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| Genetic Test: Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Ovarian Cancer | |
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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]-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.
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Policy/ Coverage: |
Effective March 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Germline and somatic BRCA1/2 variant analysis for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies 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.
Homologous recombination deficiency (HRD) analysis of tumor tissue for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies 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.
Microsatellite instability/mismatch repair (MSI/MMR) testing of tumor tissue for individuals with unresectable or metastatic ovarian, fallopian tube, or primary peritoneal cancer to select treatment with dostarlimab 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.
NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue for individuals with recurrent ovarian cancer to select candidacy for entrectinib, larotrectinib, or repotrectinib 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.
Tumor mutational burden for individuals with recurrent/persistent ovarian cancer to determine candidacy for pembrolizumab 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.
RET gene fusion expression for individuals with recurrent/persistent ovarian cancer to determine candidacy for selpercatinib 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.
Folate receptor alpha 1 (FOLR1) protein expression to determine candidacy for mirvetuximab soravtansine-gynx in individuals with Fra-expressing tumors (greater than or equal to 75% positive tumor cells) 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.
BRAF V600E testing for individuals with recurrent/persistent ovarian cancer to determine candidacy for dabrafenib plus trametinib 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.
Liquid (ctDNA) based testing (Foundation One Liquid CDx [0239U]), to identify individuals who may benefit from the use of olaparib 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
ALL of the following criteria are met:
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
All other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies do 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, all other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All other uses of HRD testing of tumor tissue to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies do 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, all other uses of HRD testing of tumor tissue to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Other uses of MSI/MMR testing of ovarian, fallopian tube, or primary peritoneal tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies do 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, other uses of MSI/MMR testing of ovarian, fallopian tube, or primary peritoneal tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Tumor mutational burden testing to guide targeted therapy or immunotherapy in individuals with ovarian, fallopian tube, or primary peritoneal cancer for any indication 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 testing to guide targeted therapy or immunotherapy in individuals with ovarian, fallopian tube, or primary peritoneal cancer for any indication 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.
Other uses of NTRK1, NTRK2, and NTRK3 gene fusion analysis of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies do 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, other uses of NTRK1, NTRK2, and NTRK3 gene fusion analysis of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Other uses of RET gene fusion expression analysis of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies do 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, other uses of RET gene fusion expression analysis of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Other uses of Folate receptor alpha 1 (FOLR1) protein expression analysis of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies do 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, other uses of Folate receptor alpha 1 (FOLR1) protein expression analysis of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Other uses of BRAF V600E testing of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies do 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, other uses of BRAF V600E testing of ovarian tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Other uses of circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer do 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, other uses of circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness.
For members with contracts without Primary Coverage Criteria, simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal 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.
Effective prior to March 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Germline and somatic BRCA1/2 variant analysis for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Homologous recombination deficiency (HRD) analysis of tumor tissue for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Microsatellite instability/mismatch repair (MSI/MMR) testing of tumor tissue for individuals with unresectable or metastatic ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved therapies meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
All other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, all other uses of germline and somatic
BRCA1/2 variant analysis to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All other uses of HRD testing of tumor tissue to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, all other uses of HRD testing of tumor tissue to guide targeted therapy or immunotherapy for ovarian, fallopian tube, or primary peritoneal cancer not addressed in this or other policies are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Other uses of MSI/MMR testing of ovarian, fallopian tube, or primary peritoneal tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, other uses of MSI/MMR testing of ovarian, fallopian tube, or primary peritoneal tumor tissue to guide targeted therapy or immunotherapy not addressed in this or other policies are 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 ovarian, fallopian tube, or primary peritoneal cancer 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 testing to predict response to immunotherapy in individuals with ovarian, fallopian tube, or primary peritoneal 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 ovarian, fallopian tube, or primary peritoneal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with ovarian, fallopian tube, or primary peritoneal cancer 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 September 2022 with a search of the PubMed database. The most recent literature update was performed through August 15, 2022.
Biomarker Testing Using Tissue Biopsy to Select Targeted Treatment and Immunotherapy (BRCA1, BRCA2, Homologous Repair Deficiency, and Microsatellite Instability/Mismatch Repair)
Ovarian cancer treatment selection is informed by tumor type, grade, stage, patient performance status and preference, prior treatments, and the molecular characteristics of the tumor such as the presence of driver mutations. One purpose of biomarker testing of patients who have advanced cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment).
Clinical trials have evaluated the effectiveness of poly adenosine diphosphate-ribose polymerase (PARP) inhibitor drugs in individuals with ovarian cancer confirmed to have a
BRCA1/2 mutation. Summarized below are the pivotal trials that supported the
BRCA variant-related FDA-approved indications in ovarian cancer.
