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| Genetic Test: Somatic Biomarker Testing (including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, RET, and HER2) | |
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Multiple biomarkers are being evaluated to select treatment with an FDA-approved targeted treatments for patients with unresectable, recurrent, relapsed, refractory, advanced or metastatic cancer. These include tissue-based testing as well as circulating tumor DNA (known as liquid biopsy).
Gene Variants Found in DNA for Targeted Therapy
ALK Gene
ALK is a tyrosine kinase (TK) that, in NSCLC, is aberrantly activated because of a chromosomal rearrangement that leads to a fusion gene and expression of a protein with constitutive TK activity that has been demonstrated to play a role in controlling cell proliferation. The EML4-ALK fusion gene results from an inversion within the short arm of chromosome 2.
The EML4-ALK rearrangement (“ALK-positive”) is detected in 3% to 6% of NSCLC patients, with the highest prevalence in never-smokers or light ex-smokers who have adenocarcinoma.
BRAF
RAF proteins are serine/threonine kinases that are downstream of RAS in the RAS-RAF-ERK-MAPK pathway. The most common variant locus is found in codon 600 of exon 15 (V600E) of the BRAF gene, causing constitutive hyperactivation, proliferation, differentiation, survival, and oncogenic transformation (Wang, 2022). BRAF variants occur in approximately 1% of breast cancer cases (Albanell, 2016).,Variants in the b-raf proto-oncogene, serine/threonine kinase (BRAF) kinase gene are common in tumors of patients with advanced melanoma and result in constitutive activation of a key signaling pathway (rapidly accelerated fibrosarcoma [RAF]-MEK-extracellular signal-regulated kinase [ERK] pathway) that is associated with oncogenic proliferation. In general, 50% to 70% of melanoma tumors harbor a BRAF variant; of these, 80% are positive for the BRAF V600E variant, and 16% are positive for BRAF V600K (Vultur, 2011). Thus, 45% to 60% of advanced melanoma patients may respond to a BRAF inhibitor targeted to this mutated kinase. There is considerable interest in targeted therapies that inhibit the RAF-MEK-ERK pathway, particularly in patients with high-grade and low-grade gliomas whose tumors are in locations that prevent full resection. Evidence from early-phase trials in patients with BRAF variant-positive melanoma with brain metastases have suggested some efficacy for brain tumor response with vemurafenib and dabrafenib indicating that these agents might be potential therapies for primary brain tumors (Dummer, 2014; Long, 2012). In this pathway, the BRAF gene is the most frequently mutated in NSCLC, in 1% to 3% of adenocarcinomas. Unlike melanoma, about 50% of the variants in NSCLC are non-V600E variants (Thunnissen, 2014). Most BRAF variants occur more frequently in smokers.
BRCA Variant Testing
The prevalence of BRCA variants is approximately 0.2% to 0.3% in the general population (Nelson, 2019). The prevalence may be much higher for particular ethnic groups with characterized founder variants (e.g., 2.5% [1/40] in the Ashkenazi Jewish population). Family history of breast and ovarian cancer is an important risk factor for the BRCA variant; additionally, age and ethnicity could be independent risk factors.
Several genetic syndromes with an autosomal dominant pattern of inheritance that features breast cancer have been identified (Hemel, 2010). Of these, hereditary breast and ovarian cancer (HBOC) and some cases of hereditary site-specific breast cancer have in common causative variants in BRCA (breast cancer susceptibility) genes. Families suspected of having HBOC syndrome are characterized by an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer at any age, as well as cancer of the fallopian tube and primary peritoneal cancer. Other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer, occur more frequently in HBOC families. Hereditary site-specific breast cancer families are characterized by early-onset breast cancer with or without male cases, but without ovarian cancer. For this evidence review, BCBSA refers collectively to both as hereditary breast and/or ovarian cancer.
Germline variants in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in most HBOC families, especially if ovarian cancer or male breast cancer are features (Yoshida, 2021). However, in site-specific cancer, BRCA variants are responsible only for a proportion of affected families. BRCA gene variants are inherited in an autosomal dominant fashion through maternal or paternal lineage. It is possible to test for abnormalities in BRCA1 and BRCA2 genes to identify the specific variant in cancer cases and to identify family members at increased cancer risk. Family members without existing cancer who are found to have BRCA variants can consider preventive interventions for reducing risk and mortality.
Young age of onset of breast cancer, even in the absence of family history, is a risk factor for BRCA1 variants. Winchester estimated that hereditary breast cancers account for 36% to 85% of patients diagnosed before age 30 (Winchester, 1996). In several studies, BRCA variants were independently predicted by early age at onset, being present in 6% to 10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (age range, 35-50 years) (Winchester, 1996; Frank, 2002; Langston, 1996; Malone, 1998). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 variants is in the 40s (Ford, 1998). In the Ashkenazi Jewish population, Frank et al reported that 13% of 248 cases with no known family history and diagnosed before 50 years of age had BRCA variants (Frank, 2002). In a similar study by Gershoni-Baruch et al, 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA variants (Gershoni, 2000). Other studies have indicated that early age of breast cancer diagnosis is a significant predictor of BRCA variants in the absence of family history in this population (Warner, 1999; Hartge, 1999; Hodgson, 1999).
In patients with “triple-negative” breast cancer (i.e., negative for expression of estrogen, progesterone, and overexpression of human epidermal growth factor receptor 2 [HER2] receptors), there is an increased prevalence of BRCA variants. Pathophysiologic research has suggested that the physiologic pathway for the development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer (de Ruijter, 2011). Young et al studied 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing (Young, 2009). Six BRCA variants (5 BRCA1, 1 BRCA2) were found, for a variant rate of 11%. Finally, Gonzalez-Angulo et al in a study of 77 patients with triple-negative breast cancer, reported that 15 patients (19.5%) had BRCA variants (12 in BRCA1, 3 in BRCA2) (Gonzalez-Angulo, 2011).
CLDN18
Claudin-18 (CLDN18) is a transmembrane protein that forms tight junctions between epithelial cells and regulate the flow and movement of ions across epithelial cells. Overexpression of this protein is implicated in the development of various primary malignant tumors, such as gastric cancer/gastroesophageal junction (GC/GEJ) cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer, and non-small-cell lung cancer (Cao, 2022; Huang, 2025). More specifically, CLDN18.2 is an isoform that is exclusively expressed in the tight junctions of gastric mucosal cells and participates in the proliferation, differentiation and migration of tumor cells. Studies have reported that CLDN18.2 is expressed in approximately 70% of gastric cancers and up to 60% of pancreatic adenocarcinomas (Tojiari, 2024).
EGFR
EGFR, a receptor tyrosine kinase (TK), is frequently overexpressed and activated in NSCLC. Drugs that inhibit EGFR signaling either prevent ligand binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small-molecule tyrosine kinase inhibitors [TKIs]). These targeted therapies dampen signal transduction through pathways downstream to the EGFR, such as the RAS/RAF/MAPK cascade. RAS proteins are G proteins that cycle between active and inactive forms in response to stimulation from cell surface receptors, such as EGFR, acting as binary switches between cell surface EGFR and downstream signaling pathways. These pathways are important in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.
Somatic variants in the TK domain of the EGFR gene, notably small deletions in exon 19 and a point mutation in exon 21 (L858R, indicating substitution of leucine by arginine at codon position 858) are the most commonly found EGFR variants associated with sensitivity to EGFR TKIs (afatinib, erlotinib, gefitinib). These variants are referred to as sensitizing variants. Almost all patients who initially respond to an EGFR TKI experience disease progression. The most common of these secondary variants, called resistance variants, involves the substitution of methionine for threonine at position 790 (T790M) on exon 20.
Fang et al reported EGFR variants (all L858R) in 3 (2%) of 146 consecutively treated Chinese patients with early-stage squamous cell carcinoma (SCC) (Fang, 2013). In a separate cohort of 63 Chinese patients with SCC who received erlotinib or gefitinib as second- or third-line treatment (63% never-smokers, 21% women), EGFR variant prevalence (all exon 19 deletion or L858R) was 23.8%. In a comprehensive analysis of 14 studies involving 2880 patients, Mitsudomi et al reported EGFR variants in 10% of men, 7% of non-Asian patients, 7% of current or former smokers, and 2% of patients with nonadenocarcinoma histologies (Mitsudomi, 2006). Eberhard et al observed EGFR variants in 6.4% of patients with SCC and Rosell et al observed EGFR variants in 11.5% of patients with large cell carcinomas (Eberhard, 2005; Rosell, 2009). Both studies had small sample sizes. In 2 other studies, the acquired EGFR T790M variant has been estimated to be present in 50% to 60% of TKI-resistant cases in approximately 200 patients (Yu, 2013; Sequist, 2011).
