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| Genetic Test: Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB) | |
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| Description: |
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]-mitogen activated protein kinase [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 CTCs. 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.
BRAF testing is also used for indications outside the scope of this policy (e.g., to select individuals for targeted treatment with BRAF or MEK inhibitors); refer to the following related policies:
2011061 Genetic Test: Melanoma and Glioma, Testing to Predict Response to Targeted Therapy
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Policy/ Coverage: |
Effective June 1, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
BRAF V600 variant testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy 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 when the following criteria are met:
Member receives a “recommended” determination from InterQual® criteria review for BRAF V600 variant testing of tumor tissue based on diagnosis and requested service.
Mismatch repair/microsatellite instability (MMR/MSI) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy 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 when the following criteria are met:
Member receives a “recommended” determination from InterQual® criteria review for MMR/MSI testing of tumor based on diagnosis and requested service.
Programmed cell death ligand protein-1 (PD-L1) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy 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 when the following criteria are met:
Member receives a “recommended” determination from InterQual® criteria review for PD-L1 testing based on diagnosis and requested service.
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
Analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations 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, analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations 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.
Mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations 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, mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations 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.
PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations 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, PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations 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.
Tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations 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, tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations 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.
Click the following link to view the InterQual® criteria:
Effective June 2024 to May 31, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
BRAF V600 variant testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy 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 in the following circumstances:
AND
Mismatch repair/microsatellite instability (MMR/MSI) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy 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 in the following circumstances:
AND
Programmed cell death ligand protein-1 (PD-L1) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy 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 in the following circumstances:
AND
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations 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, analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations 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.
Mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations 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, mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations 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.
PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations 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, PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations 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.
Tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations 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, tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations 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.
Effective September 15, 2023 – May 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
BRAF V600 variant testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
AND
Mismatch repair/microsatellite instability (MMR/MSI) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
AND
Programmed cell death ligand protein-1 (PD-L1) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
AND
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations 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 testing to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.in all other situations.
For members with contracts without primary coverage criteria, mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.in all other situations.
For members with contracts without primary coverage criteria, PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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This evidence review was created in April 2023 with a search of the PubMed database. The most recent literature update was performed through March 26, 2023.
Somatic Testing for the BRAF V600E Variant to Guide Immune Checkpoint Inhibitor Therapy
Gutzmer et al reported primary results from IMspire150, a phase 3, double-blind, randomized controlled trial (RCT) of atezolizumab, vemurafenib, and cobimetinib (n=256) compared to placebo, vemurafenib, and cobimetinib (n=258) as first-line treatment for unresectable advanced BRAF V600-positive melanoma (Gutzmer, 2020). The primary endpoint was investigator-assessed PFS. The median follow-up in the overall study population was 18.9 months. At data cut-off, 327 patients had progressive disease by investigator assessment or had died, including 148 (58%) patients in the atezolizumab group and 179 (69%) in the control group. The atezolizumab with vemurafenib and cobimetinib group experienced a median PFS per investigator assessment of 15.1 months (95% confidence interval [CI], 0.63 to 0.97) compared to 10.6 months (95% CI, 9.3 to 12.7) in the control group (hazard ratio [HR], 0.78; 95% CI, 0.63 to 0 97; p=.025).
Based on clinical trial results, testing for the
BRAF V600E variant in individuals with unresectable or metastatic melanoma for determining treatment with atezolizumab in combination with cobimetinib and vemurafenib has received FDA approval and an NCCN recommendation.
Microsatellite Instability High/Mismatch Repair Deficient Testing to Guide Immune Checkpoint Inhibitor Therapy
Evidence for the effectiveness of pembrolizumab in patients with MSI-high/MMR-deficient (MSI-H/dMMR) metastatic colorectal cancer (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). 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 of 153 (22%) patients in the pembrolizumab group versus 95 of 143 (66%) patients in the chemotherapy group.
The FDA approval for pembrolizumab in advanced endometrial cancer that is MMR proficient was based on the KEYNOTE-775 phase 3 trial, reported by Makker et al (Makker, 2022).