Niraparib
FDA approval for niraparib for treatment of ovarian cancer was based on the QUADRA phase 2 clinical trial (Moore, 2019). QUADRA evaluated the safety and activity of niraparib in adult patients with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with 3 or more previous chemotherapy regimens. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with HRD-positive tumors (including patients with BRCA and without
BRCA pathogenic variants) sensitive to their last platinum-based therapy who had received 3 or 4 previous anticancer therapy regimens (primary efficacy population). Thirteen of 47 patients (28%) in the primary efficacy population achieved an overall response according to RECIST (95% CI, 15.6% to 42.6%; p=.00053).
Olaparib
The effectiveness of olaparib as maintenance therapy in newly diagnosed advanced ovarian cancer was demonstrated in the phase 3 SOLO-1 RCT comparing olaparib to placebo in 391 individuals with newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a
BRCA mutation (Moore, 2018)). After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan-Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% CI, 0.23 to 0.41; p<.001).
Rucaparib
Several companion diagnostic tests have been FDA-approved to select individuals with
BRCA1/2 variants for treatment with rucaparib for ovarian cancer. Subsequently, however, the indication for rucaparib was changed to no longer require
BRCA testing for this indication (FDA, 2022). The indication change was based on results from the ATHENA trial (NCT03522246) which showed improvement in progression-free survival (PFS) regardless of
BRCA variant status (Monk, 2022).
Pembrolizumab
FDA approval of pembrolizumab was supported by the phase 2 KEYNOTE-158 study. The trial included a total of 233 previously treated participants with MSI-H/dMMR solid tumors, 15 of whom had ovarian cancer. In the full cohort, the overall response rate 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%) (Marabelle, 2020).
Clinical trials have demonstrated clinical benefit when testing was used to identify individuals for treatment with FDA-approved therapies.
Tumor Mutational Burden Testing to Guide Treatment for Ovarian Cancer
The purpose of tumor mutational burden (TMB) testing in patients who have ovarian cancer is to inform a decision on whether patients should receive immunotherapy versus another systemic therapy. The goal of immunotherapy is to preferentially kill malignant cells without significant damage to normal cells so that there is improved therapeutic efficacy along with decreased toxicity.
FoundationOne CDx is FDA-approved as a companion diagnostic for use with pembrolizumab in patients with TMB-high (≥ 10 mutations per megabase) solid tumors. Approval was based on results of the KEYNOTE-158 study that enrolled patients with solid tumors, but none of the patients evaluated had ovarian cancer.
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 (i.e., PD-L1 combined positive score of
≥1) and in 6 (21%; 95% CI, 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 ovarian 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.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. There is no direct evidence of clinical utility of TMB testing to guide ovarian cancer treatment.
Indirect evidence on clinical utility rests on clinical validity. Because the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
In a prespecified exploratory analysis of a nonrandomized trial of pembrolizumab in patients with various solid tumors, 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. A TMB-high status was associated with improved response irrespective of PD-L1 status. Median OS and PFS survival were not significantly different between TMB groups. Because no patients with ovarian, fallopian tube, or primary peritoneal 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. These results need to be confirmed in well-designed prospective studies enrolling patients in the relevant population.
Circulating Tumor DNA Testing (Liquid Biopsy) to Guide Treatment for Ovarian Cancer
One purpose of liquid biopsy testing of patients who have ovarian cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment).
True-positive liquid biopsy test results lead to the initiation of appropriate treatment (e.g., targeted therapy) without a tissue biopsy. False-positive liquid biopsy test results lead to the initiation of inappropriate therapy, which could shorten PFS.
In patients able to undergo a tissue biopsy, negative liquid biopsies reflex to tissue testing. In patients unable to undergo a tissue biopsy, a negative liquid biopsy result would not change empirical treatment. Therefore, health outcomes related to negative test results do not differ between liquid biopsy and tissue biopsy.
In October 2020, FoundationOne Liquid was FDA-approved as a companion diagnostic to identify individuals with
BRCA-mutated ovarian cancer to select patients for treatment with rucaparib (FDA, 2020). Approval was based on analysis of pre-treatment plasma samples from the phase 2 ARIEL2 study. Subsequently, in June 2022 the indication for rucaparib was changed to no longer require BRCA testing.
There are no other FDA -cleared or -approved liquid biopsy companion diagnostic tests for use in selecting targeted treatment or immunotherapy in individuals with ovarian cancer.
In 2018, the American Society of Clinical Oncology and College of American Pathologists jointly convened an expert panel to review the current evidence on the use of ctDNA assays (Merker, 2018). The literature review included a search for publications on the use of ctDNA assays for solid tumors in March 2017 and covers several different indications for the use of liquid biopsy. The search identified 1338 references to which an additional 31 references were supplied by the expert panel. Seventy-seven articles were selected for inclusion. Much of the literature on the use of ctDNA to guide treatment selection was for non-small-cell lung cancer, metastatic colorectal cancer, and breast cancer, The literature review did not specifically address ovarian cancer. The authors concluded that "There is little evidence of clinical validity and clinical utility to support the widespread use of ctDNA assays in most patients with advanced cancer, with the exception of those with demonstrated clinical utility or those with regulatory approval."
