Medical Policy

Policy Num:      11.003.004
Policy Name:    Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, NTRK, RET and HER2)
Policy ID:          [11.003.004]  [Ac / B / M+ / P+]  [2.04.53]

Last Review:     August 18, 2025
Next Review:    August 20, 2026
 

Related Policies:

11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
11.003.026 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
11.003.089 - Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
11.003.015 - Gene Expression Profile Testing and Circulating Tumor DNA Testing for Predicting Recurrence in Colon Cancer
05.001.034 - Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion

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

SUMMARY

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, 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. RET gene fusions, which are also rare, are a potential therapeutic target for CRC patients who may benefit from tyrosine kinase 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.

Summary of Evidence

For individuals with metastatic colorectal cancer (CRC) who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for KRAS, NRAS, BRAF, NTRK, or RET variants using tissue biopsy specimens to guide treatment, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for HER2 overexpression using tissue biopsy specimens, the evidence identified includes 2 systematic reviews/meta-analyses and 4 randomized clinical trials (RCTs) as well as the pivotal studies leading to FDA-approved medications and NCCN recommendations. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Results from the meta-analysis by Bekaii-Saab et al (2023) showed there was a 2.84 (95% CI, 1.44 to 5.60) times higher risk of death or progression in patients with HER2-positive RAS WT metastatic CRC (mCRC) treated with anti-EGFR regimens compared with those who were HER2 negative. Furthermore, data from 8 clinical studies of mCRC patients with HER2 amplification confirmed by immunohistochemical staining and fluorescence in situ hybridization and treated with HER2-targeted inhibitors was pooled and demonstrated an objective response rate (ORR) of 29 percent. Overall, the 4 RCTs demonstrated that higher levels of HER2 amplification were associated with greater degree of clinical benefit from anti-HER2 therapy and had clinically meaningful anti-tumor activity with a favorable tolerability profile. No tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with FDA-approved targeted therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for KRAS and NRAS variants using circulating tumor DNA (ctDNA; liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for BRAF variants using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for NTRK gene fusion using ctDNA (liquid biopsy) to guide targeted treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for RET rearrangements using ctDNA (liquid biopsy), no evidence was identified. No plasma tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with RAS inhibitors. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. and no studies were identified.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for HER2 overexpression using ctDNA (liquid biopsy), no evidence was identified. No plasma tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with kinase inhibitors or anti-HER2 monoclonal antibodies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. and no studies were identified.

Additional Information

Not applicable.

Objective

The objective of this review is to summarize the evidence and guidelines on using biomarker testing to select treatment with U.S. Food and Drug Administration (FDA)-approved targeted therapy for individuals with metastatic colorectal cancer (CRC).

Policy statements

KRAS, NRAS, BRAF, NTRK, or RET testing of tumor tissue biopsy specimens may be considered medically necessary for individuals with metastatic colorectal cancer (CRC) to select individuals for treatment with U.S. Food and Drug Administration (FDA)-approved therapies.

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

HER2 testing of tumor tissue biopsy specimens may be considered medically necessary for individuals with metastatic CRC to select individuals for treatment with U.S. Food and Drug Administration (FDA)-approved therapies.

All other uses of HER2 testing of tumor tissue to guide CRC targeted therapy are considered investigational.

Analysis of plasma (liquid biopsy) for somatic variants of the KRAS (eg, G12C) and RAS variants using an FDA-approved companion diagnostic plasma test to detect circulating tumor (ctDNA) may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

All other uses of analysis of KRAS and NRAS variants in plasma are considered investigational.

Analysis of plasma (liquid biopsy) for the somatic BRAF V600E variants using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

All other uses of analysis of BRAF V600E variant in plasma are considered investigational.

Analysis of plasma (liquid biopsy) for NTRK gene fusions using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels (see Policy Guidelines).

All other uses of analysis of NTRK fusions in plasma are considered investigational.

Analysis of plasma (liquid biopsy) for somatic RET variants is considered investigational as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC.