ESR1
Variants in estrogen receptor 1 (ESR1), which occur in approximately 10-20% of patients with metastatic estrogen receptor-positive breast cancer, confer resistance to endocrine therapy via constitutive activation of estrogen receptor-mediated growth activity (Toy, 2013; Jeselsohn, 2014).
EZH2
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltrasnferase responsible for generating epigenetic markers that regulate gene function with the most common being trimethylation of Lys-27 in histone 3 (H3K27me3) (Duan, 2020). EZH2 is overexpressed in numerous tumor types including melanoma, ovarian, breast, endometrial, bladder, renal cell, lung, and liver cancer, and is associated with aggressive disease, leading to its classification as an oncogene. It is commonly overexpressed or harbors gain-of-function mutations that enhance the catalytic activity within 25 percent of follicular lymphomas (Romero, 2024).
FGFR2 and FGFR3
The fibroblast growth factor receptor (FGFR) family is an integral signaling pathway for cellular activities, including proliferation, tissue repair, regeneration, chemotaxis, angiogenesis, differentiation, and survival (Seraji, 2025). Thus, dysregulation of this pathway with alterations of these genes has been implicated in numerous cancers, including uroepithelial carcinoma (32–14.8%), colorectal carcinoma (31%), breast carcinoma (12.6–18%), gastric carcinoma (16.8–25.6%), endometrial carcinoma (13%), squamous lung carcinoma (6.8–13%), esophageal carcinoma (12.7%), ovarian carcinoma (9%), and lung adenocarcinoma (1.3%). Most of these abnormalities were gene amplifications (53.7–66%), followed by mutations (26–38.8%), and rearrangements/fusions (5.6–8%). The frequencies of aberration for FGFR2 and FGFR3 were 14.2–19% and 17.7–26%, respectively (Zhang, 2024; Du, 2023).
FLT3 (ITD/TDK)
Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 25% to 30% of acute myeloid leukemia (AML) cases and results in more severe outcomes, including higher relapse rates and reduced overall survival, after standard of care treatment (Fedorov, 2023; Rataj, 2025; Tamburini, 2023). Variants in FLT3 were found in 30% of newly diagnosed AML patients, with FLT3-ITD variants occurring with a frequency of 24% and variants within the activation loop (FLT3-TKD mutations) occurring at a frequency of 7%.
FOLR1
Folate receptor alpha, encoded by the FOLR1 gene, is an attractive target for cancer therapeutics due to its high expression in several cancer types including lung, breast, and epithelial ovarian cancer (EOC) with overexpression in approximately 80% of EOCs (Mai, 2023).
Homologous Recombination Deficiency and Homologous Recombination Repair
DNA damage happens daily, and most are repaired to allow normal cell functioning. Double strand breaks (DSB) in the DNA are particularly damaging. Repair of DSB utilizes the homologous recombination repair (HRR) pathway. Many types of cancer, however, are unable to repair DNA damage. This leads to the accumulation of genetic errors, such as loss of DNA, rearrangements in the DNA, and loss of entire genes. The consequence of these errors is genomic instability. The loss of the HRR and associated genomic instability is called homologous recombination deficiency (HRD). HRD is associated with several types of cancer including ovarian cancer (NCI, 2026: Mateo, 2017). HRD is associated with several types of cancer including prostate cancer, where estimates as high as 30% of metastatic castrate-resistant prostate cancer (mCRPC) tumors have genetic changes that result in the loss of DNA repair capacity (Mateo, 2017). Specific to prostate cancer, the National Comprehensive Cancer Network (NCCN) prostate cancer guideline gives examples of HRR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) (NCCN, 2026). Poly adenosine diphosphate-ribose polymerase (PARP) inhibitors are used to target tumor cells with alterations in the HRR genes BRCA1 and BRCA2.
In ovarian cancer targeted therapies, HRD-positive status is generally defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Myriad MyChoice is an FDA-approved companion diagnostic for the assessment of tumor genomic instability score (GIS) and the detection and classification of variants in the BRCA1 and BRCA2 genes, for the selection of patients who are eligible for targeted treatment. A patient’s Myriad HRD status is determined by detecting single nucleotide variants (SNVs), variants in homopolymer stretches, insertions and deletions (indels), and large rearrangements (LRs) in the BRCA1 and BRCA2 genes, and determining a genomic instability score (GIS) using DNA obtained from ovarian tumor tissue. A positive Myriad HRD Status result is due to either the presence of a pathogenic variant in BRCA1 and/or BRCA2 and/or a GIS above a defined threshold (Myriad Genetics, 2024). Approximately 41% to 50% of epithelial ovarian cancers are estimated to exhibit HRD. Germline alterations in BRCA1 and BRCA2 genes have been identified in up to 17% of individuals diagnosed with epithelial ovarian cancer, and somatic mutations are found in an additional 7% (Tew, 2022).
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%) (Singh, 2024). 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.
Human Leukocyte Antigen
The human leukocyte antigen (HLA) is a complex system of genes in humans that encode cell-surface proteins responsible for the regulation of the immune system. HLA molecular pathways present tumor antigens to T-cells to facilitate the recognition of tumor cells by the immune system. HLA genes are highly polymorphic allowing them to fine-tune the immune response through multiple unique combinations. HLA variants are crucial for targeted therapy as these drugs are engineered to bind to specific HLA constructs to evoke an immune response against tumor cells (Wang, 2020).
IDH1 and IDH2
Mutations in isocitrate dehydrogenase-1 (IDH1) or -2 (IDH2) genes lead to aberrant accumulated production of D-2-hydroxyglutarate, disrupting gene expression and cellular differentiation. WHO grade 2 and 3 astrocytomas and oligodendrogliomas are defined by IDH mutations, distinguishing lower-grade gliomas from glioblastomas. IDH1 and IDH2 mutations are generally associated with a more favorable prognosis, and have been important biomarkers for stratification in clinical trials. IDH mutations are detected in over 50% of gliomas in patients aged 55 or older (NCCN, 2026).
KIT
KIT, also known as c-KIT, is a tyrosine kinase expressed on the surface of cells and plays a significant role in cell survival, proliferation, and differentiation via signaling pathways. For instance, KIT signaling is required for melanocyte survival, and is involved in hematopoiesis and gametogenesis. Gain-of-function variants within this gene are highly associated with cancer as it is implicated in numerous signaling pathways, such as RAS-MAPK and PI-3K.KIT variants are present in 85% to 95% of gastrointestinal stromal tumors (GIST) and systemic mastocytosis cancers (Heinrich, 2003).
KMT2A
Lysine methyltransferase 2A (KMT2A), located at chromosome 11q23, encodes a histone H3 lysine 4 methyltransferase that functions as an epigenetic regulator of hematopoietic stem cell self-renewal through control of HOX-A and MEIS1 transcription. Chromosomal rearrangements at the KMT2A locus generate in-frame fusion proteins joining the N-terminus of KMT2A to one of more than 90 documented partner genes (most commonly MLLT3, MLLT10, AFDN, ELL, and MLLT1) that drive aberrant upregulation of HOX-A and MEIS1 to arrest myeloid differentiation. KMT2A rearrangements (KMT2A-r) are identified in approximately 5% to 10% of de novo adult acute myeloid leukemia (AML) and at substantially higher frequencies in pediatric AML, reaching 50% to 60% in infants under 2 years of age (Testa, 2026).
MET
MET alteration is one of the critical events for acquired resistance in EGFR-mutated adenocarcinomas refractory to EGFR TKIs (Thunnissen, 2014).
Mismatch Repair Deficiency/Microsatellite Instability
Mismatch repair deficiency (dMMR) and high levels of microsatellite instability (MSI-H) describe cells that have alterations in certain genes involved in correcting errors made when DNA is replicated. dMMR tumors are characterized by a high tumor mutational load and potential responsiveness to anti-programmed cell death ligand-1 (PD-L1)-immunotherapy. Mismatch repair (MMR) deficiency is most common in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer, but it may also be found in other cancers including breast cancer.
Testing for dMMR and MSI is used to identify individuals most likely to respond to anti-PD-L1 therapy. Either MMR testing or MSI testing can be used to screen for MMR functional defects. MMR testing is performed using IHC for 4 MMR proteins (MLH1, MSH2, PMS2, and MSH6). Microsatellite instability testing is generally performed using polymerase chain reaction (PCR) for 5 biomarkers (MLH1, MSH2, MSH6, PMS1 and PMS2). High MSI is defined as 2 or more of the 5 biomarkers showing instability or more than 30% of the tested biomarkers showing instability depending on what panel is used (Bonneville, 2020).
