Medical Policy: 02.04.20 

Original Effective Date: October 2008 

Reviewed: March 2017 

Revised: December 2017 


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.


This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.



Cetuximab (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.  Some individuals with colorectal cancer have tumors with a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation that may affect tumor response to these EGFR inhibitors.


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 colorectal cancer tumors and are common in other tumor types.  KRAS and BRAF mutations are considered to be mutually exclusive.


Cetuximab and panitumumab are approved in the treatment of metastatic colorectal cancer (mCRC) in the setting of refractory disease. Data from randomized controlled trials have consistently shown a lack of clinical response to cetuximab and panitumumab in patients with mutated KRAS, with tumor response and prolongation of progression-free survival observed only in patients with wild-type KRAS mutations. KRAS mutation analysis using polymerase-chain reaction (PCR) methods is commercially available as a laboratory-developed test in a CLIA-licensed laboratory.


Clinical trial data show that patients with KRAS-mutated metastatic colorectal cancer do not benefit from cetuximab (Erbitux®) or panitumumab (Vectibix®) when given in combination with other treatment regimens or when used alone.


Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network (NCCN) guidelines (v2.20156 on the treatment of colon cancer, and the guideline on rectal cancer (v.1.2016) recommend that tumor KRAS gene status testing be performed for all patients with metastatic colorectal cancer. Testing should be performed on archived specimens of primary tumor or a metastasis at the time of diagnosis of metastatic disease. The guidelines indicate that cetuximab and panitumumab are appropriate only for patients with tumor that expresses the WT KRAS gene.


Current NCCN guidelines (v 4.2016) indicate that KRAS mutational status may be prognostic of survival and predictive of therapeutic efficacy from EGFR-TKIs, specific recommendations are not made with regard to the use of KRAS mutation testing in the selection of TKI and anti-EGFR monoclonal antibody therapies for NSCLC.


In 2015 NCCN guidelines for both colon and rectal cancer were updated to include the addition of RAS mutation analysis which includes both KRAS and NRAS gene testing in the workup for all patients with metastatic colorectal cancer. The guidelines state that cetuximab and panitumumab are only indicated for patients with tumors that express the wild-type KRAS/NRAS gene.


NCCN guidelines for colon cancer state that patients with a BRAF V600E mutation appear to have a poorer prognosis. Evidence is insufficient to guide the use of anti-EGFR therapy in the first-line setting with active chemotherapy based on BRAF V600E mutation status.


NCCN guidelines for melanoma, version 3.2016, recommend vemurafenib, dabrafenib, and trametinib “only for patients with V600 mutation of the BRAF gene, as documented by an FDA-approved or CLIA-approved facility.”  Vemurafenib and dabrafenib both have category 1 recommendations as preferred regimens for advanced or metastatic melanoma. Trametinib (monotherapy) has a category 1 recommendation as an “other active regimen”.


International Association for the Study of Lung Cancer and the Association for Molecular Pathology

The International Association for the Study of Lung Cancer and the Association for Molecular Pathology published evidence-based guidelines addressing molecular testing to select individuals with lung cancer for treatment with EGFR and alkaline phosphatase TKI therapy.  Based on a category B rating (good quality evidence), the authors do not recommend KRAS mutation testing as a sole determinant of EGFR TKI therapy. The guideline states: The significance of KRAS mutational analysis may become increasingly important with the further development of new therapies targeting downstream RAS pathways, such as PI3K/AKT/mTOR and RAS/RAF/MEK, but at this time, the absence of a KRAS mutation does not add clinically useful information to the EGFR mutation result and should not be used as a determinant of EGFR TKI therapy.


EGAPP (Evaluation of Genomic Applications in Practice and Prevention)

Summary of recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.


The EWG found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario. The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low.



Another RAS gene is the neuroblastoma RAS viral (v-ras) oncogene homolog, or (NRAS). NRAS mutations are found in 2-7% of CRCs and occur most commonly in codon 61 rather than codon 12 or 13. NRAS mutations are mutually exclusive from KRAS and NRAS mutation testing should be performed when KRAS is wild-type. The presence of NRAS mutations is associated with lack of response to cetuximab therapy.  NRAS, another member of the RAS family of protooncogenes, which can harbor mutations in codons 12, 13, and 61. Thus, the NRAS oncogene also may have an impact on outcomes of anti-EGFR treatments for CRC. Compared with KRAS, NRAS mutations are extremely rare. Although NRAS mutations account for approximately 15% of all RAS mutations, they are found in perhaps 2% to 7% of all CRC.