Analysis of plasma (liquid biopsy) for somatic HER2 variants is considered investigational as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC.

All other uses of ctDNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered investigational. (see Policy Guidelines)

Policy Guidelines

This policy does not address germline testing for inherited risk of developing cancer.

The National Comprehensive Cancer Network (NCCN) colon cancer guidelines v.3.2025 and rectal cancer guidelines v.2.2025 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 evidence review 11.003.026.

Testing for other variants may become available between policy updates.

Testing for individual genes (not gene panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics for therapies with NCCN) recommendations of 2A or higher are not subject to extensive evidence 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 evidence review 11.003.140.

Note that TMB is often included in panel tests, and might not have separate coding; Plans with coverage for panels might consider local decision for TMB.

FDA approves tests in between policy review cycles. As such, newly approved tests might need to be considered per local Plan discretion. 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.

Note: Extensive evidence review is not included for somatic tests of individual genes (not gene panels) associated with FDA-approved therapies with NCCN recommendations of 2A or higher. The pivotal evidence is included in Table 2 for informational purposes. Additionally, no evidence review is provided for somatic tests of individual genes that do not have associated FDA-approved therapies regardless of NCCN recommendations, as these off-label therapies are deemed investigational per the Blue Cross and Blue Shield Association Medical Policy Program Policies and Procedures.

Concurrent Somatic Liquid-Based and Tissue-Based Genomic Testing

Liquid biopsy testing uses blood samples and assesses cancer DNA and non-cancer DNA in the same blood sample. The goal is to identify options for genome-informed treatment. Some providers will order a liquid biopsy test and a tissue biopsy test at the same time to hasten time to treatment. If the intent of concurrent testing is to follow an individual over time to monitor for resistance variants, then consideration could be given to doing liquid biopsy at diagnosis with the tissue biopsy to make sure that mutations that are going to be followed longitudinally can be detected by the liquid biopsy.

Recommended Testing Strategies

Individuals who meet criteria for genetic testing as outlined in the policy statements above should be tested for the variants specified.

• When tumor tissue is available, use of tissue for testing of any/all variants and biomarkers outlined in this policy is recommended, but is not required in all situations. In certain situations, circulating tumor DNA testing (liquid biopsy) may be an option.

Coding

Please see the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

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 diphosphate) 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 due to anti-EGFR monoclonal antibody therapy or are 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 CRC 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.^1,

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 4% of patients with CRC, with higher prevalence in RAS/BRAF-wild type tumors (5% to 14%). ^2,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. ^3, 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.

RET Gene Fusion Testing

RET (rearranged during transfection) is a proto-oncogene that encodes a receptor tyrosine kinase growth factor. Translocations that result in fusion genes with several partners have been rarely reported, with RET fusions occurring in roughly 0.2% colorectal cancers.^4, Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify RET gene fusions as well as other actionable alterations with minimal tissue needed. ^5,

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 CRC have been developed (Table 1).

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

Table 2 summarizes the targeted treatments approved by the FDA for patients with CRC, along with the approved companion diagnostic tests. The information in Table 2 was current as of May 24, 2025 ; FDA maintains a list of cleared or approved companion diagnostic devices that is updated regularly.^6,

In June 2022, FDA granted accelerated approval to 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.^7, Therefore, BRAF V600E variant testing to select individuals for treatment with dabrafenib in combination with trametinib is not included in this evidence review and is not listed in Table 2.

Table 2. Targeted Treatments for Metastatic Colorectal Cancer and U.S. Food and Drug Administration-Approved Companion Diagnostic Tests

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 (CLIA). Laboratories that offer laboratory-developed tests must be licensed under CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

Rationale

This evidence review was created in October 2008 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 23, 2025.

Testing for individual genes (not gene panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics (ie, as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. The pivotal evidence is included in Table 1 for informational purposes. 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.