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 (TRK Fusion Cancer, 2025). 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.
PIK3CA Testing
Alterations in the protein coding gene PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) occur in approximately 40% of patients with hormone receptor (HR)-positive, HER2-negative breast cancer. (Karakas, 2006).
Platelet-Derived Growth Factor Receptor Alpha and Beta
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors and are members of the platelet-derived growth factor (PDGF) family. PDGF subunits alpha and beta play important roles in regulating cell proliferation, cellular differentiation, cell growth and development with alterations in these genes being heavily implicated in oncogenesis. PDGFRA variants occur in approximately 10–15% of GISTs, however, PDGFRB rearrangements are rare with approximately 2% of myeloproliferative neoplasms containing these fusions (Sun, 2022; Ondrejka, 2014).
Programmed Cell Death Ligand Protein-1
Programmed cell death ligand-1 is a transmembrane protein expressed on the surface of multiple tissue types, including many tumor cells. Blocking the PD-L1 protein may prevent cancer cells from inactivating T cells.
FDA-approved PD-L1 immune checkpoint inhibitors include atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.
RAS (KRAS and NRAS)
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.
The KRAS gene (which encodes RAS proteins) can harbor oncogenic variants that result in a constitutively activated protein, independent of signaling from the EGFR, possibly rendering a tumor resistant to therapies that target the EGFR. Variants in the KRAS gene, mainly codons 12 and 13, have been reported in 20% to 30% of NSCLC, and occur most often in adenocarcinomas in heavy smokers. KRAS variants can be detected by direct sequencing, polymerase chain reaction technologies, or next-generation sequencing. EGFR, ALK, ROS1, and KRAS driver mutations are considered to be mutually exclusive.
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 (i.e., 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.
Rearranged During Transfection
The REarranged during Transfection (RET) proto-oncogene encodes a receptor tyrosine kinase growth factor (Regua, 2022). Translocations that result in fusion genes with several partners have been reported, and occur in about 5-10% of thyroid cancer cases (primarily papillary thyroid carcinoma), 1%-2% of non-small-cell lung cancer cases, and occurring in roughly 0.2% colorectal cancers (Thunnissen, 2014; Nagasaka, 2023). RET fusions in breast cancer, occur in less than 1% of cases (Santoro, 2020).
ROS1
ROS1 codes for a receptor tyrosine kinase of the insulin receptor family and chromosomal rearrangements result in fusion genes. The prevalence of ROS1 fusions in NSCLC varies from 0.9% to 3.7% (Thunnissen, 2014). Patients with ROS1 fusions are typically never-smokers with adenocarcinoma.
Tumor Mutational Burden
Tumor mutational burden (TMB) is a measure of gene mutations within cancer cells. Initially, assessments of TMB involved whole exome sequencing (WES). More recently, targeted next generation sequencing (NGS) panels are being adapted to estimate TMB. Currently FoundationOne CDx is the only U.S. Food and Drug Administration (FDA) approved panel for estimating TMB, but others are in development. (Merino, 2020).
Tumor Protein p53
Tumor protein p53 (TP53) is a transcription factor protein that binds to DNA and regulates gene expression to prevent alterations of the genome. Accumulating evidence indicates that p53 is the most frequently mutated gene in human cancers and are commonly found in the ovary (47.27%), colon and rectum (44.55%), lung (40.8%), pancreas (38.53%), stomach (36.78%), urethra (35.01%), liver (29.17%), breast (26.44%), prostate (22.52%), bone (16.19%), thyroid (11.13%), hematopoietic and lymphatic (10.13%) and kidney (8.75%) (Wang, 2023; Nishikawa, 2023).
Circulating Tumor DNA
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.
Regulatory Status
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 by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.
An up-to-date list of FDA cleared or approved companion diagnostics is available at
https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.
Coding
Effective in 2012, there are specific CPT codes for KRAS or BRAF mutation analysis.
81210: BRAF (v-raf murine sarcoma viral oncogene homolog B1) (e.g., colon cancer), gene analysis, V600E variant
81311 NRAS (neuroblastoma RAS viral [v ras] oncogene homolog) (e.g., colorectal carcinoma), gene analysis, variants in exon 2 (e.g., codons 12 and 13) and exon 3 (e.g., codon 61)
81275: KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene) (e.g., carcinoma) gene analysis, variants in codons 12 and 13
Additionally, code 81403 would be reported for KRAS testing for variant(s) in exon 3 (e.g., codon 61).
Prior to 2012, multiple codes describing genetic analysis would likely be used to report this testing (e.g., codes from 83890-83912).
Related Policies:
Policy # 2017007 Cetuximab (Erbitux)
Policy #2017024 Panitumumab (Vectibix)
Policy # 2023023 Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)
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Policy/ Coverage: |
Effective June 15, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, RET, or HER2 variant analysis of tumor tissue meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered for individuals with metastatic colorectal cancer (mCRC) to select individuals for treatment with FDA-approved therapies when the following criteria are met:
Member receives a “recommended” determination from InterQual® criteria review for KRAS, NRAS, BRAF, RET, or HER2 variant analysis of tumor tissue based on diagnosis and requested service/procedure.
Click the following link to view the InterQual® criteria:
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, RET, or HER2 variant analysis for any use not addressed in this or other policies does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For members with contracts without Primary Coverage Criteria, any other use of KRAS, NRAS, BRAF, RET, or HER2 variant analysis not addressed in this or other policies is considered not Medically Necessary or is investigational and is not covered. Not Medically Necessary or Investigational
services are specific contract exclusions in most member benefit certificates of coverage.
PIK3CA variant analysis for any use not addressed in this or other policies does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For members with contracts without Primary Coverage Criteria, any other use of PIK3CA variant analysis not addressed in this or other policies is considered not Medically Necessary or is investigational and is not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
CTNNB1 variant analysis for any use not addressed in this or other policies does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For members with contracts without Primary Coverage Criteria, any other use of CTNNB1 variant analysis not addressed in this or other policies is considered not Medically Necessary or is investigational and is not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
For members with contracts without Primary Coverage Criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered not Medically Necessary or is investigational and is not covered. Not Medically Necessary or Investigational
services are specific contract exclusions in most member benefit certificates of coverage.
Click the following link to view the InterQual® criteria:
Effective November 2025 through June 14, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, RET, or HER2 variant analysis of tumor tissue meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with metastatic colorectal cancer (mCRC) to select individuals for treatment with FDA-approved therapies.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, RET, or HER2 variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of KRAS, NRAS, BRAF, RET, or HER2 variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
PIK3CA variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of PIK3CA variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
CTNNB1 variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of CTNNB1 variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective October 2024 – October 2025
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, or HER2 variant analysis of tumor tissue meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with metastatic colorectal cancer (mCRC) to select individuals for treatment with FDA-approved therapies.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, or HER2 variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of KRAS, NRAS, BRAF, or HER2 variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
PIK3CA variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of PIK3CA variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
CTNNB1 variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of CTNNB1 variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective October 2023 through September 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, or HER2 variant analysis of tumor tissue meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with metastatic colorectal cancer (mCRC) to select individuals for treatment with FDA-approved therapies.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
KRAS, NRAS, BRAF, or HER2 variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of KRAS, NRAS, BRAF, or HER2 variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective October 2022 through September 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS variant analysis of tumor tissue meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with metastatic colorectal cancer (mCRC) to select individuals for treatment with FDA-approved therapies.
NRAS variant analysis of tumor tissue meets member benefit certificate primary coverage criteria
that there be scientific evidence of effectiveness in improving health outcomes
for individuals with metastatic colorectal cancer to select individuals for treatment with FDA-approved therapies.
BRAF variant analysis of tumor tissue meets member benefit certificate primary coverage criteria
that there be scientific evidence of effectiveness in improving health outcomes
for individuals with metastatic colorectal cancer
who are found to be wild-type on KRAS and
NRAS variant analysis to guide management decisions, and to select individuals for treatment with FDA-approved therapies.
Mismatch repair/microsatellite instability testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes
to select individuals for treatment with FDA-approved therapies.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
KRAS variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of KRAS variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
NRAS variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any use of NRAS
variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
BRAF variant analysis for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any use of
BRAF variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Mismatch repair/microsatellite instability variant testing for any use not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any use of
mismatch repair/microsatellite instability variant analysis not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Human epidermal growth factor receptor 2 testing to predict treatment response to immunotherapy in individuals with metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, human epidermal growth factor receptor 2 testing to predict treatment response to immunotherapy in individuals with metastatic colorectal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Tumor mutational burden testing to predict response to immunotherapy in individuals with metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, tumor mutational burden testing to predict response to immunotherapy in individuals with metastatic colorectal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to October 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS Variant Analysis meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients with metastatic colorectal cancer (mCRC) to predict nonresponse prior to planned therapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab or panitumumab.
