Medical Policy: 02.04.55
Original Effective Date: June 2016
Reviewed: May 2021
Revised: May 2021
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 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 addresses Epidermal Growth Factor Receptor (EGFR) mutation analysis for all indications except non-small cell lung cancer (NSCLC). EGFR mutation analysis for non-small cell lung cancer (NSCLC) see medical policies: 02.04.78 Molecular Analysis for Targeted Therapy of Non-Small Cell Lung Cancer and 02.04.79 Circulating Tumor DNA for Management of Non-Small Cell Lung Cancer (Liquid Biopsy).
Epidermal Growth Factor Receptor (EGFR) (also called HER1 gene or ERBB1 gene) is a gene that makes a protein that is involved in cell growth and cell survival. EGFR activating mutations are found in exons 18 to 21 of the EGFR gene, which is part of the gene coding for the tyrosine kinase domain of the EGFR protein. 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) (see medical policies referenced above). Because of its critical role in tumor aggressiveness, EGFR has been an attractive target for anticancer therapy in cancers other than non-small cell lung cancer (NSCLC).
The functional activation of EGFR via mutation or amplification/overexpression has been identified in many tumor types, including but not limited to head and neck, gastroesophageal, breast, genitourinary, cutaneous and colorectal cancers, and has been associated with proliferation, invasion, and metastasis. Alterations in EGFR have also been linked to primary resistance and accelerated tumor growth (designated as hyperprogression) from immune checkpoint inhibitors. However, EGFR amplification and overexpression in tissue have not been well established as reliable biomarkers for anti-EGFR agents for anything other than non-small cell lung cancer (NSCLC). The potential reasons include heterogeneity between primary and metastatic lesions, dynamic changes in genomic alterations that may emerge along with therapeutic pressure or progression, presence of genomic coalterations associated with resistance, and potential differences in response to copy number gain due to aneuploidy versus focal EGFR amplification.
There are two main sample types used for EGFR mutation analysis either tumor tissue using Real Time PCR, Sanger Sequencing or Next Generation Sequencing (NGS) or circulating tumor DNA.
Based on review of the peer reviewed medical literature prior studies looking at the relationship between EGFR amplification and therapeutic response to EGFR inhibitors have shown inconsistent results for patients with a wide range of malignancies. While EGFR amplification/overexpression is associated with cancer aggressiveness, previous studies failed to demonstrate tissue-based assessment of EGFR overexpression to be a reliable biomarker to predict clinical outcomes after anti-EGFR therapies except in non-small cell lung cancer (NSCLC). Current NCCN guidelines for solid tumors do not recommend EGFR mutation analysis except for certain clinical situations for non-small cell lung cancer (NSCLC).
To date, there are various anti-EGFR therapies that are U.S. Food and Drug Administration (FDA) approved, including erlotinib, gefitinib, afatinib, and osimertinib for non–small-cell lung cancer (NSCLC) with specific activating EGFR mutations, and cetuximab and panitumumab for colorectal cancer without KRAS or NRAS mutations.
Because of its critical role in tumor aggressiveness, EGFR has been an attractive target for anticancer therapy in cancers other than non-small cell lung cancer (NSCLC) such as head and neck, gastroesophageal, breast, genitourinary, cutaneous and colorectal cancers. Studies have failed to demonstrate that tissue-based or circulating tumor DNA assessment of EGFR overexpression to be a reliable biomarker to predict clinical outcomes after anti-EGFR therapies except in non-small cell lung cancer (NSCLC). Current NCCN guidelines do not recommend EGFR mutation analysis except for certain clinical situations for non-small cell lung cancer (NSCLC). The evidence is insufficient to determine the effects of the technology on net health outcomes in cancer management except for non-small cell lung cancer (NSCLC), whether performed as an individual test or as part of an expanded panel test.
Does not include any information regarding testing for EGFR int eh management of acute lymphoblastic leukemia
Does not include any information regarding testing for EGFR in the management of acute myeloid leukemia
Does not include any guidelines related to testing for EGFR in the management of anal carcinoma
Does not include any information regarding testing for EGFR in the management of basal cell skin cancer
Does not include any information regarding testing for EGFR in the management of B-cell lymphomas
Does not include any information regarding testing for EGFR in the management of bladder cancer
Does not include any information regarding testing for EGFR in the management of bone cancer
Does not include any information regarding testing for EGFR in the management of breast cancer
Systemic treatment options for patients with brain metastases from NSCLC include immunotherapy agents and targeted therapies for cancer that is anaplastic lymphoma kinase (ALK) rearrangement-positive and EGFR mutation – positive
In patients with systemic cancers with options for CNS-active systemic therapies (e.g. ALK or EGFR mutations in NSCLC; BRAF mutations in metastatic melanoma), upfront systemic therapy alone may be considered in carefully selected, asymptomatic patients
Does not include any information regarding testing for EGFR in the management except when related to brain metastases from NSCLC.