The FDA approval for dostarlimab for dMMR recurrent or advanced endometrial cancer was based on the nonrandomized, phase 1, GARNET trial (NCT02715284, N=104), reported by Oaknin et al (Oaknin, 2020). At a median follow-up of 11.2 months, the confirmed objective response rate was 42%; 13% of patients had a confirmed complete response, and 30% of patients had a confirmed partial response.
Two additional phase 3 RCTs of immune checkpoint inhibitor therapy for endometrial cancer indications that do not yet have FDA approval were published in March 2023 and are discussed below.
Mirza et al reported on a trial of dostarlimab plus carboplatin-paclitaxel among patients with primary advanced or recurrent endometrial cancer (Mirza, 2023). Of the 494 patients who underwent randomization, 118 (23.9%) had dMMR, MSI-H tumors. In the dMMR, MSI-H population, estimated PFS at 24 months was 61.4% (95% CI, 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (HR for progression or death, 0.28; 95% CI, 0.16 to 0.50; p<.001). In the overall population, PFS at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (HR, 0.64; 95% CI, 0.51 to 0.80; p<.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (HR for death, 0.64; 95% CI, 0.46 to 0.87).
Eskander et al reported on a phase 3 RCT of the addition of pembrolizumab to standard chemotherapy in individuals with advanced or recurrent endometrial cancer (Eskander, 2023). Participants were stratified into 2 cohorts according to whether they had dMMR or mismatch repair-proficient (pMMR) disease. In the 12-month analysis, PFS in the dMMR cohort was 74% in the pembrolizumab group and 38% in the placebo group (HR for progression or death, 0.30; 95% CI 0.19 to 0.48; p<.001). In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (HR 0.54; 95% CI, 0.41 to 0.71; p<.001).
The FDA approval of pembrolizumab in individuals with dMMR or MSI-H solid tumors was supported by the phase 2 KEYNOTE-158 study, reported by Marabelle et al (Marabelle, 2020). The trial included a total of 233 previously treated participants with MSI-H solid tumors. The objective response rate (ORR) was 34.3% (95% CI, 28.3 to 40.8). Median PFS was 4.1 months (95% CI, 2.4 to 4.9 months) and median OS was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%).
Based on clinical trial data, MSI/MMR testing has received FDA approval and NCCN recommendations to select immune checkpoint inhibitor therapy in individuals with advanced or metastatic CRC, individuals with advanced endometrial carcinoma, and individuals with unresectable or metastatic solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.
Programmed Cell Death Ligand Protein-1 Testing to Guide Immune Checkpoint Inhibitor Therapy
In RCTs, individuals with high PD-L1 expression had longer PFS and fewer adverse events when treated with anti-PD-L1 monoclonal antibodies than with platinum chemotherapy. In the KEYNOTE trial, first-line treatment with nivolumab plus ipilimumab resulted in a longer duration of OS than did chemotherapy in patients with non-small cell lung cancer (NSCLC), independent of the PD-L1 expression level.
The EMPOWER-Lung 1 trial (NCT03088540) was a multicenter, open-label trial that randomized 710 patients 1:1 to receive either cemiplimab-rwlc or platinum-based chemotherapy (Sezer, 2021). Median OS was 22.1 months (95% CI, 17.7 to not estimable) in the cemiplimab-rwlc arm compared to 14.3 months (95% CI, 11.7 to 19.2) in the chemotherapy arm (HR, 0.68; 95% CI, 0.53 to 0.87; p=.0022). Median PFS was 6.2 months with cemiplimab-rwlc versus 5.6 months with chemotherapy (HR, 0.59; 95% CI, 0.49 to 0.72; p<.0001). Corresponding ORRs were 37% (95% CI, 32 to 42) versus 21% (95% CI, 17 to 25), respectively. The most common adverse events were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough.
Herbst et al published results of a phase 3, open label RCT of atezolizumab compared to platinum-based chemotherapy in 572 patients with NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells (NCT02409342) (Herbst, 2020). In the subgroup of patients with tumors who had the highest expression of PD-L1 (205 patients), the median OS was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; HR for death, 0.59; p=.01). Atezolizumab treatment resulted in significantly longer OS than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. Grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the atezolizumab group and the chemotherapy group, respectively.