Population Reference No. 1

KRAS, NRAS, BRAF, NTRK, and RET Variant Testing with Tissue Biopsy Specimens to Guide Treatment for Metastatic Colorectal Cancer

For individuals with metastatic colorectal cancer (mCRC) who receive KRAS, NRAS, BRAF, NTRK, or RET gene variant testing to select treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with metastatic colorectal cancer (CRC) who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for KRAS, NRAS, BRAF, NTRK, or RET variants using tissue biopsy specimens to guide treatment, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Summary

KRAS, NRAS, BRAF, NTRK, or RET testing of tumor tissue biopsy specimens may be considered medically necessary for individuals with metastatic colorectal cancer (CRC) to select individuals for treatment with U.S. Food and Drug Administration (FDA)-approved therapies.

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

Population Reference No. 2

Human Epidermal Growth Factor Receptor 2 (HER2) Overexpression Testing with Tissue Biopsy to Guide Treatment for Metastatic Colorectal Cancer

Clinical Context and Test Purpose

Colorectal cancer (CRC) treatment selection is informed by tumor type, grade, stage, patient performance status and preference, prior treatments, and the molecular characteristics of the tumor such as the presence of driver mutations. One purpose of biomarker testing of individuals who have advanced cancer is to inform a decision regarding treatment selection (eg, whether to select a targeted treatment or standard treatment).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with mCRC for whom the selection of treatment depends on the molecular characterization of the tumor.

Interventions

The test being considered is tissue biopsy using tumor tissue. Both targeted polymerase chain reaction-based assays and broad next-generation sequencing-based approaches are available.

Comparators

Decisions about treatment in CRC are based on clinical characteristics.

Outcomes

The general outcomes of interest in oncology are overall survival (OS), disease-specific survival, quality of life (QOL), treatment-related mortality and morbidity.

Beneficial outcomes resulting from a true-positive test result are prolonged survival, reduced toxicity, and improved QOL associated with receiving a more effective targeted therapy. Beneficial outcomes from a true negative result are prolonged survival associated with receiving chemotherapy in those without driver mutations.

Harmful outcomes resulting from a false-negative test result include shorter survival from receiving less effective and more cytotoxic chemotherapy in those with driver mutations; possible harmful outcomes resulting from a false-positive test result are a shorter survival from receiving potentially ineffective targeted treatment and delay in initiation of chemotherapy in those without driver mutations.

The overall response rate (ORR) may be used as a surrogate endpoint reasonably likely to predict clinical benefit in individuals with refractory solid tumors. ORR can be measured by the proportion of individuals with best overall confirmed response of complete response) or partial response by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1),^22, or Response Assessment in Neuro-Oncology criteria,^23, as appropriate by a blinded and independent adjudication committee.

There are clearly defined quantitative thresholds for the follow-up of individuals in oncology trials. A general rule is a continuation of treatment until disease progression or unacceptable toxicity. Long-term follow-up outside of a study setting is conducted to determine survival status. The duration of follow-up for the outcomes of interest is 6 months and 1 year.

The time frame for outcomes measures varies from several months to several years.

Study Selection Criteria

For the evaluation of clinical validity, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);

• Included a suitable reference standard (describe the reference standard);

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Systematic Reviews and Meta-analyses

Bekaii-Saab et al (2023) performed a systematic review and meta-analysis on the prognostic or predictive effect of HER2 amplification/overexpression on anti-epidermal growth factor receptor (EGFR) treatment outcomes.^24, Five high-quality retrospective cohort studies were included in the meta-analysis representing 594 patients with mCRC and all patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Results from the meta-analysis showed there was a 2.84 times higher risk of death or progression (95% CI, 1.44 to 5.60) in patients with HER2-positive RAS WT mCRC treated with anti-EGFR regimens compared with those who were HER2 negative. Based on meta-analysis of 3 studies reporting ORR (n=265) the odds of response to anti-EGFR treatment were almost 2 times higher in patients with mCRC who were HER2 negative compared with HER2-positive patients ([odds ratio [OR], 1.96; 95% CI, 1.10 to 3.48). Based on meta-analysis of 3 studies reporting OS (n=406) the results showed that there was no statistically significant difference in OS between patients with HER2-positive compared with HER2-negative RAS WT mCRC. While these findings do not fully account for any impact of line of therapy or confounding chemotherapy agents, they support the evidence that testing for HER2 overexpression/amplification may help inform treatment decisions and optimize outcomes for mCRC patients. Notable limitations include, but are not limited to, the retrospective study design and heterogeneity in follow-up times, treatment modalities, and doses.