NRAS variant meets member benefit certificate primary coverage criteria
that there be scientific evidence of effectiveness in improving health outcomes
for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab.
BRAF Variant Analysis meets member benefit certificate primary coverage criteria
that there be scientific evidence of effectiveness in improving health outcomes
for patients with metastatic colorectal cancer
who are found to be wild-type on KRAS and
NRAS variant analysis to guide management decisions.
Mismatch repair/microsatellite instability testing meets member benefit certificate primary coverage criteria
to predict treatment response to pembrolizumab:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
KRAS variant analysis for any use not addressed in this or other policies does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, any other use of KRAS variant analysis not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
NRAS variant analysis for any use not addressed in this or other policies does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, any other use of NRAS
variant analysis not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
BRAF variant analysis for any use not addressed in this or other policies does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any other use of
BRAF variant analysis not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
Mismatch repair/microsatellite instability testing for any use not addressed in this or other policies does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, any use of
mismatch repair/microsatellite instability analysis not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
Human epidermal growth factor receptor 2 testing to predict treatment response to immunotherapy in patients with metastatic colorectal cancer does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, human epidermal growth factor receptor 2 testing to predict treatment response to immunotherapy in patients with metastatic colorectal cancer is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
Tumor mutational burden testing to predict response to immunotherapy in patients with metastatic colorectal cancer does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, tumor mutational burden testing to predict response to immunotherapy in patients with metastatic colorectal cancer is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
Circulating tumor DNA testing (liquid biopsy) to guide treatment in patients with metastatic colorectal cancer does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in patients with metastatic colorectal cancer is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
Effective Prior to September 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS Mutation Analysis
KRAS mutation testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients with metastatic colorectal cancer (mCRC) to determine whether the tumor is likely to respond to therapy with cetuximab or panitumumab. Results of this testing with documentation of normal (wild-type) KRAS gene and negative for KRAS mutation will be required for coverage of either drug.
NRAS Mutation Analysis
NRAS variant meets member benefit certificate primary coverage criteria
for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Treatment of KRAS mutation positive mCRC
Treatment of metastatic colorectal cancer that is
KRAS mutation positive with cetuximab or panitumumab does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts without primary coverage criteria, treatment of metastatic colorectal cancer that is KRAS mutation positive with cetuximab or panitumumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
KRAS Mutation Analysis
Any other use of KRAS mutation testing not addressed in this or other policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without Primary Coverage Criteria, any other use of
KRAS mutation testing not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
NRAS Mutation Analysis
Any other use of NRAS mutation testing not addressed in this or other policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without Primary Coverage Criteria, any other use of
NRAS mutation testing not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
BRAF Mutation Analysis
BRAF mutation analysis to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, BRAF
mutation analysis is considered investigational
to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
KRAS, NRAS, and BRAF variant analysis using circulating tumor DNA or circulating tumor cell testing (liquid biopsy) to guide treatment for patients with metastatic colorectal cancer does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, KRAS, NRAS, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS Mutation Analysis
KRAS mutation testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients with metastatic colorectal cancer (mCRC) to determine whether the tumor is likely to respond to therapy with cetuximab or panitumumab. Results of this testing with documentation of normal (wild-type) KRAS gene and negative for KRAS mutation will be required for coverage of either drug.
NRAS Mutation Analysis
NRAS variant meets member benefit certificate primary coverage criteria
for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Treatment of KRAS mutation positive mCRC
Treatment of metastatic colorectal cancer that is
KRAS mutation positive with cetuximab or panitumumab does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts without primary coverage criteria, treatment of metastatic colorectal cancer that is KRAS mutation positive with cetuximab or panitumumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
KRAS Mutation Analysis
Any other use of KRAS mutation testing not addressed in this or other policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without Primary Coverage Criteria, any other use of
KRAS mutation testing not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
NRAS Mutation Analysis
Any other use of NRAS mutation testing not addressed in this or other policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without Primary Coverage Criteria, any other use of
NRAS mutation testing not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
BRAF Mutation Analysis
BRAF mutation analysis to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, BRAF
mutation analysis is considered investigational
to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 2015- December 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
KRAS Mutation Analysis
KRAS mutation testing meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients with metastatic colorectal cancer (mCRC) to determine whether the tumor is likely to respond to therapy with cetuximab or panitumumab. Results of this testing with documentation of normal (wild-type) KRAS gene and negative for KRAS mutation will be required for coverage of either drug.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Treatment of KRAS mutation positive mCRC
Treatment of metastatic colorectal cancer that is
KRAS mutation positive with cetuximab or panitumumab does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts without primary coverage criteria, treatment of metastatic colorectal cancer that is KRAS mutation positive with cetuximab or panitumumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
KRAS Mutation Analysis
Any other use of KRAS mutation testing not addressed in this or other policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without Primary Coverage Criteria, any other use of KRAS mutation testing not addressed in this or other policies is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
NRAS Mutation Analysis
NRAS mutation analysis to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, NRAS
mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
BRAF Mutation Analysis
BRAF mutation analysis to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, BRAF
mutation analysis is considered investigational
to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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KRAS Mutation Analysis
RCTs
RCTs have performed nonconcurrent subgroup analyses of the efficacy of epidermal growth factor receptor (EGFR) inhibitors in patients with wild-type (WT) versus mutated
KRAS in metastatic colorectal cancer (CRC). Data from these trials have consistently shown a lack of clinical response to cetuximab and panitumumab in patients with mutated
KRAS, with tumor response and prolongation of progression-free survival (PFS) observed only in WT
KRAS patients.
Amado et al performed a subgroup analysis of
KRAS tumor mutations in a patient population that had previously been randomly assigned to panitumumab versus best supportive care as third-line therapy for chemotherapy-refractory metastatic CRC (Amado, 2008). The original study was designed as a multicenter, RCT but was not blinded because of expected skin toxicity related to panitumumab administration.3
Patients were randomly assigned 1:1 to receive panitumumab or best supportive care. Random assignment was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs 2) and geographic region. Crossover from best supportive care to the panitumumab arm was allowed in patients who experienced disease progression. Of the 232 patients originally assigned to best supportive care alone, 176 crossed over to the panitumumab arm, at a median time to crossover of 7 weeks (range, 6.6-7.3).
Of the 463 patients in the original study, 427 (92%) were included in the
KRAS subgroup mutation analysis. A central laboratory performed the
KRAS mutational analysis in a blinded fashion, using formalin-fixed, paraffin-embedded (FFPE) tumor sections and a validated
KRAS mutation kit (DxS Ltd., Manchester, England) that identifies 7 somatic mutations located in codons 12 and 13 using real-time polymerase chain reaction (PCR).
KRAS mutation status could not be determined in 36 patients because tumor samples were not available or DNA was insufficient or poor quality for analysis. Forty-three percent of the
KRAS-evaluable patients had KRAS-mutated tumors, with similar distribution of
KRAS mutation types between treatment arms.
Patient demographics and baseline characteristics were balanced between the WT and mutated groups (MT) for panitumumab versus best supportive care including patient age, sex, and ECOG performance status. The interaction between mutational status and PFS was examined, controlling for randomization factors. PFS and tumor response rate was assessed radiographically every 4 to 8 weeks until disease progression using Response Evaluation Criteria in Solid Tumors (RECIST) criteria by blinded, central review. In the KRAS-assessable population, 20% of patients had a treatment-related grade 3 or 4 adverse event. The relative effect of panitumumab on PFS was significantly greater among patients with WT
KRAS, compared with patients with MT KRAS in whom no benefit from panitumumab was observed. No responders to panitumumab were identified in the MT group, indicating a 100% positive predictive value for nonresponse in the mutant group.
In a third trial, the randomized, phase 2 OPUS trial, the intention-to-treat (ITT) population consisted of 337 patients randomly assigned to C and folinic acid [leucovorin], 5-FU, oxaliplatin (FOLFOX) versus FOLFOX alone in the first-line treatment of metastatic CRC (Bokemeyer, 2009). A 10% higher response rate (assessed by independent reviewers) was observed in the population treated with C, but no difference in PFS was seen between the two groups. The researchers then reevaluated the efficacy in the 2 treatment arms with consideration of KRAS
mutational status of the patients’ tumors. Of the original ITT population, 233 subjects had evaluable material for
KRAS testing, and 99 (42%) were KRAS mutant. The demographics or baseline characteristics were similar between the WT and MT groups, including patient age, sex, ECOG performance status, involved disease sites, and liver-limited disease. The study showed that the addition of C to FOLFOX resulted in a significant improvement in response rate and PFS only in the WT
KRAS group.