Reck et al published results of the KEYNOTE-024 Trial (NCT02142738), which compared pembrolizumab to platinum-based chemotherapy in 305 patients with NSCLC and PD-L1 expression on at least 50% of tumor cells (Reck, 2016). At a median follow-up of 11.2 months, PFS was longer with pembrolizumab compared with chemotherapy (median PFS, 10.3 vs. 6 months; HR, 0.50; 95% CI, 0.37 to 0.68). The median duration of response was not reached in the pembrolizumab group and was 6.3 months in the chemotherapy group.
In the CHECKMATE-227 trial (NCT02477826) reported by Hellmann et al, among the patients with a PD-L1 expression level of 1% or more, the median duration of OS was 17.1 months (95% CI, 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (p=.007), with 2-year OS rates of 40.0% and 32.8%, respectively (Hellmann, 2019). The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of OS than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level.
The FDA approval of pembrolizumab for head and neck squamous cell carcinoma was based on the KEYNOTE-048 trial of pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy (Burtness, 2019).
The FDA approval of pembrolizumab monotherapy for individuals with esophageal cancer of squamous cell etiology that express PD-L1 was based on the placebo-controlled, phase 3 KEYNOTE-590 trial (Sun, 2021).
The FDA approval of pembrolizumab for individuals with persistent, recurrent, or metastatic cervical cancer was based on the phase 3 KEYNOTE-826 trial (Colombo, 2021).
The efficacy of pembrolizumab plus chemotherapy compared to placebo plus chemotherapy for previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (N=847) was evaluated in the KEYNOTE-355 study. Dual primary efficacy endpoints were PFS and overall survival in patients with PD-L1 combined positive score of at least 1. Interim study results were published in 2020, and final results were published in 2022 (Cortes, 2020; Cortes, 2022). This study formed the basis of pembrolizumab accelerated approval in patients with unresectable or metastatic triple-negative breast cancer and PD-L1 combined positive score (CPS) of at least 10. Two nonrandomized trials of pembrolizumab for patients with PD-L1 positive triple negative breast cancer reported objective response rates of 21.4% (95% CI, 13.9 to 31.4) and 18.5% (95% CI, 6.3 to 38.1) (Adams, 2019; Nanda, 2016).
In December 2022, Genentech voluntarily withdrew its accelerated approval for atezolizumab for the treatment of urothelial carcinoma after its required follow-up trial did not demonstrate improved OS for atezolizumab plus chemotherapy compared with chemotherapy alone (Medscape Medical News, 2022).
Based on clinical trial data, PD-L1 testing has received FDA approval and NCCN recommendations to select immune checkpoint inhibitor therapy in individuals with metastatic NSCLC; individuals with metastatic or unresectable, recurrent head and neck squamous cell carcinomas; individuals with locally advanced or metastatic esophageal or gastroesophageal junction carcinoma; individuals with persistent, recurrent, or metastatic cervical cancer; and individuals with locally recurrent unresectable or metastatic triple negative breast cancer.
Tumor Mutational Burden Testing to Guide Immune Checkpoint Inhibitor Therapy
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 more than 10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the tissue TMB (tTMB)-high group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the tTMB-high group and was 33.1 months in the non-tTMB-high group. Notably, TMB-high status was associated with improved response irrespective of 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 tTMB-high status and PD-L1-positive tumors (i.e., PD-L1 combined positive score of
≥1) and in 6 (21%; 95% CI, 8 to 40) of 29 participants who had tTMB-high status and PD-L1-negative tumors. The KEYNOTE-158 nonrandomized phase 2 trial examined pembrolizumab; objective responses were observed in 35% of participants who had both TMB-high status and PD-L1-positive tumors and in 21% of participants who had TMB-high status and PD-L1-negative tumors. High TMB status was associated with improved response irrespective of PD-L1 status. Median OS and PFS were not significantly different between TMB groups.
In a prespecified subgroup analysis of a nonrandomized trial of pembrolizumab in individuals with various solid tumors, objective responses were observed in 24 (35%; 95% CI, 24 to 48) of 68 participants who had both tTMB-high status and PD-L1-positive tumors and in 6 (21%; 95% CI, 8 to 40) of 29 participants who had tTMB-high status and PD-L1-negative tumors. High TMB status was associated with improved response irrespective of PD-L1 status. Median OS and progression-free survival were not significantly different between TMB groups. In exploratory analyses, retrospective observational studies have reported an association between higher TMB and longer PFS and OS in patients receiving immunotherapy.