Does not include any information regarding testing for EGFR in the management of cervical cancer.
Does not include any information regarding testing for EGFR in the management of chronic lymphocytic leukemia/small lymphocytic lymphoma
Does not include any information regarding testing for EGFR in the management of chronic myeloid leukemia
Does not include any information regarding testing for EGFR in the management of colon cancer
Does not include any information regarding testing for EGFR in the management of dermatofibrosarcoma protuberans
Does not include any information regarding testing for EGFR in the management of esophageal and esophagogastric junction cancers
Does not include any information regarding testing for EGFR in the management of gastric cancer
Does not include any information regarding testing for EGFR in the management of gastrointestinal stromal tumors (GISTs)
Does not include any information regarding testing for EGFR in the management of gestational trophoblastic neoplasia
Does not include any information regarding testing for EGFR in the management of hairy cell leukemia
Does not include any information regarding testing for EGFR in the management of head and neck cancers
Does not include any information regarding testing for EGFR in the management of hepatobiliary cancers
Does not include any information regarding testing for EGFR in the management of histiocytic neoplasms
Does not include any information regarding testing for EGFR in the management of Hodgkin lymphoma
Does not include any information regarding testing for EGFR in the management of Kaposi Sarcoma
Does not include any information regarding testing for EGFR in the management of kidney cancer
Does not include any information regarding testing for EGFR in the management of malignant pleural mesothelioma
Does not include any information regarding testing for EGFR in the management of cutaneous melanoma
Does not include any information regarding testing for EGFR in the management of uveal melanoma
Does not include any information regarding testing for EGFR in the management of merkel cell carcinoma
Does not include any information regarding testing for EGFR in the management of multiple myeloma
Does not include any information regarding testing for EGFR in the management of myelodysplastic syndromes
Does not include any information regarding testing for EGFR in the management of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes
Does not include any information regarding testing for EGFR in the management of myeloproliferative neoplasms
Does not include any information regarding testing for EGFR in the management of neuroendocrine and adrenal tumors
Does not include any information regarding testing for EGFR in the management of occult primary
Does not include any information regarding testing for EGFR in the management of ovarian cancer including fallopian tube cancer and primary peritoneal cancer
Does not include any information regarding testing for EGFR in the management of pancreatic adenocarcinoma
Does not include any information regarding testing for EGFR in the management of pediatric acute lymphoblastic leukemia
Does not include any information regarding testing for EGFR in the management of pediatric aggressive mature B-cell lymphomas
Does not include any information regarding testing for EGFR in the management of pediatric Hodgkin lymphoma
Does not include any information regarding testing for EGFR in the management of penile cancer
Does not include any information regarding testing for EGFR in the management of primary cutaneous lymphomas
Does not include any information regarding testing for EGFR in the management of prostate cancer
Does not include any information regarding testing for EGFR in the management of rectal cancer
Does not include any information regarding testing for EGFR in the management of small bowel adenocarcinoma
Does not include any information regarding testing for EGFR in the management of small cell lung cancer
Does not include any information regarding testing for EGFR in the management of small tissue sarcoma
Does not include any information regarding testing for EGFR in the management of squamous cell skin cancer
Does not include any information regarding testing for EGFR in the management of systemic light chain amyloidosis
Does not include any information regarding testing for EGFR in the management of systemic mastocytosis
Does not include any information regarding testing for EGFR in the management of T-cell lymphomas
Does not include any information regarding testing for EGFR in the management of testicular cancer
Does not include any information regarding testing for EGFR in the management of thymomas and thymic carcinomas
Does not include any information regarding testing for EGFR in the management of thyroidcCarcinoma
Does not include any information regarding testing for EGFR in the management of uterine neoplasms
Does not include any information regarding testing for EGFR in the management of vulvar cancer
Does not include any information regarding testing for EGFR in the management of Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Version
Does not include any information regarding testing for EGFR in the management of Wilms tumor
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA).
Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) (liquid biopsy) for cancer management is available under the auspices of Clinical Laboratory Improvement Amendments. Laboratories that offer LDTs must be licensed by CLIA for high complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
EGFR mutation analysis using Real Time PCR, Sanger Sequencing or Next Generation Sequencing (NGS) are commercially available and these tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA).
Not applicable
See Related Medical Policies:
Epidermal Growth Factor Receptor (EGFR) mutation analysis is considered investigational for all indications except for non-small cell lung cancer (NSCLC) whether performed as an individual test or as part of an expanded panel test.
Note: For Epidermal Growth Factor Receptor (EGFR) mutation analysis related to non-small cell lung cancer (NSCLC) see the above related medical policies.
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.
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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