Gao et al (2022) conducted a meta-analysis to systematically evaluate the efficacy and safety of HER2-targeted inhibitors for HER2-amplified mCRC.^25, Eight clinical trials of mCRC patients with HER2 amplification, confirmed by immunohistochemical staining and fluorescence in situ hybridization, treated with HER2-targeted inhibitors with at least one of the following primary outcomes available: ORR, disease control rate (DCR), progression-free survival (PFS), OS, or incidence of serious adverse events [SAEs]) were included in the meta-analysis. The pooled ORR and DCR of the 8 studies were 29% (95% CI, 20 to 40) and 71% (95% CI, 63 to 78), respectively with moderate heterogeneity in the studies using ORR and DCR as endpoints. The pooled median PFS and OS of the 8 studies were 4.89 months (95% CI, 3.82 to 5.97) and 13.04 months (95% CI, 9.45 to 16.62), respectively with high heterogeneity within the studies using PFS as the endpoint and moderate heterogeneity for studies using OS as the main outcome of interest. Furthermore, the results were considered to be unaffected by publication bias as determined by the Egger linear regression test. This meta-analysis revealed that HER2-targeted inhibitors exhibit good antitumor efficacy and safety in second line and above treatment of HER2-amplified mCRC patients. This study had some insurmountable heterogeneity issues; future large-scale, multicenter trials are required to investigate the problem in more depth. Other notable limitations include, but are not limited to, the small number of studies, insufficient sample size, lack of details regarding randomization concealment method and/or result detection method, and studies used different types and doses of therapies.

Randomized Clinical Trials

Four different regimens are recommended by the National Comprehensive Cancer Network (NCCN) panel as options for subsequent treatment of mCRC with HER2 amplifications with FDA-approved therapies: fam-trastuzumab deruxtecan-nxki (T-DXd) monotherapy or trastuzumab in combination with pertuzumab, lapatinib, or tucatinib.^26, Pivotal clinical trials that led to the FDA approval of these therapies and NCCN recommendations include the following RCTs: the phase IIa multiple basket MyPathway trial (trastuzumab + pertuzumab),^27, the multicenter, phase II HERACLES trial (trastuzumab and lapatinib),^28,29, the phase 2, multicenter DESTINY-CRC01 trial (trastuzumab + tucatinib),^30,31, and the clinical studies discussed below. Taken together these RCTs provide sufficient evidence to determine that HER2 testing using tumor tissue biopsies results in an improvement in the net health outcome.

Raghav et al (2025) conducted a randomized phase II trial (N=53) to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody–based therapy as second/third line treatment in HER2-positive mCRC.^32, Patients with RAS/BRAF-WT mCRC after central confirmation of HER2 positivity (IHC 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio >2.0]; HCR) were assigned (1:1) to either trastuzumab plus pertuzumab (TP) or cetuximab plus irinotecan (CETIRI). The primary end point was PFS. Secondary end points included objective response rate (ORR), overall survival, safety, and HER2 gene copy number (GCN ≥20/<20) as a predictive factor. Efficacy of TP versus CETIRI differed significantly by HER2 GCN (median PFS, GCN ≥20 [9.9 v 2.9 months] and GCN <20 [3.0 v 4.2 months], respectively; p=.003). On TP, ORR was 34.6% (57.1% with GCN ≥20 v 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively (p=.004). Overall, higher levels of HER2 amplification were associated with greater degree of clinical benefit from TP compared to CETIRI. Notable limitations include, but are not limited to, small sample size due to low accrual, nonblinded investigator assessments, central HER2 testing with multiple testing methods, and insufficient power for the original design assumptions.