In the CAIRO2 study, Tol et al analyzed tumor samples from 528 of 755 previously untreated patients with metastatic CRC who were randomly assigned to receive capecitabine, oxaliplatin and bevacizumab (CB regimen, n=378), or the same regimen plus C (CBC regimen, n=377) (Tol, 2009). A KRAS mutation was found in 40% of tumors (108 from patients in the CB group and 98 from the CBC group). Patients with
KRAS mutations treated with C had significantly shorter PFS than the
KRAS WT patients who received C (8.1 vs 10.5 months, respectively, p=0.04). In addition, patients who had MT
KRAS tumors who received C had significantly shorter PFS than patients with MT
KRAS tumors who did not receive C (8.1 vs 12.5 months, respectively, p=0.003) and overall survival (OS) (17.2 vs 24.9 months, respectively, p=0.03). For patients with WT tumors, no significant PFS differences were reported between the 2 groups. Overall, patients treated with C who had tumors with a mutated KRAS gene had significantly decreased PFS compared with C-treated patients with WT
KRAS tumors or patients with mutated KRAS tumors in the CB group.
Karapetis et al analyzed tumor samples from 394 of 572 patients (69%) with CRC who were randomly assigned to receive C plus BSC (n=287) versus BSC alone (n=285) for
KRAS mutations and assessed whether mutation status was associated with survival (Karapetis, 2008). The patients had advanced CRC, had failed chemotherapy and had no other standard anticancer therapy available. Of the tumors that were evaluated (198 from the C group, 196 from the BSC group), 41% and 42% had a KRAS mutation, respectively. In OS (median, 9.5 months vs 4.8 months, respectively; HR for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; p<0.001) and PFS (median, 3.7 months vs 1.9 months, respectively; HR for progression to death, 0.40; 95% CI, 0.30 to 0.54; p<0.001). For patients with MT
KRAS tumors, no significant differences were reported between those treated with C versus BSC alone with respect to OS (HR=0.98, p=0.89) or PFS (HR=0.99, p=0.96).
Douillard et al reported the results of a multicenter, phase 3 trial in which patients with no prior chemotherapy for metastatic CRC, ECOG performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4 (Douillard, 2010).
The primary end point was PFS; OS was a secondary end point. Results were prospectively analyzed on an ITT basis by tumor
KRAS status. KRAS results were available for 93% of the 1183 patients randomly assigned. In the WT
KRAS group, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 alone (median PFS, 9.6 vs 8.0 months, respectively; HR=0.80; 95% CI, 0.66 to 0.97; p=0.02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS=23.9 vs 19.7 months, respectively; HR=0.83; 95% CI, 0.67 to 1.02; p=0.072). In the mutant
KRAS group, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR=1.29; 95% CI, 1.04 to 1.62; p=0.02), and median OS was 15.5 months versus 19.3 months, respectively (HR=1.24; 95% CI, 0.98 to 1.57; p=0.068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. The study demonstrated that panitumumab-FOLFOX4 was well-tolerated and significantly improved PFS in patients with WT
KRAS tumors.
The CRYSTAL trial demonstrated that the addition of cetuximab to a combined first-line chemotherapy regimen of irinotecan, infusional fluorouracil and leucovorin (FOLFIRI) statistically significantly reduced the risk of disease progression and increased the chance of response in patients with metastatic CRC that was
KRAS WT, compared with chemotherapy alone (Van Cutsem, 2009). An updated analysis of the CRYSTAL trial reported increased follow-up time and an increased number of patients evaluable for tumor
KRAS status and considered the clinical significance of the tumor mutation status of
BRAF in the expanded population of patients with KRAS WT tumors (Van Cutsem, 2011).
Subsequent to the initial published analysis, which had a cutoff for OS of December 2007, and an associated overall median duration of follow-up of 29.7 months, additional tumor analysis allowed for the typing of an additional 523 tumors for
KRAS mutation status, representing an increase in the ascertainment rate from 45% of ITT population patients in the original analysis to 89% (540 to 1063) in the current analysis, with mutations detected in 37% of tumors. The updated analysis of OS was carried out with a new cutoff date of May 2009, giving an overall median duration of follow-up of 46 months. The addition of cetuximab to FOLFIRI in patients with
KRAS WT disease resulted in significant improvements in OS (median, 23.5 vs. 20.0 months; HR=0.796; p=0.009), PFS (median, 9.9 vs 8.4 months; HR=0.696; p=0.001), and response (rate 57.3% vs 39.7%; odds ratio [OR], 2.069; p<0.001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points.
KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI.
BRAF V600E mutations were detected in 60 (6%) of 999 tumor samples evaluable for both
BRAF and KRAS. In all but 1 case, BRAF mutations were identified in tumors that were WT for
KRAS. The impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI was examined in the population of patients with
KRAS WT disease (n=625). No evidence was reported for an independent treatment interaction by tumor
BRAF mutation status. The authors concluded that BRAF mutation status was not predictive of treatment effects of cetuximab plus FOLFIRI but that
BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy end points compared with those whose tumors were WT.
Peeters et al reported the results of a phase 3 study in which 1186 patients with metastatic CRC were randomized to receive panitumumab with FOLFIRI versus FORFIRI alone as second-line treatment (Peeters, 2010).
The study end points were PFS and OS, which were independently tested and prospectively analyzed by
KRAS status. KRAS status was available for 91% of patients: 597 (55%) with WT
KRAS tumors and 486 (45%) with MT KRAS tumors. In the WT KRAS
subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (HR=0.73; 95% CI, 0.59 to 0.90; p=0.004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR=0.85, 95% CI, 0.70 to 1.04; p=0.12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT
KRAS, no difference was reported in efficacy. Adverse events were comparable across arms. The authors concluded that panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT
KRAS metastatic colorectal cancer (mCRC).
Maughan et al reported the results of a phase 3, multicenter trial (MRC COIN trial) which randomized patients with advanced CRC who had not received previous chemotherapy to oxaliplatin and fluoropyrimidine chemotherapy (arm A) or the same combination plus cetuximab (Maughan, 2011). The comparison between arms A and B (for which the primary outcome was OS) was in patients with
KRAS WT tumors.
Baseline characteristics were well-balanced between the trial groups. Analysis was by ITT and treatment allocation was not masked. Further analysis with respect to other mutations, including
BRAF, was done; 1630 patients were randomly assigned to treatment groups (815 to standard therapy, 815 to the addition of cetuximab). Tumor samples from 1316 (81%) of patients were used for somatic mutation analyses; 43% had
KRAS mutations. In patients with KRAS WT tumors, OS did not differ between treatment groups (median survival, 17.9 months in the control group vs 17.0 months in the cetuximab group (HR=1.04; 95% CI, 0.87 to 1.23; p=0.67).
BRAF mutations were detected in 8% of patients; BRAF did not show any evidence of a benefit from the addition of cetuximab. Contrary to other trials that have assessed KRAS mutation status and the benefit of the addition of cetuximab to the regimen of WT KRAS patients, this trial did not show a benefit of the addition of cetuximab to oxaliplatin-based chemotherapy.
Systematic Reviews
Qiu et al conducted a meta-analysis of 22 studies on the predictive and prognostic value of
KRAS mutations in metastatic CRC patients treated with cetuximab (Qui, 2010).
The overall KRAS mutation rate was 38% (829/2188 patients). The results of the meta-analysis were consistent with previous reports on the use of cetuximab and
KRAS mutation status, that patients with tumors that harbor mutant-type
KRAS are more likely to have a worse response, PFS and OS when treated with cetuximab when compared with those with WT
KRAS.
Dahabreh et al conducted a systematic review of RCTs that assessed the use of
KRAS mutation testing as a predictive biomarker for treatment of advanced CRC with cetuximab and panitumumab (Dahabreh, 2011).
The authors concluded that, compared with patients with WT KRAS,
KRAS mutations are consistently associated with reduced OS and PFS and increased treatment failure rates among patients with advanced CRC who are treated with anti- EGFR antibodies.
A pooled analysis of the CRYSTAL and OPUS RCT data was performed to further investigate the findings of these trials in patients with
KRAS WT tumors, using extended survival data and following an enhancement in the ascertainment rate of
KRAS and BRAF tumor mutation status.14 Pooled individual patient data from each study were analyzed for OS, PFS and best objective response rate (ORR) in patients evaluable for
KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests. In 845 patients with
KRAS WT tumors, adding cetuximab to chemotherapy led to a significant improvement in OS (HR= 0.81; p=0.006), PFS (HR=0.66; p<0.001), and ORR (OR=2.16; p<0.001).
