CurrentCapital BluecrossPolicy MP 2.316

MEDICAL POLICY SOMATIC BIOMARKER TESTING (INCLUDING LIQUID BIoPsy) FOR TARGETED TREATMENT OF METASTATIC COLORECTAL CANCER (KRAS, NRAS, BRAF, AND HER2)

Defines medical necessity and investigational positions for KRAS, NRAS, BRAF, and HER2 somatic testing (tumor tissue) and for circulating tumor DNA/circulating tumor cell (liquid biopsy) testing to guide targeted treatment of metastatic colorectal cancer for Capital Blue Cross products; includes coding guidance and references.

Policy Summary

PayerCapital Bluecross

PolicyMEDICAL POLICY SOMATIC BIOMARKER TESTING (INCLUDING LIQUID BIoPsy) FOR TARGETED TREATMENT OF METASTATIC COLORECTAL CANCER (KRAS, NRAS, BRAF, AND HER2)

Policy CodePolicy MP 2.316

Change TypeAdministrative and minor review (coding and stance consolidation)

Effective DateJul 1, 2024

Next Review Date

Key ActionDocument metastatic colorectal cancer diagnosis and clinical rationale that testing is to select FDA-approved therapy; ensure tissue specimen testing is preferred and record if HER2 testing is for RAS wild-type patients.

SourceLink

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 Summary

Overview: This policy addresses somatic biomarker testing for metastatic colorectal cancer, including KRAS, NRAS, BRAF, and HER2, and consideration of circulating tumor DNA/circulating tumor cell (liquid biopsy) testing. Scope: defines medical necessity for tumor tissue testing to select individuals for FDA-approved therapies and considers liquid biopsy investigational. Effective date: 7/1/2024. Last review: 6/11/2024. Coverage stance: mixed.

Quick Facts

Key genes coveredKRAS, NRAS, BRAF, HER2

Preferred specimenTumor tissue (tissue preferred over liquid biopsy)

Policy stanceMixed — tissue testing medically necessary for specified uses; liquid biopsy investigational

Medical Necessity Criteria

Medically Necessary

KRAS, NRAS, BRAF, or HER2 testing of tumor tissue may be considered medically necessary for individuals with metastatic colorectal cancer to select individuals for treatment with FDA-approved therapies:

Medically Necessary criteria

Metastatic CRC diagnosis: Individual has metastatic colorectal cancer (see allowed ICD-10 list).
Specimen and testing: Testing is performed on tumor tissue (genotyping for RAS (KRAS and NRAS) and BRAF mutations individually or as part of an NGS panel).
Purpose of testing: Purpose is to select individuals for treatment with FDA-approved therapies (e.g., to determine eligibility for anti-EGFR monoclonal antibodies or HER2-targeted therapy).

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Policy Guideline / Preferred Specimen

Testing guidance and sequencing recommendations:

Policy Guideline / Preferred Specimen criteria

Genotype all metastatic CRC: All patients with metastatic colorectal cancer should have tumor genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of an NGS panel.
Specimen preference: Testing may be performed using either tissue or blood-based biopsy, with testing on tissue being preferred (NCCN).
HER2 testing guidance: Identification of HER2 amplification by IHC or FISH is recommended in RAS wild-type patients; HER2-directed therapy typically only influences treatment after at least first-line progression.

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Investigational and Not Medically Necessary

Investigational / Not Medically Necessary

All other uses or specimen types not meeting above criteria:

Investigational / Not Medically Necessary criteria

Other uses investigational: All other uses of KRAS, NRAS, BRAF, or HER2 variant testing of tumor tissue to guide colorectal cancer targeted therapy or immunotherapy are considered investigational.
Liquid biopsy investigational: Circulating tumor cell (CTC) or circulating tumor DNA (ctDNA) liquid biopsy testing to guide treatment for patients with metastatic colorectal cancer is considered investigational.