Raghav et al (2024) carried out a multicenter, randomized, 2-stage, 2-arm, phase 2 study (N=122) to assess antitumor activity, safety, and exploratory biomarkers of trastuzumab deruxtecan doses of 5.4 mg/kg and 6.4 mg/kg to evaluate its benefit–risk profile in patients with HER2-positive, RAS wild-type or variant mCRC who had previously received standard chemotherapy.^33, In stage 1, patients were randomly assigned (1:1) to receive 5.4 mg/kg (n=40) or 6.4 mg/kg (n=40) trastuzumab deruxtecan administered intravenously every 21 days and in stage 2, patients were only assigned to the 5.4mg/kg (n=42) treatment group. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned. The confirmed objective response rate was 37.8% (95% CI, 27.3 to 49.2) in the 5.4 mg/kg group and 27.5% (95% CI, 14.6 to 43.9) in the 6.4 mg/kg group. The confirmed disease control rate was 86.6% (95% CI, 77.3 to 93.1) in the 5.4 mg/kg group and 85.0% (95% CI, 70.2 to 94.3) in the 6.4 mg/kg group with a median PFS of 5.8 months (95% CI, 4.6 to 7.0) and 5.5 months (95% CI, 4.2 to 7.0), respectively. Notable limitations include, but are not limited to, the absence of a control group, small sample size for subgroup analysis, centralized HER2 testing with archival tissue, and PFS and OS were premature at time of the primary analysis.

Strickler et al (2023) assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or mCRC in a global, open-label, phase 2 study. ^14, Between Aug 8, 2017, and Sept 22, 2021,117 patients enrolled into 3 cohorts (Cohort A: tucatinib plus trastuzumab [n=45], Cohort B: tucatinib plus trastuzumab [n=41], and Cohort C tucatinib monotherapy [n=31]), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set). As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed ORR per blinded independent central review was 38.1% (95% CI, 27.7 to 49.3; 3 patients had a complete response and 29 had a partial response). Tucatinib plus trastuzumab had clinically meaningful anti-tumor activity and favorable tolerability. Notable limitations include, but are not limited to, the open-label design, absence of power for a formal comparative study, heterogeneity in imaging intervals and frequency due to the study being expanded, and insufficient follow-up time for cohort C.

Gupta et al (2022) evaluated the results from the TAPUR study, a pragmatic phase II basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations, and reported data from 2 cohorts of patients with CRC with either ERBB2 amplifications or ERBB2 or ERBB3 (ERBB2/3) variants treated with pertuzumab plus trastuzumab. ^34, Pertuzumab plus trastuzumab treatment was shown to have antitumor activity in patients with heavily pretreated colorectal cancer with ERBB2 amplification (disease control [DC]: 54%, objective response [OR]: 25%, median PFS: 17.2 weeks [95% CI: 11.1 to 27.4] median OS: 60.0 weeks [95% CI: 32.1 to 102.3]) but did not demonstrate antitumor activity in patients with ERBB2 or ERBB3 variants (DC: 10%, OR: 0%, median PFS: 9.6 weeks [95% CI: 5.1 to 16.0], median OS: 28.8 weeks [95% CI: 7.6 to 146.3]). Notable limitations include, but are not limited to, the absence of a control group, nonblinded investigator assessments, small patient cohorts, local ERBB2 testing with multiple testing methods, and incomplete reporting of RAS mutation status.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: HER2 Overexpression Testing with Tissue Biopsy to Guide Treatment for Metastatic Colorectal Cancer