BRAF mutations were detected in 70 of 800 (8.8%) evaluable tumors. No significant differences were found in outcome between the treatment groups in these patients. However, prognosis was worse in each treatment arm for patients with
BRAF tumor and OPUS studies confirms the consistency of the benefit obtained across all efficacy end points from adding cetuximab to first-line chemotherapy in patients with
KRAS WT mCRC. It further suggests that BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.
Single-Arm Studies (Cetuximab or Panitumumab)
In addition to the 3 randomized trials outlined here, a number of single-arm studies retrospectively evaluated
KRAS mutational status and treatment response in patients with metastatic CRC (Benvenuti, 2007; De Rook, 2008; Di Fiore, 2007; Khambata-Ford, 2007); Lievre, 2008).
Overall they showed similar nonresponse to anti-EGFR monoclonal antibodies in patients with MT
KRAS tumors. Two of these single-arm studies also reported a difference in PFS and OS (De Roock, 2008; Lievre, 2008).
NRAS Mutation Analysis
No RCT evidence is available to evaluate an effect of NRAS
mutation status alone on anti-EGFR therapies in CRC. Evidence is available on
RAS mutations (KRAS and NRAS) in tumor samples from patients enrolled in the PRIME RCT (Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) (Douillard, 2013).
In a prospective-retrospective analysis, a total of 108 of 641(17%) tumor specimens that did not harbor
KRAS mutations in exon 2 had mutations in other RAS exons, including
NRAS (exons 2 or 4) and KRAS (exons 3 and 4). Among the WT
KRAS exon in 2 patients (n=656), OS was significantly better with panitumumab added to FOLFOX4 (n=325, median 23.8 months) versus FOLFOX4 alone (n=331, median 19.4 months, p=0.03). Among patients with no
KRAS exon 2 mutation but with one type of RAS mutation, median OS with panitumumab-FOLFOX4 was shorter (n=51, 17.1 months) than with FOLFOX4 alone (n=57, 17.8 months) (p=0.01). These data suggest mutation in a
RAS gene exon other than KRAS exon 2 negatively affects anti-EGFR therapy. However, the investigators do not discriminate specific types of
RAS mutations, so it is not possible to relate NRAS to these results. Furthermore, the numbers of patients involved are very small, further limiting conclusions.
Tumor specimens (n=288 of 320) from a second RCT3
were analyzed using massively parallel multigene sequencing (next-generation sequencing) to investigate whether EGFR pathway mutations predicted response to monotherapy with panitumumab compared with BSC (Peeters, 2013).
This analysis showed that NRAS was mutated in 14 of 282 (5%) samples with available data. Among patients with WT
KRAS (codons 12, 13, 61) and WT NRAS (n=138), treatment with panitumumab was associated with improved PFS (HR=0.39; 95% CI, 0.27, 0.56; p<0.001) compared with BSC. Among those with WT
KRAS but mutated NRAS (n=11), treatment with panitumumab was no longer associated with longer PFS (HR=1.94; 95% CI, 0.44, 8.44; p=0.379). A treatment interaction analysis was suggestive but not significantly indicative of an interaction between the presence of mutated NRAS and poorer outcome (p==0.076). The authors suggest their data are consistent with a hypothesis that
NRAS mutations may limit the efficacy of anti-EGFR therapy. However, because the prevalence of
NRAS mutations is low, their true predictive or prognostic value is unclear.
A retrospective consortium analysis reported results of centrally performed high-throughput mass spectrometric mutation profiling of CRC specimens gathered from 11 centers in 7 European countries (De Roock, 2010).
Patients had been treated with panitumumab alone, cetuximab alone, or cetuximab plus chemotherapy. Among 747 of 773 samples with data,
KRAS was mutated in 299 (40%), including codons 12, 13, 61, and 146. By contrast,
NRAS mutations were identified in 17 of 644 (2.6%) samples with data, primarily in codon 61.
KRAS and NRAS mutations were mutually exclusive. Among WT KRAS
samples from patients treated with cetuximab plus chemotherapy, NRAS
mutation was associated with an ORR of 7.7% (1 of 13) compared with WT NRAS
(ORR=38%, p=0.013). However, there were no significant differences between NRAS
mutants and WT in median PFS (14 versus 26 weeks, p=0.055) or OS (38 versus 50 weeks, p=0.051). Similar to the results previously reported, the results for this analysis show a very low prevalence of
NRAS mutations and are inconclusive as to whether NRAS mutation is predictive of non-response to anti-EGFR therapy or is a prognostic indicator of poor outcomes of CRC.
The rarity of NRAS mutations reported in the studies previously outlined in this Policy is also shown in a study that used PCR and pyrosequencing (Qiagen, Valencia, CA) to assess tumor samples from individuals who developed CRC and were identified within the databases of 2 prospective cohort studies: the Nurses ‘Health Study and the Health Professionals Follow-Up Study (Irahara, 2010).
Among 225 CRC specimens, NRAS mutations were identified in 5 (2.2%). Because of the low frequency of
NRAS mutations, they were not associated with any clinical or pathologic features or with patient survival.
A recent meta-analysis (MA) evaluated the predictive value of
NRAS mutations on clinical outcomes of anti-EGFR therapy in CRC (Therkildsen, 2014).
The MA included data from 3 studies included in this policy (Douillard, 2013; Peeters, 2013; De Roock, 2010).
The investigators suggest that the pooled analyses showed a trend toward poor odds ratio (OR) based on 17 events, but significant effects on PFS (HR=2.30; 95% CI, 1.30 to 4.07) and OS (HR=1.85; 95% CI, 1.23 to 2.78) among patients with WT
KRAS. These results are limited by the small pool of mutations, permitting no conclusions as to whether
NRAS mutations have an effect on anti-EGFR therapy.
BRAF Mutation Analysis
A meta-analysis of BRAF mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic CRC was performed (Mao, 2011).
The primary end point of eligible studies was ORR, defined as the sum of complete and partial tumor response (CR, PR). A total of 11 studies (Cappuzzo, 2008; Di Nicolantonio, 2008; Freeman, 2008; Laurent-Puig, 2009; Loupakis, 2009; Molinari, 2009; Moroni, 2005; Perrone, 2009; Sartore-Bianchi, 2009; Tol, 2009) reported sample sizes ranging from 31 to 259 patients. All studies were conducted retrospectively (1 study was a nonconcurrent analysis of response in a population previously randomized (Tol, 2009). Anti-EGFR therapy was given as first-line treatment in one study and as second-line or greater in the other (Peeters, 2010). In 2 studies, the anti-EGFR monoclonal antibody was given as monotherapy, and in 9 studies, patients received various chemotherapies. Seven studies were performed in unselected patients (ie,
KRAS mutational status was unknown) totaling 546 patients, for whom 520 were assessable for tumor response. In the unselected population, a
BRAF mutation was detected in 8.8% of patients, and the ORR for patients with mutant
BRAF was 29.2% (14/48) and for WT BRAF was 33.5% (158/472; p=0.048). Four studies were performed in patients with WT
KRAS metastatic CRC. BRAF mutational status was performed on 376
KRAS WT tumors. BRAF mutation was detected in 10.6% (n=40) of primary tumors. Among the 376 analyzed, all patients were assessable for tumor response. ORR of patients with mutant
BRAF was 0% (0/40), whereas the ORR of patients with WT BRAF was 36.3% (122/336). Only 3 studies presented data on PFS and OS; and therefore, a pooled analysis was not performed. The authors conclude that although the meta-analysis provided evidence that BRAF mutation is associated with lack of response to anti-EGFR monoclonal antibodies in WT
KRAS metastatic CRC, the number of studies and number of patients included in the meta analysis were relatively small and that large studies are needed to confirm the results of the meta-analysis using homogenous metastatic CRC patients with assessors blinded to the clinical data.
Mao et al conducted a meta-analysis of BRAF mutation
V600E and resistance to anti-EGFR monoclonal antibodies in patients with metastatic CRC (Mao, 2011).
Eleven studies were included, with sample sizes ranging from 31 to 259; all of the studies were retrospective analyses. Seven of the studies included unselected patients, and 4 included only patients with WT
KRAS. The primary end point was ORR. In the 7 studies with unselected patients,
BRAF mutational status was performed successfully on 546 mCRC. BRAF
mutation was detected in 8.8% of primary tumors. The ORR of mCRC patients with mCRC with mutant
BRAF was 29.2% versus 33.5% in patients with WT BRAF. In the 4 studies that included patients with WT
KRAS, BRAF mutational status was performed successfully on 376
KRAS WT mCRC. BRAF mutations were detected in 10.6% of primary tumors. The ORR of patients with mutant
BRAF was 0.0%, whereas the ORR of patients with WT BRAF was 36.3%. The authors concluded that the results of their meta-analysis provided evidence that
BRAF mutation is associated with lack of response in WT KRAS mCRC treated with anti-EGFR monoclonal antibodies.
