Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)

POLICY NUMBER

A.2.04.53

DESCRIPTION

The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC). EGFR-targeted therapy combined with monoclonal antibodies cetuximab and panitumumab has shown a clear survival benefit in patients with metastatic CRC. However, this benefit depends on a lack of variants in certain genes in the signaling pathway downstream from the EGFR. It has been hypothesized that knowledge of tumor cell KRAS, NRAS, and BRAF variant status might be used to predict nonresponse to anti-EGFR monoclonal antibody therapy. NTRK gene fusions, which are rare kinase fusion events, are a potential therapeutic target for CRC patients who may benefit from tropomysosin receptor kinase (TRK) inhibitor therapy. More recently, human epidermal growth factor receptor 2 (HER2) testing to select patients for targeted therapy has been proposed. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA or circulating tumor cell testing (also known as a liquid biopsy) is proposed as a non-invasive alternative.

KRAS, NRAS, and BRAF Variants

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. The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. The RAS proteins are G-proteins that cycle between active (RAS guanosine triphosphate) and inactive (RAS guanosine disphosphate) forms in response to stimulation from a cell surface receptor, such as EGFR, and they act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic variants that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. Approximately 40% of colorectal cancers (CRCs) have KRAS variants in codons 12 and 13 in exon 2. Another proto-oncogene that acts downstream from KRAS–NRAS harbors oncogenic variants in codons 12, 13, or 61 that result in constitutive activation of the EGFR-mediated pathway. These variants are less common compared with KRAS, detected in 2% to 7% of CRC specimens. It is unclear whether NRAS variants predict poor response to anti-EGFR monoclonal antibody therapy, or are a prognostic of poor CRC outcomes in general. A third proto-oncogene, BRAF, encodes a protein kinase and is involved in intracellular signaling and cell growth; BRAF is also a principal downstream effector of KRAS. BRAF variants occur in fewer than 10% to 15% of CRCs and appear to be a marker of poor prognosis. KRAS and BRAF variants are considered to be mutually exclusive.

Cetuximab and panitumumab have marketing approval from the U.S. Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer in the refractory disease setting. The FDA approval for panitumumab indicates that panitumumab is not indicated for the treatment of patients with KRAS or NRAS variant-positive disease in combination with oxaliplatin-based chemotherapy.

A large body of literature has shown that metastatic CRC tumors with a variant in exon 2 (codon 12 or 13) of the KRAS gene do not respond to cetuximab or panitumumab therapy. More recent evidence has shown that variants in KRAS outside exon 2 (ie, in exons 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) and variants in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) also predict a lack of response to these monoclonal antibodies. Variant testing of these exons outside the KRAS exon 2 is referred to as extended RAS testing.

Human Epidermal Growth Factor Receptor 2 Amplification/Overexpression

Human epidermal growth factor receptor 2 (HER2) is a member of the HER (EGFR) family of tyrosine kinase receptors and has no specific ligand. When activated, it forms dimers with other EGFR family members. Amplification of HER2 is detected in approximately 3% of patients with CRC, with higher prevalence in RAS/BRAF-wild type tumors (5% to 14%). In addition to its role as a predictive marker for HER2-targeted therapy, HER2 amplification/overexpression is being investigated as a predictor of resistance to EGFR-targeting monoclonal antibodies.

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing

The presence of NTRK gene fusion can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry. Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify NTRK gene fusions as well as other actionable alterations, with minimal tissue needed. The fluorescence in situ hybridization using break-apart probes can detect gene rearrangements in DNA that may generate a fusion transcript. The immunohistochemistry techniques have generally been used in the research setting. Reverse transcription-polymerase chain reaction is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners.

Detecting Circulating Tumor DNA and Circulating Tumor Cells (Liquid Biopsy)

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or circulating tumor cells. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor.

Typically, the evaluation of RAS mutation status requires tissue biopsy. Circulating tumor DNA (ctDNA) testing is proposed as a non-invasive alternative.

Detection of ctDNA is challenging because ctDNA is diluted by nonmalignant circulating DNA and usually represents a small fraction (<1%) of total ctDNA. Therefore, more sensitive methods than the standard sequencing approaches (eg, Sanger sequencing) are needed.

Highly sensitive and specific methods have been developed to detect ctDNA, for both single nucleotide variants (eg BEAMing [which combines emulsion polymerase chain reaction with magnetic beads and flow cytometry] and digital polymerase chain reaction) and copy-number variants. Digital genomic technologies allow for enumeration of rare variants in complex mixtures of DNA.