For individuals with mCRC who are being considered for targeted therapy with FDA-approved therapeutics and undergo somatic testing for HER2 overexpression using tissue biopsy specimens, the evidence identified includes 2 systematic reviews/meta-analyses and 4 randomized clinical trials (RCTs). Relevant outcomes include OS, disease-specific survival, test validity, QOL, and treatment-related morbidity. Results from the meta-analysis by Bekaii-Saab et al (2023) showed there was a 2.84 times higher risk of death or progression (95% CI, 1.44 to 5.60) in patients with HER2-positive RAS WT mCRC treated with anti-EGFR regimens compared with those who were HER2-negative. Furthermore, data from 8 clinical studies of mCRC patients with HER2 amplification, confirmed by immunohistochemical staining and fluorescence in situ hybridization, treated with HER2-targeted inhibitors was pooled and demonstrated an ORR of 29 percent. The 4 RCTs demonstrated that anti-HER2 therapy in mCRC patients with amplified or overexpression of HER2 had ORRs ranging from 28 to 38 percent with favorable tolerability. No tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with FDA-approved therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for HER2 overexpression using tissue biopsy specimens, the evidence identified includes 2 systematic reviews/meta-analyses and 4 randomized clinical trials (RCTs) as well as the pivotal studies leading to FDA-approved medications and NCCN recommendations. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Results from the meta-analysis by Bekaii-Saab et al (2023) showed there was a 2.84 (95% CI, 1.44 to 5.60) times higher risk of death or progression in patients with HER2-positive RAS WT metastatic CRC (mCRC) treated with anti-EGFR regimens compared with those who were HER2 negative. Furthermore, data from 8 clinical studies of mCRC patients with HER2 amplification confirmed by immunohistochemical staining and fluorescence in situ hybridization and treated with HER2-targeted inhibitors was pooled and demonstrated an objective response rate (ORR) of 29 percent. Overall, the 4 RCTs demonstrated that higher levels of HER2 amplification were associated with greater degree of clinical benefit from anti-HER2 therapy and had clinically meaningful anti-tumor activity with a favorable tolerability profile. No tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with FDA-approved targeted therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Summary

HER2 testing of tumor tissue biopsy specimens may be considered medically necessary for individuals with metastatic CRC to select individuals for treatment with U.S. Food and Drug Administration (FDA)-approved therapies.

All other uses of HER2 testing of tumor tissue to guide CRC targeted therapy are considered investigational.

Population Reference No. 3

Testing for KRAS or NRAS Variants with Circulating Tumor DNA (Liquid Biopsy)

For individuals with mCRC who receive somatic testing for KRAS and NRAS variants using circulating tumor DNA (ctDNA) (liquid biopsy) to guide targeted treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for KRAS and NRAS variants using circulating tumor DNA (ctDNA; liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Summary

Analysis of plasma (liquid biopsy) for somatic variants of the KRAS (eg, G12C) and RAS variants using an FDA-approved companion diagnostic plasma test to detect circulating tumor (ctDNA) may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

All other uses of analysis of KRAS and NRAS variants in plasma are considered investigational.

Population Reference No. 4

Testing BRAF Variants with Circulating Tumor DNA (Liquid Biopsy)

For individuals with mCRC who receive somatic testing for BRAF variants using ctDNA (liquid biopsy) to guide targeted treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for BRAF variants using ctDNA (liquid biopsy), the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Summary

Analysis of plasma (liquid biopsy) for the somatic BRAF V600E variants using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label (see Policy Guidelines).

All other uses of analysis of BRAF V600E variant in plasma are considered investigational.

Population Reference No. 5

Testing for NTRK Gene Fusion with Circulating Tumor DNA (Liquid Biopsy)

For individuals with metastatic CRC who receive somatic testing for NTRK gene fusion using ctDNA (liquid biopsy) to guide targeted treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for NTRK gene fusion using ctDNA (liquid biopsy) to guide targeted treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and NCCN recommendations.

Summary

Analysis of plasma (liquid biopsy) for NTRK gene fusions using an FDA-approved companion diagnostic plasma test to detect ctDNA may be considered medically necessary as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels (see Policy Guidelines).