Phillips et al analyzed the data from 4 studies that reported tumor response and survival in patients with mCRC treated with anti-EGFR monoclonal antibodies as related to
BRAF mutational status (Phillips, 2010). Di Nicolantonio et al looked retrospectively at 113 patients with mCRC who had received cetuximab or panitumumab (Di Nicolantonio, 2008).
None of the BRAF-mutated tumors responded to treatment (0/11), whereas 32.4% (22/68) of the
BRAF WT did. Loupakis et al retrospectively assessed 87 patients receiving irinotecan and cetuximab (Loupakis, 2009).
Of the 87 patients in the study, BRAF was mutated in 13 cases, and none of them responded to chemotherapy, compared with 32% (24/74) with WT
BRAF who did. In the CAIRO2 study, a retrospective analysis of BRAF
mutations was performed in 516 available tumors from patients previously randomized to CB regimen or the same regimen plus cetuximab (CBC regimen) (Tol, 2009).
A BRAF mutation was found in 8.7% (n=45) of the tumors. Patients with a
BRAF mutation had a shorter median PFS and OS compared with WT BRAF
tumors in both treatment arms. The authors concluded that a BRAF mutation is a negative prognostic marker in patients with mCRC and that this effect, in contrast with
KRAS mutations, is not restricted to the outcome of cetuximab treatment. In the CRYSTAL trial, Van Cutsem et al randomized 1198 patients with untreated mCRC to FOLFIRI with or without cetuximab (Van Cutsem, 2009).
A recent analysis of BRAF mutations in this patient population and the influence on outcome was presented at the 2010 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (Peeters, 2014).
The authors showed that of the KRAS WT/BRAF-mutated patients, the OS for FOLFIRI plus cetuximab and FOLFIRI alone was 14.1 and 10.3 months, respectively (p=0.744). Although this was not statistically significant, it showed a trend toward improved OS, PFS, and response, suggesting that KRAS
WT/BRAF-mutant patients may benefit from anti-EGFR therapy. This unpublished analysis is the first to show a possible benefit of anti-EGFR therapy in patients with
BRAF-mutant tumors.
De Roock et al reported the effects of 4 mutations, including
BRAF, on the efficacy of cetuximab and chemotherapy in chemotherapy-refractory metastatic CRC in 773 primary tumor samples (De Roock, 2010). Tumor samples were from fresh frozen or FFPE tissue, and the mutation status was compared with retrospectively collected clinical outcomes including objective response, PFS, and OS. BRAF
mutations were found in 36 of 761 tumors (4.7%). In patients with WT KRAS, carriers of
BRAF mutations had a significantly lower response rate (8.3% or 2 of 24 patients) than
BRAF WT (38.0% or 124 of 326 patients; OR=0.15; 95% CI, 0.02 to 0.51; p=0.001). PFS for
BRAF-mutated versus WT was a median of 8 weeks versus 26 weeks, respectively (HR=3.74; 95% CI, 2.44 to 5.75; p<0.001) and OS median 26 weeks versus 54 weeks, respectively (HR=3.03; 95% CI, 1.98 to 4.63; p<0.001).
An updated analysis of the CRYSTAL trial reported increased follow-up time and an increased number of patients evaluable for tumor
KRAS status and considered the clinical significance of the tumor mutation status of
BRAF in the expanded population of patients with KRAS WT tumors (Van Cutsem, 2011).
The impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI was examined in the population of patients with
KRAS WT disease (n=625). No evidence was reported for an independent treatment interaction by tumor
BRAF mutation status. The authors concluded that BRAF mutation status was not predictive of treatment effects of cetuximab plus FOLFIRI but that
BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy end points compared with those whose tumors were WT.
At the latest review of this policy (December 2013), no new clinical trials were identified on the use of
BRAF mutation analysis to guide use of anti-EGFR therapy in patients with metastatic CRC.
Summary of Evidence
Clinical trial data show that patients with KRAS-mutated metastatic colorectal cancer (CRC) do not benefit from cetuximab or panitumumab, either as monotherapy or in combination with other treatment regimens. These data support the use of KRAS mutation analysis of tumor DNA before considering use of cetuximab or panitumumab in a treatment regimen. Identifying patients whose tumors express mutated
KRAS will avoid exposing patients to ineffective drugs and unnecessary drug toxicities and expedites the use of alternative therapies. Thus,
KRAS mutation analysis may be considered medically necessary to predict nonresponse to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of metastatic CRC.
Another member of the RAS family of protooncogenes,
NRAS, can harbor mutations in codons 12, 13 and 61 that constitutively activate the EGFR-mediated signaling pathway as do specific mutations in
KRAS. Thus, the NRAS oncogene also may have an impact on outcomes of anti-EGFR treatments for CRC. Compared with
KRAS, NRAS mutations are extremely rare. Although NRAS mutations account for approximately 15% of all
RAS mutations, they are found in perhaps 2% to 7% of all CRC. As a consequence of the low prevalence of
NRAS mutations in CRC, it is difficult to assess their effect on cancer behavior or therapy. Current clinical evidence is sparse and inconclusive as to whether
NRAS mutations are prognostic markers for poor outcomes similar to BRAF
(discussed next) or may be like KRAS mutations, acting as predictive markers for poor response to anti-EGFR therapy. Given these uncertainties,
NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies in the treatment of metastatic CRC.
The data for patients with metastatic CRC and a BRAF
mutation have shown consistently that a BRAF mutation is a poor prognostic marker, as it is associated with shorter progression-free survival and overall survival, regardless of treatment. Most of the data for a
BRAF mutation predicting response to anti-EGFR therapy are limited by small numbers of patients and conflicting results among studies. No evidence is available from a randomized trial designed specifically to assess the clinical utility of
BRAF mutation analysis in guiding management of patients with metastatic CRC. The large, randomized CRYSTAL trial, with nonconcurrent subgroup analyses of
BRAF mutations in patients previously randomized, reported the impact of
BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI in the population of patients with
KRAS wild-type (WT) disease. No evidence was reported for an independent treatment interaction by tumor
BRAF mutation status, and the trial showed that BRAF mutation status was not predictive of treatment effects of cetuximab plus folinic acid [leucovorin], 5-fluorouracil (5-FU), and irinotecan (FOLFIRI).
BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy end points compared with those whose tumors were
BRAF WT. Thus, BRAF mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies in the treatment of metastatic CRC.
National Cancer Institute PDQ® Clinical Trials Registry
A search of the National Cancer Institute PDQ® clinical trials registry on November 3, 2014, did not identify any phase 3 clinical trials in which
BRAF, NRAS, or KRAS mutation testing was used to guide management of CRC patients.
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) guidelines (http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf, v2.2015) on the treatment of colon cancer recommend that tumor KRAS and NRAS gene status testing be performed for all patients with metastatic colon cancer. Testing should be performed on archived specimens of primary tumor or a metastasis at the time of diagnosis of metastatic disease. The guidelines indicate that cetuximab and panitumumab are appropriate only for patients with a tumor that expresses the WT
KRAS and NRAS gene. The guidelines further state that if the tumor harbors the WT
KRAS and NRAS gene, the clinician should consider testing for
BRAF mutation status.
NCCN guidelines also state that patients with a BRAF V600E mutation appear to have a poorer prognosis. However, evidence is insufficient to guide the use of anti-EGFR therapy in the first-line setting with active chemotherapy based on
BRAF V600E mutation status. Limited evidence suggests lack of antitumor activity from anti-EGFR monoclonal antibodies in the presence of a
BRAF V600E mutation when used after a patient has progressed on first-line therapy.
An evidence review published in 2013 by the American College of Medical Genetics and Genomics,
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group,
states that evidence is insufficient to support the clinical validity or utility of testing CRC specimens for
NRAS mutations to guide patient management (EGAPP Working Group, 2013). In the same review, EGAPP found no guidelines on
NRAS testing from any other U.S. group. The EGAPP recommendations align with the Policy statements in this Policy document.
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
NRAS Mutations
Randomized Controlled Trials
RCTs have performed non-concurrent subgroup analyses of the efficacy of EGFR inhibitors in patients with wild-type versus mutated
RAS in metastatic CRC.
In 2015, Peeters and colleagues reported the influence of
RAS mutation status in a prospective/retrospective analysis of a randomized, multicenter phase 3 trial of panitumumab plus FOLFIRI versus FOLFIRI alone as second-line therapy in patients with metastatic CRC (Peeters, 2015).
