Medical Policy: 02.04.55 

Original Effective Date: June 2016 

Reviewed: May 2017 

Revised: May 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.



EGFR is a growth factor receptor that is activated by the binding of specific ligands, resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately leading to cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression for many solid tumors. Targeted therapies directed to tumors harboring activating mutations within the EGFR tyrosine kinase domain (exons 18-21) have demonstrated some success in treating a subset of patients with non-small-cell lung cancer (NSCLC) by preventing ATP-binding at the active site. Gefitinib and erlotinib have been approved by the FDA for use in treating patients with NSCLC who previously failed to respond to the traditional platinum-based doublet chemotherapy. These 2 drugs have also recently been shown to increase progression-free and overall survival in patients who receive EGFR-tyrosine kinase inhibitor therapy as a first-line therapy for the treatment of NSCLC.


Agents such as gefitinib and erlotinib, which prevent ATP binding to EGFR kinase, do not appear to have any meaningful inhibitor activity on tumors that demonstrate the presence of the specific drug-resistant EGFR mutation T790M. Therefore, current data suggest that the efficacy of EGFR-targeted therapies in NSCLC is confined to patients with tumors demonstrating the presence of EGFR- activating mutations such as L858R, L861Q, G719A/S/C, S768I or small deletions within exon 19 and the absence of the drug-resistant mutation T790M. As a result, the mutation status of EGFR can be a useful marker by which patients are selected for EGFR-targeted therapy.


Gene Amplification

Another issue related to EGFR and NSCLC is gene amplification, which is defined as the presence of an increased number of copies of a specific gene fragment in a chromosome.  This is measured using a laboratory method referred to as in-situ hybridization.  Gene amplification may lead to production of increased numbers of a gene copies, a process referred to as elevated gene expression.  Gene expression is measured by immunohistochemical testing. 


It has been proposed that the measurement of EGFR amplification in NSCLC tumor tissue can be used for the prediction of response to TKI drug therapy.  The evidence regarding this question is currently mixed. 


The use of EGFR amplification testing for conditions other than NCSLC has been limited.  There have been several small studies that have investigated the use of EGFR amplification status in subjects with glioblastoma, head and neck squamous cell cancer (HNSCC), colon and gastric cancers.  Several of these studies have shown some benefit from EGFR amplification testing.  However, at this time the clinical utility of such testing has not been established.


Both EGFR mutation analysis (PCR amplification and gene sequencing) and EGFR gene amplification (fluorescence in-situ hybridization or FISH) are commercially available (Genzyme Genetics Westborough, MA).  These tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA).  Pre-market approval from the FDA is not required when the assay is performed in a laboratory that observes the CLIA regulations.


Proteomic Testing

Proteomic testing has been proposed as a way to predict survival outcomes and the response to and selection of targeted therapy for patients with non-small-cell lung cancer (NSCLC). One commercially available test, the VeriStrat® assay, has been investigated as a predictive marker for response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).


NCCN Guidelines

The NCCN guideline for the treatment of NSCLC (Version 2.2017) includes a category 1 recommendation for EGFR testing for the following NSCLC (non-squamous cell lung cancer) histologies, adenocarcinoma, large cell, and NSCLC NOS (not otherwise specified).  The NCCN concluded that EGFR mutation testing is not routinely recommended for squamous cell carcinoma of the lung.


In 2013, the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP) issued a joint recommendation for the molecular testing for selection of individuals with lung cancer for EGFR and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors.  This document included recommendations supporting the use of EGFR molecular testing for receiving TKI therapy for NSCLC.


For additional testing, please see policy 02.04.63 Expanded Genetic Panels to Identify Targeted Cancer Therapy.


Prior Approval:


Not applicable



Analysis of mutations in the gene (only at exons 19 and 21) for the epidermal growth factor receptor (EGFR) is considered medically necessary as a technique to predict treatment response for individuals with non-small cell, non-squamous cell lung cancer undergoing treatment with EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva®], gefitinib [Iressa®], or afatinib [Gilotrif®]).


The use of proteomic testing, including but not limited to the VeriStrat assay, is considered medically necessary in the management of non-small-cell lung cancer only:

  • When EGFR status is wild-type (no mutation detected).  There would be an expectation that EGFR status is completed and known prior to the use of proteomic testing if possible .
  • Individual has failed first-line systemic chemotherapy
  • Erlotinib (Tarceva®) therapy is planned
  • Test results will be used to decide whether to proceed with erlotinib (Tarceva®) therapy


Analysis of mutations in the gene for epidermal growth factor receptor (EGFR) is considered investigational for all other indications, including squamous cell-type and colon cancer.


Analysis of gene amplification for epidermal growth factor receptor (EGFR) is considered investigational, including as a technique to predict treatment response to tyrosine kinase inhibitor therapy (for example, erlotinib [Tarceva®], gefitinib [Iressa®], or afatinib [Gilotrif®]) in individuals with non-small cell lung cancer (NSCLC).


Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81235 EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)
  • 81401 Molecular pathology procedure, Level 2
  • 81538 Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival (i.e. VeriStrat).
  • 88365 In situ hybridization (eg, FISH), per specimen; initial single probe stain procedure


Selected References:

  • Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol. 2009; 27(36):6251-6266.
  • Blue Cross Blue Shield Association. Epidermal growth factor receptor mutations and tyrosine kinase inhibitor therapy in advanced non-small-cell lung cancer. TEC Assessment, 2007; 22(6).
  • Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy J Clin Oncol. 2011; 29(15):2121-2127.
  • Lindeman NI, Cagle PT, Beasley MB, et al. 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, and Association for Molecular Pathology. J Mol Diagn. 2013; 15(4):415-453
  • National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. v4.2015. Updated January 30, 2015.
  • National Cancer Institute. Non-Small Cell Cancer Treatment (PDQ®)
  • van Zandwijk N, Mathy A, Boerrigter L, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007; 18(1):99-103.
  • da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010; 116(24):5599-5607.
  • Douillard JY, Pirker R, O'Byrne KJ, et al. Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer. J Thorac Oncol. 2014; 9(5):717-724.
  • Rosell R, Moran T, Queralt C, et al.; Spanish Lung Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009; 361(10):958-967.
  • National Comprehensive Cancer Network. (2016). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-Small Cell Lung Cancer. Version 2.2017.
  • Lindeman NI, Cagle PT, Beasley MB, et al. 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, and Association for Molecular Pathology. Arch Pathol Lab Med 2013; 137:828.


Policy History:

  • May 2017 - Annual Review, Policy Revised
  • June 2016 - New Policy, Policy Implemented

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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