Approaches to detecting ctDNA can be considered targeted, which includes the analysis of known genetic mutations from the primary tumor in a small set of frequently occurring driver mutations, or untargeted without knowledge of specific variants present in the primary tumor, which includes array comparative genomic hybridization, next-generation sequencing, and whole exome and genome sequencing. Targeted testing may impact therapy selection.

Circulating tumor cell assays usually start with an enrichment step that increases the concentration of circulating tumor cells, either by biologic properties (expression of protein markers) or physical properties (size, density, electric charge). Circulating tumor cells can then be detected using immunologic, molecular, or functional assays.

A number of liquid biopsy tests related to targeted treatment of metastatic colorectal cancer have been developed (Table 1).

Table 1. Examples of Liquid Biopsy Tests Related to Targeted Treatment of Metastatic Colorectal Cancer

CTC: circulating tumor cell; ctDNA: circulating tumor DNA

Table 2 summarizes the targeted treatments approved by the U.S. Food and Drug Administration (FDA) for patients with CRC, along with the approved companion diagnostic tests. The information in Table 2 was current as of May 24, 2024; The FDA maintains a list of cleared or approved companion diagnostic devices that is updated regularly.

In June 2022, the FDA granted accelerated approval to dabrafenib (Tafinlar®, Novartis) in combination with trametinib (Mekinist®, Novartis) for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutations who have progressed following prior treatment and have no satisfactory alternative treatment options. However, dabrafenib in combination with trametinib is not indicated for patients with CRC because of known intrinsic resistance to BRAF inhibition. Therefore, BRAF V600E variant testing to select individuals for treatment with dabrafenib in combination with trametinib is not included in this policy and is not listed in Table 2.

Table 2. Targeted Treatments for Metastatic Colorectal Cancer and FDA Approved Companion Diagnostic Tests

CRC: colorectal cancer; EGFR: epidermal growth factor receptor; FOLFIRI: leucovorin, fluorouracil and irinotecan; FOLFOX: leucovorin, fluorouracil, and oxaliplatin; HER2: human epidermal growth factor receptor 2; mCRC: metastatic CRC; NCCN: National Comprehensive Cancer Network

Laboratory-Developed Tests

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

KRAS, NRAS, BRAF, NTRK, or HER2 testing of tumor tissue may be considered medically necessary for individuals with metastatic colorectal cancer to select individuals for treatment with FDA-approved therapies.

All other uses of KRAS, NRAS, BRAF, NTRK, or HER2 testing of tumor tissue to guide colorectal cancer targeted therapy are considered investigational.

Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered investigational. (See Policy Guidelines)

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

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

The NCCN colon cancer guidelines v. 3.2024 and rectal cancer guidelines v. 3.2024 do not recommend testing for specific genes over a next generation sequencing panel. The guidelines additionally state that testing may be performed using either tissue or blood-based biopsy, with testing on tissue being preferred.

For expanded panel testing, see the Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies medical policy.

Testing for individual genes (not gene panels) associated with FDA-approved therapeutics for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive policy review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

For somatic biomarker testing related to use of immune checkpoint inhibitor therapy (BRAF, microsatellite instability/mismatch repair [MSI/MMR], PD-L1, tumor mutational burden [TMB]), see the Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB) medical policy.

Note that TMB is often included in panel tests, and might not have separate coding.

For guidance on testing criteria between policy updates, refer to the FDA's List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) ( https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools ) for an updated list of FDA-approved tumor markers and consult the most current version of NCCN management algorithms.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

10/9/2008: Policy added.

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, 81403, and 81275 to the Code Reference section.

04/08/2014: Policy description updated. Kras policy statement updated with the following minor wording changes: “to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer” was changed to “for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab.” Removed deleted HCPCS code S3713 from the Covered Codes table in the Code Reference section.

12/31/2014: Code Reference section updated to revise the description of the following CPT code: 81403.

08/31/2015: Policy title changed from "KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer" to "KRAS, NRAS, and BRAF Mutation Analysis in Metastatic Colorectal Cancer." Policy description updated to include information regarding NRAS. Added the following policy statement: NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Added CPT code 81404 to the Investigational Codes table.

12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions. Code Reference section updated to revise code descriptions for CPT codes 81275 and 81210 with an effective date of 01/01/2016. Added new 2016 CPT code 81311 to the investigational codes table.

01/26/2016: Code Reference section updated to add new 2016 CPT code 81276.

06/06/2016: Policy number A.2.04.53 added.