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Coding

Covered when medically necessary (procedure codes listed in policy)mixedCovered

88374	Morphologic or immunohistochemical testing - listed in policy coding section
0111U	Proprietary / lab test code listed in policy
0471U	Proprietary / lab test code listed in policy
81210	KRAS gene mutation analysis
81275	BRAF gene mutation analysis
81276	NRAS gene mutation analysis
81311	NGS panel / somatic testing code listed
88363	Immunohistochemistry procedure code listed
88365	IHC interpretation/procedure code listed

Considered investigational (procedure codes listed in policy)mixedExperimental

0421U	New code listed as investigational
0464U	Code listed under investigational

ICD-10-CM Diagnosis Codes (relevant indications listed)ICD-10

C18.0	Malignant neoplasm of cecum
C18.1	Malignant neoplasm of appendix
C18.2	Malignant neoplasm of ascending colon
C18.3	Malignant neoplasm of hepatic flexure
C18.4	Malignant neoplasm of transverse colon
C18.5	Malignant neoplasm of splenic flexure
C18.6	Malignant neoplasm of descending colon
C18.7	Malignant neoplasm of sigmoid colon
C18.8	Malignant neoplasm of overlapping sites of colon
C18.9	Malignant neoplasm of colon, unspecified

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Billing Rule

Use appropriate code category

Report the specific procedure (CPT/PLA) code corresponding to the test. Identification of a code in the coding section does not denote coverage; coverage is determined by the member's benefit plan and not by the presence of a code listing.

88374
0111U
0471U
81210
81275
81276
81311
88363
88365
0421U
0464U

Provider Actions

Documentation Required

Indication documentation

Document that the test is being ordered for metastatic colorectal cancer and state the clinical rationale that testing is to select an FDA‑approved therapy (e.g., to determine eligibility for anti‑EGFR or HER2‑targeted treatment). Note that tumor tissue is the preferred specimen for RAS/BRAF/HER2 testing per guidelines, and that HER2 testing is typically considered in RAS wild‑type patients and may influence therapy after first‑line progression.

Document ICD-10 diagnosis codes (see coding section)

Note

Prior authorization / coverage determination

Coverage and prior‑authorization requirements depend on the member’s specific health benefit plan. Codes listed in the policy have varying designations; some codes are covered when medically necessary and others are considered investigational (for example, 0421U and 0464U are listed as investigational per recent administrative updates).

Background, Evidence, and Definitions

Background: Somatic variants in KRAS, NRAS, and BRAF affect response to anti-EGFR therapies—KRAS and some NRAS variants predict nonresponse to cetuximab and panitumumab; BRAF variants are less common and associated with poorer prognosis. HER2 amplification/overexpression occurs in a minority of colorectal cancers and may guide HER2-targeted therapy, typically after first-line progression. Liquid biopsy methods (ctDNA and CTC assays) exist as noninvasive alternatives to tissue testing, but clinical utility data are limited compared with tissue-based testing.

Evidence topic	Summary
KRAS/NRAS evidence	Multiple systematic reviews and randomized trial analyses consistently show that KRAS and extended RAS (NRAS) variants predict nonresponse to anti-EGFR monoclonal antibodies (cetuximab, panitumumab). Evidence is sufficient to support tumor tissue RAS testing to guide therapy selection.
BRAF evidence	Meta-analyses and pooled studies have shown inconsistent results for the effect of BRAF variants on benefit from anti-EGFR therapy; individual studies are small and results inconsistent, so evidence is insufficient to determine impact on health outcomes for guiding anti‑EGFR therapy.
Liquid biopsy evidence	Observational studies of ctDNA/CTC assays report variable sensitivity and specificity versus tissue (e.g., sensitivity 70%–96%, specificity 83%–94%, positive percent agreement ~80% overall), but no published studies demonstrate clinical outcomes or utility; liquid biopsy to guide treatment is considered investigational.

Definitions:

• Variant of uncertain significance: Change in DNA sequence with uncertain effects on disease.

• Pathogenic / Likely pathogenic / Likely benign / Benign: ACMG-AMP standard terminology to describe variants identified in genetic testing.

Medicare Determinations

Medicare determinations: The policy references FDA companion diagnostics resources for guidance on approved tests; see the FDA companion diagnostics list referenced in the policy history and regulatory sections. Note: this policy lists covered and investigational CPT/PLA codes and indicates some codes are considered investigational (e.g., codes listed as investigational in coding section).

Revision History

11/20/2023revisedLatest

Minor Review: Policy stance consolidated for KRAS, NRAS and BRAF; HER2 now medically necessary; CPT 81301 removed and 88365 added.

12/12/2023clarified

Administrative Update: New code 0421U added as investigational, effective 1/1/2024.

06/11/2024clarified