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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.
12/12/2023 Administrative Update: New code 0421U added as investigational, effective 1/1/2024.
06/11/2024 Administrative Update: New codes 0471U and 0464U added, effective 7/1/2024.
11/20/2023 Minor Review: Policy stance consolidated for KRAS, NRAS and BRAF; HER2 now medically necessary; CPT 81301 removed and 88365 added.
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.
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
Policy Guideline / Preferred Specimen
Testing guidance and sequencing recommendations:
Policy Guideline / Preferred Specimen criteria
Investigational / Not Medically Necessary
All other uses or specimen types not meeting above criteria:
Investigational / Not Medically Necessary criteria
Liquid biopsy evidence: Observational studies report variable sensitivity and specificity for ctDNA/CTC assays compared with tissue, with sensitivity and specificity ranges differing by assay and study; methods to detect ctDNA require high analytic sensitivity because ctDNA is often a small fraction of total circulating DNA. There are no published studies demonstrating clinical outcomes or clinical utility when using liquid biopsy to guide treatment in metastatic colorectal cancer; therefore evidence is insufficient to support its use to guide therapy selection.
| 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 |
| 0421U | New code listed as investigational |
| 0464U | Code listed under investigational |
| 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 |
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.
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.
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: 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: 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).
Minor Review: Policy stance consolidated for KRAS, NRAS and BRAF; HER2 now medically necessary; CPT 81301 removed and 88365 added.
Administrative Update: New code 0421U added as investigational, effective 1/1/2024.
Administrative Update: New codes 0471U and 0464U added, effective 7/1/2024.