If a tumor was wild-type KRAS exon 2, extended RAS
mutations beyond KRAS exon 2 was performed (KRAS exons 3 and 4;
NRAS exons 2, 3, and 4; BRAF exon 15). Primary end points were PFS and OS.
RAS mutations were obtained in 85% of the specimens from the original trial; 18% of wild-type
KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the HR for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type
RAS population than in the wild-type KRAS exon 2 population (PFS HR= 0.70; 95% CI, 0.54 to 0.91; p=0.007 vs PFS HR=0.73; 95% CI, 0.59 to 0.90; p=0.004; OS HR=0.81; 95% CI, 0.63 to 1.03; p=0.08 vs OS HR=0.85; 95% CI, 0.70 to 1.04; p=0.12). Patients with RAS mutations were unlikely to benefit from panitumumab. Among
RAS wild-type patients, the ORR was 41% in the panitumumab plus FOLFIRI group and 10% in the FOLFIRI group.
In 2015, van Cutsem and colleagues reported results of a prospective/retrospective extended
RAS mutation analysis in tumor samples from the randomized phase 3 CRYSTAL trial, which compared FOLFIRI to FOLFIRI plus cetuximab in wild-type
KRAS exon 2 patients (van Cutsem, 2015). Mutation status was available in 430 (64.6%) of 666 patients from the trial. A pooled analysis of
RAS mutations, other than KRAS exon 2, found a lack of benefit from the addition of cetuximab to FOLFIRI for median PFS (7.4 months vs 7.5 months; p=NS) and median OS (16.4 months vs 17.7 months; p=NS). Patients with tumors that had no RAS mutations experienced significant benefit in median PFS (9.9 months vs 8.4 months; p<0.05) and median OS (23.5 months vs 20 months; p<.05) with the addition of cetuximab to chemotherapy.
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) guidelines on the treatment of colon cancer strongly recommend that
KRAS and NRAS tumor gene status testing be performed for all patients with metastatic colon cancer (v.2.2016) (NCCN, 2016).
Testing should be performed on archived specimens of primary tumor or a metastasis at the time of diagnosis of metastatic disease. The guidelines indicate that cetuximab and panitumumab are appropriate only for patients with a tumor that expresses wild-type KRAS and NRAS genes. The guidelines further state if the tumor harbors wild-type
KRAS and NRAS mutations, the clinician should consider testing for
BRAF mutation status.
NCCN guidelines also state that patients with a BRAF
V600E mutation appear to have a poorer prognosis. However, evidence is insufficient to guide the use of anti-EGFR therapy in the first-line setting with active chemotherapy based on
BRAF V600E mutation status, and testing for BRAF is currently optional but not necessary part of decision-making on use of anti-EGFR agents. Limited evidence suggests lack of antitumor activity with anti-EGFR monoclonal antibodies in the presence of a BRAF V600E mutation when used after a patient has progressed on first-line therapy.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2018. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The FoundationACT ctDNA assay, the predecessor of FoundationOne Liquid, was compared to tissue biopsy using the FoundationOne assay in one manufacturer sponsored study (Li, 2019).
The researchers reported results on the subset of 51 patients with KRAS, NRAS, and BRAF variants. Positive percent agreement was 80% for all time points for short variants and increased to 90% for cases in which tissue and liquid biopsy were measured less than 270 days apart. Clinical validity studies were limited by unclear reporting of blinding, use of convenience rather than consecutive samples, and variation in the timing of sample collection. There are no published studies reporting clinical outcomes or clinical utility.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Evidence for the effectiveness of pembrolizumab in patients with MSI-H/dMMR metastatic CRC comes from the KEYNOTE-177 trial, reported by Andre et al (Andre, 2020).
The trial demonstrated a statistically significant improvement in PFS for patients randomized to pembrolizumab compared with chemotherapy (HR=0.60; 95% CI 0.45 to 0.80; p=.0002). At the time of the PFS analysis, the overall survival data were not mature (66% of the required number of events for the OS final analysis). The median follow-up time was 32.4 months (range: 24.0 to 48.3 months). The independent data monitoring committee recommended the continued masking of overall survival data until 190 deaths for the final analysis of overall survival have been observed or 12 months have elapsed since the last data review.
Hainsworth et al reported results of MyPathway, an open-label, phase 2, nonrandomized basket trial of targeted treatment in 251 patients with various advanced refractory solid tumors harboring genetic alterations (Hainsworth, 2018). The cohort included 37 patients with HER2-ampified/overexpressed metastatic CRC. Treatment with trastuzumab plus pertuzumab produced partial response in 14 patients (38%; 95% CI, 23% to 55%) and the median duration of response was 11 months (range1 to 16+ months; 95% CI, 2.8 months to not estimable).
In an open-label, phase 2 trial of trastuzumab deruxtecan, objective response, the primary outcome, was observed in 24 of 53 patients with HER2-positive metastatic CRC (45.3%; 95% CI 31.6 to 59·6) after a median follow-up of 27.1 weeks (interquartile range [IQR] 19.3 to 40.1) (Siena, 2021). One (2%) patient had a complete response, and 23 (43%) had a partial response. Median PFS was 6.9 months (4.1 to not evaluable). Median OS had not been reached at data cutoff (95% CI.74 months to not evaluable).
Preliminary evidence has suggested that HER2 amplification/overexpression may be predictive of nonresponse to EGFR-targeted therapy (Sartore, 2019).
Marabelle et al reported the association of high TMB to response to pembrolizumab in patients with solid tumors enrolled in a prespecified exploratory analysis of the KEYNOTE-158 study (Marabelle, 2020). High TMB was defined as >10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the TMB-high group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the TMB-high group and was 33.1 months in the non-TMB-high group. Notably, TMB-high status was associated with improved response irrespective of programmed death-ligand 1 (PD-L1). Median PFS and OS did not differ between the high and non-high TMB groups. Objective responses were observed in 24 (35%; 95% CI 24 to 48) of 68 participants who had both TMB-high status and PD-L1-positive tumors (ie, PD-L1 combined positive score of
≥1) and in 6 (21%; 8 to 40) of 29 participants who had TMB-high status and PD-L1-negative tumors. Study eligible cancers were limited to anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar. Because no patients with colorectal cancer were included in these analyses, it is not possible to draw conclusions about the clinical validity and utility of TMB in this group of patients.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Evidence for the effectiveness of pembrolizumab in patients with MSI-H/dMMR metastatic CRC comes from the KEYNOTE-177 trial, reported by Andre et al (Andre, 2020). The trial demonstrated a statistically significant improvement in PFS for patients randomized to pembrolizumab compared with chemotherapy (HR 0.60; 95% confidence interval [CI], 0.45 to 0.80; p=.0002). Final results were reported by Diaz et al (Diaz, 2022). Median PFS was 16.5 months (95% CI, 5.4 to 38.1) with pembrolizumab versus 8.2 months (6.1 to 10.2) with chemotherapy (HR 0.59, 95% CI 0.45 to 0.79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group.
Preliminary evidence has suggested that HER2 amplification/overexpression may be predictive of nonresponse to EGFR-targeted therapy (Sartore-Bianchi, 2019; Huang, 2022).
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2025. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Bekaii-Saab et al 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 (Bekaii-Saab, 2023). 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 conducted a meta-analysis to systematically evaluate the efficacy and safety of HER2-targeted inhibitors for HER2-amplified mCRC (Gao, 2022). 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.
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 (NCCN, 2025). 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), the multicenter, phase II HERACLES trial (trastuzumab and lapatinib), the phase 2, multicenter DESTINY-CRC01 trial (trastuzumab + tucatinib), and the clinical studies discussed below (Meric-Bernstam, 2019; Sartoer-Bianchi, 2016; Sartore-Bianchi, 2020; Siena, 2021; Yoshino, 2023). 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 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 (Raghav, 2025). Patients with RAS/BRAF-WT mCRC after central confirmation of HER2 positivity (IHC 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio greater than 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 greater than or equal to 20/less than 20) as a predictive factor. Efficacy of TP versus CETIRI differed significantly by HER2 GCN (median PFS, GCN greater than or equal to 20 [9.9 v 2.9 months] and GCN less than 20 [3.0 v 4.2 months], respectively; p=.003). On TP, ORR was 34.6% (57.1% with GCN greater than or equal to 20 v 9.1% with GCN less than 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 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 (Raghav, 2024). 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 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 (Strickler, 2023). 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 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 (Gupta, 2022). 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.
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 (Chakravarty, 2022).
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.
Section 3: Testing for gene fusions and exon skipping variants
Section 4: Framework for decision making on panel tests with no approved disease-specific markers.
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2026. No new literature was identified that would prompt a change in the coverage statement.
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