BRAF (also known as serine/threonine-protein kinase B-Raf, v-raf murine sarcoma viral oncogene homolog B1) encodes a protein kinase which is implicated in intracellular signaling and cell growth and is a direct downstream effector of KRAS.


The presence of the V600E BRAF mutation in tumors is associated with a poor prognosis in colorectal cancer, colon cancer, and several other cancer types. V600E BRAF mutation is linked to a poor response to anti-EGFR therapies and shorter survival independent of anti-EGFR therapies. The published literature does not yet clearly define the role of BRAF status in response to EGFR inhibitor therapy.  It is still unclear to what extent the lack of response in individuals with KRAS wild-type is solely due to BRAF mutations. The determination of BRAF mutation analysis within the NCCN guidelines in 2016 for colon and rectal cancer is the first step in the treatment algorithm.


The EGFR signaling system is quite complex which may explain the modest objective response rates that have been achieved with clinical trials of EGFR inhibitors to date, as well as the disparities observed between clinical and preclinical findings. Metastatic colorectal predictive algorithms to identify additional patients with metastatic colorectal cancer who are unlikely to respond to treatment with an EGFR-targeted monoclonal antibody are being developed. These algorithms include the addition of BRAF, expression to NRAS/KRAS analysis. BRAF testing is included in the 2016 NCCN guidelines under principles of pathologic review.


In 2017, vemurafenib (Zelboraf) was approved by the FDA for Erdheim-Chester disease with BRAFV600 mutation. Zelboraf is the first FDA-approved treatment for Erdheim-Chester disease (ECD), a rare blood disease. The need to obtain BRAF mutation analysis prior to the planned treatment with vemurafenib in Erdheim-Chester disease is essential in the treatment planning process.


Prior Approval:


Not applicable



KRAS and NRAS mutation analysis may be considered medically necessary to predict nonresponse to cetuximab and panitumumab in the treatment of metastatic (Stage IV) colorectal cancer.  Testing must be done prior to initiation of therapy.


Testing for the BRAF V600E mutation may be considered medically necessary to further stratify those patients with KRAS wild type tumors and to guide treatment for colorectal cancer. Testing must be completed prior to therapy.


BRAF mutation analysis with a diagnosis of stage IIIC or IV (metastatic or unresectable) metastatic melanoma to predict nonresponse to vemurafenib, dabrafenib, or trametinib may be considered medically necessary.  Testing must be completed prior to initiation of therapy.


BRAF mutation analysis with a diagnosis of Erdheim-Chester to predict nonresponse to vemurafenib, may be considered medically necessary. Testing must be completed prior to initiation of therapy.


KRAS, NRAS or BRAF mutation analysis for all other indications, including but not limited to the following, is considered investigational:

  • Breast Cancer, including breast cancer assays
  • Prostate Cancer
  • Anal Cancer
  • Rectal cancer
  • Lung Cancers
  • Benign Neoplasms
  • Leukemias

KRAS, NRAS, or BRAF is considered investigational for routine testing at initial diagnosis.


Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
  • 81275 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (eg, codons 12 and 13)
  • 81276 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; additional variant(s) (eg, codon 61, codon 146)
  • 81311 NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (eg, colorectal carcinoma), gene analysis, variants in exon 2 (eg, codons 12 and 13) and exon 3 (eg, codon 61)
  • 88363 Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis)


Selected References:

  • Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(10):1626-34.
  • Linardou H, Dahabreh IJ, Kanaloupiti D et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncology 2008 Sept 17. [Epub ahead of print].
  • Lievre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008; 26(3):374-9.
  • Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25(13):1658-64.
  • Khambata-Ford S, Garrett CR, Meropol NJ et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007; 25(22):3230-7.
  • Punt CJ, Tol J, Rodenburg CJ et al. Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 2008; 26(15 suppl); abstract LBA4011.
  • De Roock W, Piessevaux H, De Schutter J et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008 Mar;19(3):508-15. [E-pub 2007 Nov 12].
  • Peeters M, Balfour J, Arnold D. Review Article: Panitumumab- A fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer. Aliment Pharmacol Ther. 2008;28(3):269-81.
  • Amado RG, Wolf M, Peeters M et al. Wild-Type KRAS is required for Panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Apr 1; 26(10):1626-34.
  • Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer. N Engl J Med 2008 Oct 23;359 (17):1757-65.
  • Price TJ, Hardingham JE, Lee CK et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX Trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 2011;29(19): 2675-82.
  • Dahabreh IJ, Terasawa T, Castaldi PJ et al. Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern med. 2011;154:37-49.
  • Santini D, Spoto C, Loupakis F et al. High concordance of BRAF status between primary colorectal tumours and related metastatic sites: implications for clinical practice. Ann Oncol 2012; 21:1565.
  • Mao C, Liao RY, Qiu LX et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep 2011;38(4):2219-23.
  • Maughan TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomized phase 3 MRC COIN trial. Lancet 2011;377(9783):2103-14.
  • NCCN Clinical Practice Guidelines in Oncology™ Colon cancer. Version 1.2017 Cancer Network, Inc.
  • NCCN Clinical Practice Guidelines in Oncology™ Rectal cancer. Version 2.2017 Cancer Network, Inc.
  • NCCN Clinical Practice Guidelines in Oncology™ Anal Carcinoma. Version 1.2017 Cancer Network, Inc.
  • NCCN Clinical Practice Guidelines in Oncology™ Non-Small Cell Lung Cancer. Version 4.2017 Cancer Network, Inc.
  • NCCN Clinical Practice Guidelines in Oncology™ Melanoma. Version 1.2017 Cancer Network, Inc.
  • NCCN Clinical Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 2.2016 Cancer Network, Inc.
  • NCCN Clinical Practice Guidelines in Oncology™. Hairy Cell Leukemia. Version 2.2017 Cancer Network, Inc. 
  • Bokemeyer C., Cutsem E.V., Rougier P., Ciardiello F., Heeger S., Schlichting M., Celik I., Kohne C.-H. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials (2012)  European Journal of Cancer,  48  (10) , pp. 1466-1475
  • Cushman-Vokoun AM. Stover DG et al. Clinical Utility of KRAS and BRAF Mutations in a Cohort of Patients With Colorectal Neoplasms Submitted for Microsatellite Instability Testing.(2013) Clinical Colorectal Cancer epub ahead of print.
  • Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer [trunc]. Arch Pathol Lab Med. 2013 Jun;137(6):828-860.
  • American College of Medical Genetics and Genomics, Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genetics in Med. 2013 July:15(7): 517-527.
  • Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to antiepidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091–2096.
  • AHRQ Tech Assessment, Technology assessment of molecular pathology testing for the estimation of prognosis for common cancers May 29, 2014.
  • Klingbiel D, Tejpar S. Microsatellite instability and BRAF and KRAS mutations in Stage III colon cancer. Jama Oncology January 14, 2016; doi:10.1001/jamaoncol.2015.5226
  • Shea M, et al. Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther Adv Respir Dis 2016 Apr;10(2):113-29.
  • Barone C, Pinto C, Normanno N, Capussotti L, Cognetti F, et al. (2014) KRAS Early Testing: Consensus Initiative and Cost-Effectiveness Evaluation for Metastatic Colorectal Patients in an Italian Setting. PLoS ONE 9(1): e85897. doi:10.1371/journal.pone.0085897
  • F Sahm, D Capper, M Preusser , etal : BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis Blood 120: e28– e34,2012
  • T Satoh, A Smith, A Sarde , etal : B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease PLoS One 7: e33891,2012
  • J Haroche, F Charlotte, L Arnaud , etal : High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses Blood 120: 2700– 2703,2012
  • Stempel, J., Alvaraz, J., et. al. Erdheim-Chester disease, moving away from the orphan diseases: A case report. Resp.Medicine Case Reports, 2017, 55-58.


Policy History:

  • December 2017 - Interim Review, Policy Revised
  • March 2017 - Annual Review, Policy Revised
  • March 2016 - Annual Review, Policy Revised
  • April 2015 - Annual Review, Policy Revised
  • May 2014 - Annual Review, Policy Revised
  • July 2013 - Annual Review, Policy Revised
  • May 2013 - Annual Review, Policy Revised
  • August 2012 - Annual Review, Policy Renewed
  • August 2011 - Annual Review, Policy Renewed

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.


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