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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. 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.

Cetuximab and panitumumab are approved in the 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. It has been shown that patients with a KRAS mutant tumor do not respond to cetuximab or panitumumab. However, there are still patients with KRAS wild-type tumors that do not respond to these agents, suggesting that other factors, such as alterations in other EGFR effectors could drive resistance to anti-EGFR therapy, and therefore, BRAF mutations are now increasingly being investigated in metastatic colorectal cancer. KRAS and BRAF mutations are considered to be mutually exclusive.

KRAS and BRAF mutation analysis using PCR methodology is commercially available as a laboratory-developed test. 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 mutational status as a predictor of nonresponse to EGFR-targeted therapy with monoclonal antibodies cetuximab and panitumumab in patients with 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.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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, 81404, and 81275 to the Code Reference section.

The code(s) listed below are ONLY covered if the procedure is performed according to the "Policy" section of this document.  

Covered Codes

This is not an all-inclusive list of non-covered procedure codes.

The code(s) listed below and ANY code not listed in the previous section are considered non-covered for this procedure.

Non-Covered Codes