American Society of Clinical Oncology
Solid Tumors
In 2022, the American Society of Clinical Oncology (ASCO) published a provisional clinical opinion (PCO) on the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors (Chakravarty, 2022). The opinion notes the following:
PCO 1.1. Genomic testing should be performed for patients with metastatic or advanced solid tumors with adequate performance status in the following 2 clinical scenarios:
PCO 1.2.1. For patients with metastatic or advanced solid tumors, genomic testing using multigene genomic sequencing is preferred whenever patients are eligible for a genomic biomarker-linked therapy that a regulatory agency has approved (strength of recommendation: moderate).
PCO 1.2.2. Multigene panel-based genomic testing should be used whenever more than one genomic biomarker is linked to a regulatory agency-approved therapy (strength of recommendation: strong).
PCO 2.1. Mismatch repair deficiency (dMMR) status should be evaluated on patients with metastatic or advanced solid tumors who are candidates for immunotherapy. There are multiple approaches, including using large multigene panel-based testing to assess microsatellite instability (MSI). Consider the prevalence of dMMR and/or MSI-high (MSI-H) status in individual tumor types when making this decision (strength of recommendation: strong).
PCO 2.2. When tumor mutational burden (TMB) may influence the decision to use immunotherapy, testing should be performed with either large multigene panels with validated TMB testing or whole-exome analysis (strength of recommendation: strong).
PCO 4.1. Genomic testing should be considered to determine candidacy for tumor-agnostic therapies in patients with metastatic or advanced solid tumors without approved genomic biomarker–linked therapies (strength of recommendation: moderate).
Head and Neck Cancers
In 2023, the ASCO released a guideline on immunotherapy and biomarker testing in recurrent and metastatic head and neck cancers (Yilmaz, 2023). The guideline included a recommendation for programmed cell death ligand protein-1 (PD-L1) testing for individuals with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), and a consideration for TMB testing for individuals with recurrent or metastatic disease when the PD-L1 combined positive score is not available or in individuals with rare tumors.
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) cancer-specific guidelines provide recommendations for biomarkers that should be tested to guide decisions about immune checkpoint inhibitor therapy and recommend testing techniques. Guidelines are updated frequently; refer to the source documents for current recommendations. The following NCCN guidelines were used to inform this evidence opinion:
Ongoing and Unpublished Clinical Trials
Some currently ongoing trials that might influence this review are listed below:
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024. 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 April 2025. No new literature was identified that would prompt a change in the coverage statement.
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2026. No new literature was identified that would prompt a change in the coverage statement.
Additional 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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Adams S, Loi S, Toppmeyer D, et al.(2019) Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol. Mar 01 2019; 30(3): 405-411. PMID 30475947
Albanell J, Elvin JA, Suh J, et al.(2016) BRAF Genetic Alterations in Breast Cancer. Ann Oncol. October 1 2016; 27(Supp 6): v170. André T, Shiu KK, Kim TW, et al.(2020) Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. Dec 03 2020; 383(23): 2207-2218. PMID 33264544 Bonneville R, Krook MA, Chen HZ, et al.(2020) Detection of Microsatellite Instability Biomarkers via Next-Generation Sequencing. Methods Mol Biol. 2020; 2055: 119-132. PMID 31502149 Burtness B, Harrington KJ, Greil R, et al.(2019) Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. Nov 23 2019; 394(10212): 1915-1928. PMID 31679945 Chakravarty D, Johnson A, Sklar J, et al.(2022) Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol. Apr 10 2022; 40(11): 1231-1258. PMID 35175857 Colombo N, Dubot C, Lorusso D, et al.(2021) Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. Nov 11 2021; 385(20): 1856-1867. PMID 34534429 Cortes J, Cescon DW, Rugo HS, et al.(2020) Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. Dec 05 2020; 396(10265): 1817-1828. PMID 33278935 Cortes J, Rugo HS, Cescon DW, et al.(2022) Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. Jul 21 2022; 387(3): 217-226. PMID 35857659 Diaz LA, Shiu KK, Kim TW, et al.