assays; otherwise, the test may be denied as not covered.

CTC enumeration testing (CPT 86152) and other CTC methods that have not demonstrated a meaningful impact on clinical management are considered investigational and not covered by the policy.

The policy references guideline and CMS LCD language indicating that while CTC enumeration can be prognostic, there is insufficient evidence that its use leads to management changes that improve outcomes.

Several previously listed tests and CPT entries were removed from the policy reference table and criteria during the most recent update (for example, certain CELLSEARCH and colorectal CTC entries). The policy notes that test entries were both added and removed to reflect current availability and evidence, and tests without sufficient evidence or availability were removed from covered criteria.

Providers should consult the updated policy reference table for the current list of included test entries and codes.

Eligibility Requirements and Limits

General eligibility for ctDNA broad molecular profiling panels requires that the member has a listed diagnosis, progression, or recurrence of one of the enumerated advanced/unresectable or metastatic tumor types (examples include advanced/metastatic lung cancers, metastatic pancreatic or gastric cancers, metastatic prostate cancer, stage III+ melanoma, metastatic colorectal cancer, recurrent ovarian/fallopian tube/peritoneal cancer, and recurrent or stage IV breast cancer).

When a broad ctDNA panel is performed simultaneously with tissue testing, eligibility for concurrent testing is limited to specified lung cancer diagnoses (lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or NSCLC NOS).

Eligibility for certain single‑gene variant ctDNA tests is tied to specific clinical and therapy considerations. For example, PIK3CA ctDNA testing (CPT codes 0177U, 81309) is eligible only for members with recurrent, unresectable, or stage IV hormone receptor‑positive/HER2‑negative breast cancer who are being considered for alpelisib plus fulvestrant or capivasertib plus fulvestrant and who have progressed on at least one prior line of therapy.

Similarly, EGFR ctDNA analysis is limited to patients with advanced or metastatic NSCLC when EGFR TKI therapy is being considered; other single‑gene ctDNA tests have specific tumor and treatment‑linked eligibility as described in the policy.

The policy requires documentation when tissue testing is feasible but not performed: tests should be ordered with medical record documentation that tissue‑based testing is infeasible or insufficient (for example, insufficient quantity, medically contraindicated, or other CMS LCD‑listed reasons).

For AR‑V7 CTC analysis, eligibility is further constrained: it is allowed only when tissue testing is not feasible, is limited to one test per cancer diagnosis (with CMS LCD exceptions permitting a second test only if reasonable and necessary), and ordered for newly metastatic disease or disease progression.

Background and Definitions

Cell‑free circulating tumor DNA (ctDNA) is fragmented, tumor‑derived DNA released into the bloodstream from dying tumor cells and can be assayed noninvasively via a liquid biopsy to detect driver or acquired mutations that may inform targeted therapy.

Circulating tumor cells (CTCs) are intact tumor cells shed into the bloodstream or lymphatics; CTC assays are primarily used for prognostic quantification rather than routine therapeutic decision‑making. The policy emphasizes that ctDNA is an adjunct to tissue testing and that negative ctDNA results should prompt confirmatory tissue analysis when feasible.

ctDNA / cfDNA definition

Concise definitionCell-free circulating tumor DNA (ctDNA or cfDNA) — fragmented, tumor-derived DNA released into the bloodstream from tumor cells; analyzable via liquid biopsy to detect tumor mutations.

Source and useOriginates from primary tumor or metastasis as cells die and release DNA; used as a noninvasive alternative to tissue biopsy for mutation detection and disease monitoring.

LimitationsA negative ctDNA result should prompt follow-up tissue-based analysis when clinically indicated; ctDNA should not replace histologic tissue diagnosis.

Policy Revision History and Changes

11/2024criteria_revisionLatest

Coverage criteria revised to align with NCCN and CMS LCD guidance, including terminology changes (e.g., 'Comprehensive' to 'Broad'), expanded tumor types, and allowing concurrent ctDNA and tissue testing for advanced/metastatic NSCLC.

04/2024criteria_update

Minor expansion and clarification of criteria across multiple variant analyses (EGFR, BRAF, KRAS) and removal of requirement that tissue testing be unavailable to better align with guidelines.

11/23

OpenPayer

Concert Genetic Oncology: Circulating Tumor DNA and Circulating Tumor Cells (Liquid Biopsy)

Coverage Criteria for ctDNA and CTC Testing

Covered Indications and Tumor Types

Coding and Test Codes

Provider Actions, Prior Authorization, and Documentation

Not Covered and Investigational Uses

Eligibility Requirements and Limits

Background and Definitions

Policy Revision History and Changes