Medical Policy: 02.04.55 

Original Effective Date: June 2016 

Reviewed: May 2020 

Revised: September 2019 



This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.


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.



This policy does not address the condition of Non-small cell lung cancer. See policy section for related policy information.


EGFR—also called HER1—is one type of cell surface receptor. It is a transmembrane receptor. It expands from the outside of the cell through the membrane to the inside of the cell. It is turned on by a molecule outside of the cell called epidermal growth factor. Once turned on, EGFR stimulates the cell to divide. In many cancers, too many signals for the cell to divide are sent by EGFRs causing the cancer to grow uncontrollably. EGFR inhibitors help stop the cancer from growing. EGFR 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.


Recent research has focused on the development of EGFR-specific treatments.

  • Cetuximab (Erbitux®) attaches to the end of EGFR that is outside the cell to block epidermal growth factor. It is used for colon, rectal, head & neck cancers, non-small lung cancers, and non-melanoma skin cancers.
  • Panitumumab (Vectibix®) also attaches to end of EGFR that is outside the cell to block epidermal growth factor. It is used for colon, penile, and rectal cancers. 


Gene Amplification

Another issue related to EGFR 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.


The use of EGFR amplification testing for conditions outside of lung cancer 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.


Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN Guidelines

As use of NGS testing increases, additional EGFR variants are increasingly identified: however the clinical implications of individual alterations are unlikely to be well established in patients with squamous cell carcinoma, the frequency of EGFR mutations does not justify routine testing of all tumor specimens.


In patients with squamous cell skin cancer, the frequency of EGFR mutations does not justify routine testing of all tumor specimens. Per NCCN (Version 1.2020) squamous cell skin cancer (cSCC) In the absence of prospective comparative trial data, it is unclear whether the EGFR inhibitors being studied in combination with radiation therapy improve any disease-related outcome in patients.


Per NCCN (Version 1.2020) Colon Cancer EGFR testing of colorectal tumor cells has no proven predictive value in determining likelihood of response to either cetuximab or panitumimab. Routine EGFR testing is not recommended, and no patient should be considered for or excluded from therapy based on EGFR test results.


There are no additional NCCN guidelines that recommend testing of EGFR mutations (outside of NSCLC)


Prior Approval:

Not applicable



See related policies:

  • 02.04.63 Expanded Genetic Panels to Identify Targeted Cancer Therapy
  • 02.04.16 Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsies)
  • 02.04.79 Circulating Tumor DNA for Management of Non-Small Cell Lung Cancer (Liquid Biopsy)
  • 02.04.77 Proteomic Testing for Systematic Therapy in Non-Small Cell Lung Cancer
  • 02.04.78 Molecular Analysis for Targeted Therapy of Non-Small Cell Lung Cancer


Analysis of mutations in the gene for epidermal growth factor receptor (EGFR) is considered investigational for all indications outside of NSCLC, specifically for squamous cell skin cancer, penile cancer, kidney cancer, and colon cancer.


The following analyses/tests are considered investigational:

  • Testing for EGFR or variants
  • Expanded panel testing to determine EGFR status outside of 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)
  • 81479 Unlisted molecular pathology procedure


Selected References:

  • 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 4.2019.
  • Leighl, Natasha B. et al. “Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline.” Journal of Clinical Oncology 32.32 (2014): 3673–3679.
  • American Society of Clinical Oncology (ASCO). Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. 2017. doi/pdf/10.1200/JCO.2016.71.9807
  • National Comprehensive Cancer Network. (2020). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Squamous Cell Skin Cancer. Version 1.2020.
  • National Comprehensive Cancer Network. (2020). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Colon Cancer Version 1.2020.
  • National Comprehensive Cancer Network. (2020). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Kidney Cancer Version 2.2020.


Policy History:

  • May 2020 - Annual Review, Policy Renewed
  • September 2019 - Interim Review, Policy Revised
  • May 2019 - Annual Review, Policy Revised
  • May 2018 - Annual Review, Policy Revised
  • 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.


*CPT® is a registered trademark of the American Medical Association.