(2022) Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. May 2022; 23(5): 659-670. PMID 35427471 Dummer R, Goldinger SM, Turtschi CP, et al.(2014) Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. Feb 2014; 50(3): 611-21. PMID 24295639 Eskander RN, Sill MW, Beffa L, et al.(2023) Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med. Mar 27 2023. PMID 36972022 Gutzmer R, Stroyakovskiy D, Gogas H, et al.(2020) Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Jun 13 2020; 395(10240): 1835-1844. PMID 32534646 Hellmann MD, Paz-Ares L, Bernabe Caro R, et al.(2019) Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. Nov 21 2019; 381(21): 2020-2031. PMID 31562796 Herbst RS, Giaccone G, de Marinis F, et al.(2020) Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. Oct 01 2020; 383(14): 1328-1339. PMID 32997907 Long GV, Trefzer U, Davies MA, et al.(2012) Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. Nov 2012; 13(11): 1087-95. PMID 23051966 Makker V, Colombo N, Casado Herráez A, et al.(2022) Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. Feb 03 2022; 386(5): 437-448. PMID 35045221 Marabelle A, Fakih M, Lopez J, et al.(2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. Oct 2020; 21(10): 1353-1365. PMID 32919526 Marabelle A, Le DT, Ascierto PA, et al.(2020) Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. Jan 01 2020; 38(1): 1-10. PMID 31682550 Medscape Medical News. 2022.(2022) Atezolizumab (Tecentriq) Bladder Cancer Indication Withdrawn in US. https://www.medscape.com/viewarticle/984722#:~:text=Atezolizumab%20(Tecentriq)%20is%20no%20longer,and%20liver%20cancer%20and%20melanoma. Accessed April 6, 2023. Merino DM, McShane LM, Fabrizio D, et al.(2020) Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer. Mar 2020; 8(1). PMID 32217756 Mirza MR, Chase DM, Slomovitz BM, et al.(2023) Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. Nanda R, Chow LQ, Dees EC, et al.(2016) Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. Jul 20 2016; 34(21): 2460-7. PMID 27138582 National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. V.1.2023. v. Accessed April 6, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.4.2023. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed April 5, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. V.1.2023. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed April 4, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. V.1.2023. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed April 3, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers. V.2.2023. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed April 2, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. V.1.2023. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed April 1, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Melanoma: Cutaneous. V.2.2023. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed March 31, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. V.2.2023. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 30, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms. V.1.2023. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed March 29, 2023. Oaknin A, Tinker AV, Gilbert L, et al.(2020) Clinical Activity and Safety of the Anti-Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair-Deficient Endometrial Cancer: A Nonrandomized Phase 1 Clinical Trial. JAMA Oncol. Nov 01 2020; 6(11): 1766-1772. PMID 33001143 Reck M, Rodríguez-Abreu D, Robinson AG, et al.(2016) Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. Nov 10 2016; 375(19): 1823-1833. PMID 27718847 Sezer A, Kilickap S, Gümüs M, et al.(2021) Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. Feb 13 2021; 397(10274): 592-604. PMID 33581821 Sun JM, Shen L, Shah MA, et al.(2021) Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. Aug 28 2021; 398(10302): 759-771. PMID 34454674 Thunnissen E, van der Oord K, den Bakker M.(2014) Prognostic and predictive biomarkers in lung cancer. A Review. Virchows Arch. Mar 2014; 464(3): 347-58. PMID 24420742 U.S. Food & Drug Administration (FDA). 2023.(2023) Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed April 6, 2023. Accessed April 4, 2023. U.S. Food & Drug Administration (FDA). 2023.(2023) List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools Vultur A, Villanueva J, Herlyn M.(2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res. Apr 01 2011; 17(7): 1658-63. PMID 21447722 Wang L, Lu Q, Jiang K, et al.(2022) BRAF V600E Mutation in Triple-Negative Breast Cancer: A Case Report and Literature Review. Oncol Res Treat. 2022; 45(1-2): 54-61. PMID 34818649 Yilmaz E, Ismaila N, Bauman JE, et al.(2023) Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline. J Clin Oncol. Feb 10 2023; 41(5): 1132-1146. PMID 36521102 |
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