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. There is no direct evidence of clinical utility of ctDNA testing to guide ovarian cancer treatment.
The clinical utility of FoundationOne liquid was evaluated using plasma samples from participants in the ARIEL2 trial. However,
BRCA testing is no longer indicated prior to rucaparib treatment in ovarian cancer and so the relevance of this evidence is uncertain.
The clinical utility of FoundationOne liquid was evaluated using plasma samples from participants in the ARIEL2 trial. However,
BRCA testing is no longer indicated prior to rucaparib treatment in ovarian cancer and so the relevance of this evidence is uncertain. Clinical validity has not been demonstrated in multiple well-designed and conducted studies; therefore, a chain of indirect evidence to show clinical utility cannot be established.
American Society of Clinical Oncology
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). 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 status (dMMR) should be evaluated in 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-H status in individual tumor types when making this decision (strength of recommendation: strong).
PCO 2.2. When 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).
National Comprehensive Cancer Network
The current NCCN guidelines for ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) are version 4.2022 (NCCN, 2022). Guidelines are updated frequently; refer to the source for most current recommendations.
In the up-front setting, choice of somatic testing should, at a minimum, optimize identification of molecular alterations that can inform use of interventions that have demonstrated benefit in this setting, including BRCA1/2, loss of heterozygosity (LOH), or homologous recombination (HR) status in the absence of a germline BRCA mutation.
In the recurrence setting, tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit including, but not limited to, BRCA1/2, HR status, MSI, MMR, TMB, BRAF, and NTRK if prior testing did not include these markers.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in August 2022 did not identify any trials that would likely influence this review.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2022, the American Society of Clinical Oncology published updated recommendations on poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in the management of ovarian cancer (Tew, 2022). The recommendations included the following:
Newly Diagnosed Ovarian Cancer
"Recommendation 2.1. Patients with newly diagnosed stage III-IV EOC [epithelial ovarian cancer] who are in complete or partial response to first-line platinum-based chemotherapy should be offered PARP inhibitor maintenance therapy in high-grade serous or endometrioid ovarian cancer. For those with germline or somatic pathogenic or likely pathogenic variants in
BRCA1 or BRCA2 genes, options should include olaparib (300 mg orally every 12 hours for 2 years), niraparib (200-300 mg orally daily for 3 years) or rucaparib (600 mg twice a day for 2 years). Longer duration could be considered in selected individuals after discussion of risks. For those who are HRD [homologous recombination deficiency] positive, determined using FDA-approved companion diagnostic tests, rucaparib and niraparib are options. Niraparib or rucaparib may be offered for non-BRCA
mutated/HRD negative patients. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.)"
Recurrent Ovarian Cancer: Second-Line or Greater Maintenance and Treatment
"Recommendation 3.0. PARP inhibitor monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARP inhibitor and who have responded to platinum-based therapy regardless of BRCA mutation status; treatment is continued until progression of disease or toxicity despite dose reductions and best supportive care. Options include olaparib 300 mg every 12 hours, rucaparib 600 mg every 12 hours or niraparib 200-300 mg once daily. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.) Maintenance treatment with niraparib for patients without germline or somatic
BRCA mutation should weigh potential PFS benefit against possible OS decrement. (Type: Evidence-based, benefits outweigh harms; Evidence quality: Low; Strength of recommendation: Moderate.)"
"Recommendations 3.1/3.2. PARP inhibitor monotherapy should not be routinely offered to patients for the treatment of recurrent platinum sensitive EOC. (Type: Evidence-based, benefits outweigh harms; Evidence quality: Intermediate; Strength of recommendation: Moderate.) Evidence on PARP inhibitor use in this setting is evolving and data are continuing to emerge. Any decision to proceed with PARP inhibitor treatment in select populations (BRCA mutation, No prior PARP inhibitor use, Platinum Sensitive, Advanced Lines of Treatment) should be based on individualized patient and provider assessment of risks, benefits, and preferences."
"Recommendation 3.3. PARP inhibitor monotherapy is not recommended for treatment for patients with either
BRCA wild-type or platinum-resistant recurrent EOC. (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong.)"
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The current NCCN guidelines for ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) are version 3.2024 (NCCN, 2024). Guidelines are updated frequently; refer to the source for most current recommendations.
The guidelines include the following relevant recommendations on biomarker testing to guide targeted therapy in ovarian cancer:
Recommendations on the use of PARP inhibitors for ovarian cancer include the following:
Maintenance Therapy After Recurrence
First-Line Maintenance Therapy
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through September 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 June 2026. No new literature was identified that would prompt a change in the coverage statement.
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AstraZeneca.(2022) Dear Healthcare Professional (Lynparza). https://shorturl.at/hprEQ. Accessed September 3, 2023.
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