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DESCRIPTIONCetuximab (Erbitux®, ImClone Systems) and panitumumab (Vectibix®, Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing intrinsic ligand binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.
The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. RAS proteins are G-proteins that cycle between active (RAS-GTP) and inactive (RAS-GDP) forms, in response to stimulation from a cell surface receptor such as EGFR, and act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. KRAS mutations are found in approximately 30–50% of CRC tumors and are common in other tumor types. Another proto-oncogene that acts downstream from KRAS–NRAS harbors oncogenic mutations in codons 12, 13, or 61 that result in constitutive activation of the EGFR-mediated pathway. These mutations are relatively rare compared with KRAS, detected in perhaps 2% to 7% of CRC specimens. It is unclear whether NRAS mutations predict poor response to anti-EGFR monoclonal antibody therapy or are prognostic of poor CRC outcome in general. A third proto-oncogene, BRAF, encodes a protein kinase and is involved in intracellular signaling and cell growth and is a principal downstream effector of KRAS. BRAF mutations occur in less than 10–15% of colorectal cancers, and appear to be a marker of poor prognosis. KRAS and BRAF mutations are considered to be mutually exclusive.
Cetuximab and panitumumab have FDA marketing approval for treatment of metastatic colorectal cancer in the refractory disease setting, and ongoing studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy.
KRAS, NRAS, and BRAF mutation analyses using PCR methodology are commercially available as laboratory-developed tests. Such tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.
This policy summarizes the evidence for using tumor cell KRAS, NRAS, and BRAF mutational status as a predictor of response to EGFR-targeted therapy with monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer.
KRAS mutation analysis may be considered medically necessary for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab and panitumumab.
NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.
BRAF mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY10/9/2008: Policy added
11/20/2008: Approved by Medical Policy Advisory Committee
12/28/2010: Policy title and description updated to indicate inclusion of BRAF testing to the policy; BRAF testing policy statement added as investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer; KRAS policy statement unchanged. FEP verbiage added to the Policy Exceptions section. Added HCPCS S3713 to the Covered Codes table.
01/18/2012: Policy reviewed; no changes.
01/10/2013: Added CPT codes 81210, 81403, and 81275 to the Code Reference section.
04/08/2014: Policy description updated. Kras policy statement updated with the following minor wording changes: “to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer” was changed to “for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab.” Removed deleted HCPCS code S3713 from the Covered Codes table in the Code Reference section.
12/31/2014: Code Reference section updated to revise the description of the following CPT code: 81403.
08/31/2015: Policy title changed from "KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer" to "KRAS, NRAS, and BRAF Mutation Analysis in Metastatic Colorectal Cancer." Policy description updated to include information regarding NRAS. Added the following policy statement: NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Added CPT code 81404 to the Investigational Codes table.
SOURCE(S)Blue Cross & Blue Shield Association Policy # 2.04.53
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.