All other uses of analysis of NTRK fusions in plasma are considered investigational.

Population Reference No. 6

Testing for RET Gene Fusion with Circulating Tumor DNA (Liquid Biopsy)

No plasma tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with RET inhibitors and no studies were identified.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for RET rearrangements using ctDNA (liquid biopsy), no evidence was identified. No plasma tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with RAS inhibitors. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. and no studies were identified.

Summary

Analysis of plasma (liquid biopsy) for somatic RET variants is considered investigational as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC.

Population Reference No. 7

Testing for HER2 Overexpression with Circulating Tumor DNA (Liquid Biopsy)

No plasma tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with kinase inhibitors or anti-HER2 monoclonal antibodies and no studies were identified.

For individuals with metastatic CRC who are being considered for targeted therapy with an FDA-approved drug and undergo somatic testing for HER2 overexpression using ctDNA (liquid biopsy), no evidence was identified. No plasma tests have received FDA approval as companion diagnostics to select individuals with CRC for treatment with kinase inhibitors or anti-HER2 monoclonal antibodies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. and no studies were identified.

Summary

Analysis of plasma (liquid biopsy) for somatic HER2 variants is considered investigational as an alternative to tissue biopsy (see Policy Guidelines) to predict treatment response to an FDA-approved therapy in individuals with metastatic CRC.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the reference medical policy conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology et al

In 2022, the American Society of Clinical Oncology published a provisional clinical opinion on the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors. ^35,

Provisional Clinical Opinion

Informal consensus is based on the review of existing approved testing and therapy combinations, available marker prevalence data, and expert opinion. As no formal systematic review of the clinical trial evidence was conducted for this provisional clinical opinion (PCO), and all the recommendations are based on the informal consensus of the expert panel, no recommendation-by-recommendation
statement of evidence quality is provided.

Section 1: Framework for decision making on multigene panel–based genomic sequencing with disease-specific approved markers.

1. PCO 1.1. Genomic testing should be performed for patients with metastatic or advanced solid tumors with adequate performance status in the following two clinical scenarios:

   1. When there are genomic biomarker–linked therapies approved by regulatory agencies for their cancer.

   2. When considering a treatment for which there are specific genomic biomarker–based contraindications or exclusions (strength of recommendation: strong).

Section 3: Testing for gene fusions and exon skipping variants

1. PCO 3.1. In patients with metastatic or advanced solid tumors, fusion testing should be performed if there are fusion-targeted therapies with regulatory approval for that specific disease (strength of recommendation: strong).

2. PCO 3.2.1. NTRK fusion testing should be performed in patients with metastatic or advanced solid tumors who may be candidates for TRK-inhibitor therapy, considering the prevalence of NTRK fusions in individual tumor types (strength of recommendation: strong).

3. PCO 3.2.2. Testing for other fusions is recommended in patients with metastatic or advanced solid tumors if no oncogenic driver alterations are identified on large panel DNA sequencing (strength of recommendation: moderate).

Section 4: Framework for decision making on panel tests with no approved disease-specific markers.

1. PCO 4.1. Genomic testing should be considered to determine candidacy for tumor-agnostic therapies in patients with metastatic or advanced solid tumors without approved genomic biomarker–linked therapies (strength of recommendation: moderate).

2. PCO 4.2. For tumors with actionable genomic alterations without approved genomic biomarker–linked targeted therapies, patient participation in clinical trials is encouraged after considering the expected efficacy of available standard-of-care options (strength of recommendation: strong).

3. PCO 4.3. Off-label and off-study use of genomic biomarker–linked therapies approved in other diseases is not recommended when a clinical trial is available or without clinical evidence of meaningful efficacy (strength of recommendation: strong).

In 2017, the American Society of Clinical Oncology along with American Society for Clinical Pathology, College of American Pathologists, and Association for Molecular Pathology published guidelines on molecular biomarkers for the evaluation of colorectal cancer.^36, Table 3 summarizes the relevant guidelines.