12/31/2016: Policy description updated regarding EGFR-targeted therapy and laboratory-developed tests. Policy statement regarding NRAS mutation analysis changed from investigational to medically necessary for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab. It previously stated: NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Code Reference section updated to move CPT code 81311 from the investigational codes table to the covered codes table with an effective date of 01/01/2017. Code Reference section updated to add new 2017 HCPCS codes G9840 and G9843.

02/10/2017: Code Reference section updated to remove HCPCS codes G9840 and G9843.

06/27/2017: Code Reference section updated to revise code descriptions for CPT codes 81403 and 81404, effective 07/01/2017.

12/22/2017: Code Reference section updated to revise descriptions for CPT codes 81403 and 81404 effective 01/01/2018.

02/22/2018: Policy title updated to change "Mutation" to "Variant." Policy description updated regarding companion diagnostic tests. Policy statement updated to state that BRAF variant analysis is considered medically necessary for patients with metastatic colorectal cancer who are found to be wild-type on KRAS and NRAS variant analysis to guide management decisions. It previously stated: BRAF mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Policy Guidelines updated regarding BRAF V600 testing and genetics nomenclature. Code Reference section updated to move CPT code 81210 from investigational to covered. Removed investigational codes table and CPT codes 81403 and 81404.

08/07/2018: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding genetics nomenclature.

09/16/2019: Code Reference section updated to add new CPT code 0111U, effective 10/01/2019.

01/05/2021: Policy title changed from "KRAS, NRAS, and BRAF Variant Analysis in Metastatic Colorectal Cancer" to "KRAS, NRAS, and BRAF Variant Analysis (Including Liquid Biopsy) in Metastatic Colorectal Cancer." Policy description updated regarding detecting ctDNA and circulating tumor cells. Added examples of liquid biopsy and companion diagnostic tests. Added policy statement that KRAS, NRAF, and BRAF variant analysis using circulating tumor DNA or circulating tumor cell testing (liquid biopsy) to guide treatment for patients with metastatic colorectal cancer is considered investigational. Policy Guidelines updated to remove genetics nomenclature information. Code Reference section updated to add CPT codes 0091U, 86152, and 86153 as investigational.

06/13/2022: Policy title changed from "KRAS, NRAS, and BRAF Variant Analysis (Including Liquid Biopsy) in Metastatic Colorectal Cancer" to "Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer." Policy description updated regarding human epidermal growth factor receptor 2, mismatch repair deficiency/microsatellite instability, tumor mutational burden, circulating tumor DNA and cells, and tests. Added medically necessary statement for mismatch repair/microsatellite instability and investigational statements for human epidermal growth factor receptor 2 testing and tumor mutational burden testing. Code Reference section updated to add 81301 and 88363 as covered.

01/17/2023: Policy title changed from "Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer" to "Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, MMR/MSI, HER2, and TMB)." Policy description updated regarding targeted treatments. Medically necessary policy statements for KRAS, NRAS, BRAF, and mismatch repair/microsatellite instability testing updated to include selecting individuals for treatment with FDA-approved therapies. Added investigational policy statements regarding all other uses of KRAS, NRAS, BRAF, and mismatch repair/microsatellite instability variant testing. Policy Guidelines updated to add related policy links and to add information regarding testing.

04/01/2024: Policy title changed from "Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, MMR/MSI, HER2, and TMB)" to "Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)." Policy description and policy statements updated to remove information regarding testing for microsatellite instability/mismatch repair and tumor mutational burden status to select patients for immunotherapy. Updated targeted treatments for metastatic colorectal cancer and FDA approved companion diagnostic tests. Policy section updated to combine policy statements for KRAS, NRAS, and BRAF testing. Testing for HER2 in individuals with metastatic colorectal cancer to select individuals for targeted treatment changed from investigational to medically necessary. Policy Guidelines updated regarding NCCN guidelines for colon and rectal cancer. Code Reference section updated to remove CPT code 81301.

07/01/2024: Code Reference section updated to add new CPT code 0471U as investigational.

10/01/2024: Code Reference section updated to add new CPT code 0498U.

01/15/2025: Policy description updated regarding NTRK gene fusion testing and targeted treatments for metastatic colorectal cancer. Policy section updated to add NTRK testing as medically necessary for individuals with metastatic colorectal cancer to select individuals for treatment with FDA-approved therapies. Policy Guidelines updated. Code Reference section updated to add CPT codes 81191, 81192, 81193, and 81194 to the Covered Codes table.

SOURCE(S)

Blue Cross & Blue Shield Association Policy # 2.04.53

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

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

Covered Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.