Table 3. Summary of Recommendations

The following information is based on the National Comprehensive Cancer Network (NCCN) guidelines on the treatment of colon cancer ( v.3.2025).^10,Guidelines are updated frequently; refer to the source document for most recent updates and for additional detail.

RAS and BRAF Testing

The guidelines recommend that all patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRAS and NRAS) and BRAF variants, individually or as part of a next-generation sequencing panel, for all patients with metastatic colon cancer. Patients with any known KRAS mutation (exon 2, 3, 4) or NRAS mutation (exon 2, 3, 4) should not be treated with either cetuximab or panitumumab unless given as part of a regimen targeting a KRAS G12C mutation (Category 2A). BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor (Category 2A).

NTRK

The guidelines acknowledge that NTRK fusions are extremely rare in colorectal cancer and typically limited to tumors that are wild type for KRAS, NRAS, and BRAF. NTRK inhibitors have been shown to have activity only in those cases with NTRK fusions, and not with NTRK point mutations. Selection of the appropriate assay for NTRK fusion detection is stated to depend on "tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently."

Human Epidermal Receptor 2 Testing

The guidelines recommend testing for human epidermal receptor 2 (HER2) amplifications for patients with metastatic colorectal cancer. Anti-HER2 therapy is only indicated in HER2-ampliified tumors that are also RAS and BRAF wild type. If the tumor is already known to have a KRAS/NRAS or BRAF mutation, HER2 testing is not indicated (Category 2A). HER2 testing is performed via immunohistochemistry (IHC) with some results requiring reflex to fluorescence in situ hybridization (FISH); and next-generation sequencing (NGS) is another methodology endorsed for testing for HER2 amplification.

RET

The guidelines acknowledge that RET fusions are extremely rare in colorectal cancer and typically limited to tumors that are wild type for KRAS, NRAS, and BRAF. RET inhibitor, selpercatinib, is FDA-approved for patients with solid tumors harboring activating RET fusions. "The presence of RET fusions can be interrogated through a variety of techniques, including IHC, FISH, PCR, and either DNA- or RNA-based NGS assays. RNA-based NGS assays are fusion agnostic and as such have the advantage of identifying RET fusions involving any partner gene."

Circulating Tumor DNA

The NCCN colon cancer guidelines state that determination of gene status for KRAS/NRAS and BRAF mutations may be carried out using either a tissue or blood-based (eg, liquid) biopsy, although tissue-based testing is preferred.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

A March 2018 decision memo from the Centers for Medicare & Medicaid Services addressed next-generation sequencing for Medicare beneficiaries with advanced cancer.^37, The memo states:

The Centers for Medicare & Medicaid Services has determined that NGS as a diagnostic laboratory test is reasonable and necessary and covered nationally when performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

1. Patient has:

1. 1. 1. either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and

      2. either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician; and

      3. decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

2. The diagnostic laboratory test using NGS must have:

1. 1. FDA [U.S. Food and Drug Administration] approval or clearance as a companion in vitro diagnostic; and

   2. an FDA [U.S. Food and Drug Administration] approved or cleared indication for use in that patient's cancer; and

   3. results provided to the treating physician for management of the patient using a report template to specify treatment options.

Regarding liquid biopsies, the memo states, "The NCD does not limit coverage to how to prepare a sample for performing a diagnostic laboratory test using NGS. Commenters submitted published articles on liquid biopsies (also referred to as circulating tumor DNA (ctDNA) or plasma cell-free DNA (cfDNA) tests). We reviewed and included in the evidence and analysis of 4 studies on liquid biopsies. At this time, liquid-based multi-gene sequencing panel tests are left to contractor discretion if certain patient criteria are met."^37,

Ongoing and Unpublished Clinical Trials

Currently unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Ongoing Trials

   NCT: national clinical trial.

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