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| Genetic Test: Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate 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 (Liquid Biopsy)
Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or circulating tumor cells. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA (ctDNA) 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 January 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Germline Testing
Germline BRCA1/2 variant analysis (e.g., Myriad BRACAnalysis CDx) for individuals with metastatic castrate-resistant prostate cancer (mCRPC) to select treatment with FDA-approved targeted therapies or immunotherapy 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.
Note: Germline testing is allowed once per lifetime.
Somatic Testing
Somatic testing using tissue biopsy for homologous recombination repair (HRR) gene alterations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) to select treatment for mCRPC with FDA-approved targeted therapies or immunotherapy 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 testing for microsatellite instability (MSI) or mismatch repair (MMR) to select treatment for unresectable or metastatic prostate cancer with FDA-approved targeted therapies or immunotherapy 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 Biopsy
BRCA1/2 and ATM variant analysis using ctDNA (liquid biopsy) (FoundationOne Liquid CDx, 0239U) for individuals with mCRPC to select treatment with FDA-approved targeted 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.
Liquid (ctDNA) (FoundationOne Liquid CDx, 0239U) based testing meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered for individuals with metastatic adenocarcinoma 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 BRCA1/2 variant analysis to guide prostate cancer 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, all other uses of germline BRCA1/2 variant analysis to guide prostate cancer 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.
All other uses of somatic testing for HRR gene alterations to guide prostate cancer 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, all other uses of somatic testing for HRR gene alterations to guide prostate cancer 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.
All other uses of tumor testing for MSI or MMR to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other polices 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 tumor testing for MSI or MMR to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other polices 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 biomarker testing with ctDNA (liquid biopsy) to guide prostate cancer 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, all other uses of biomarker testing with ctDNA (liquid biopsy) to guide prostate cancer 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 (TMB) testing to guide prostate cancer targeted therapy or immunotherapy 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 to guide prostate cancer targeted therapy or immunotherapy 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.
Simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with prostate cancer does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without Primary Coverage Criteria, simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with prostate 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 January 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Germline BRCA1/2 variant analysis for individuals with metastatic castrate-resistant prostate cancer (mCRPC) to select treatment with FDA-approved targeted therapies or immunotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Somatic testing using tissue biopsy for homologous recombination repair (HRR) gene alterations (BRCA1,
BRCA2, ATM, BARD1, BRIP1, CDK12,
CHEK1, CHEK2, FANCL, PALB2, RAD51B,
RAD51C, RAD51D, and RAD54L) to select treatment for mCRPC with FDA-approved targeted therapies or immunotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Tumor testing for microsatellite instability (MSI) or mismatch repair (MMR) to select treatment for unresectable or metastatic prostate cancer with FDA-approved targeted therapies or immunotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
BRCA1/2 and ATM variant analysis using ctDNA (liquid biopsy) for individuals with mCRPC to select treatment with FDA-approved targeted 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 BRCA1/2 variant analysis to guide prostate cancer 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, all other uses of germline
BRCA1/2 variant analysis to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other policies considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All other uses of somatic testing for HRR gene alterations to guide prostate cancer 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, all other uses of somatic testing for HRR gene alterations to guide prostate cancer 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.
All other uses of tumor testing for MSI or MMR to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other polices 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 tumor testing for MSI or MMR to guide prostate cancer targeted therapy or immunotherapy not addressed in this or other polices are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
All other uses of biomarker testing with ctDNA (liquid biopsy) to guide prostate cancer 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, all other uses of biomarker testing with ctDNA (liquid biopsy) to guide prostate cancer 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 (TMB) testing to guide prostate cancer targeted therapy or immunotherapy 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 to guide prostate cancer targeted therapy or immunotherapy 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 prostate 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 prostate 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
Prostate 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 prostate cancer confirmed to have a
BRCA1, BRCA2, or ATM alteration. Summarized below are the pivotal trials that supported the
BRCA variant-related FDA-approved indications in prostate cancer.
Olaparib
Hussain et al published results from the open-label, multicenter, phase 3 PROfound trial (NCT02987543), which randomized individuals with metastatic castration-resistant prostate cancer (mCRPC) and disease progression following prior treatment with a next-generation hormonal agent to treatment with olaparib 300 mg twice daily (n=256) or investigator's choice of enzalutamide or abiraterone acetate plus prednisone (n=131) (Hussain, 2020). Study participants were divided into 2 cohorts based on their HRR gene mutation status. Specifically, individuals with mutations in
BRCA1, BRCA2, or ATM were randomized to cohort A (n=245) and those with mutations in 12 other HRR pathway genes (BRIP1,
BARD1, CDK12, CHEK1, CHEK2, FANCL,
PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and
RAD54L) were randomized to cohort B (n=142). Participants with co-mutations were assigned to cohort A. The primary efficacy outcome was radiological progression-free survival (rPFS) in cohort A, which demonstrated a statistically significant improvement for olaparib compared to control with a median rPFS of 7.4 months versus 3.6 months (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.25 to 0.47; p <.0001). The median duration of OS in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (HR, 0.69; 95% CI, 0.50 to 0.97; p =.02). In cohort B, the median duration of OS was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months.
Rucaparib
Abida et al published results from the phase 2, multi-center, single-arm clinical trial of rucaparib in individuals with
BRCA-mutated mCRPC that supported its accelerated FDA approval in 2020 (TRITON2) (Abida, 2020). This trial enrolled 115 participants who were treated with rucaparib 600 mg twice daily. For the efficacy population, median treatment duration was 8.1 months and median follow-up was 17.1 months. The primary endpoint of objective response rate, which was rated by blinded, independent radiology review, was 43.5% (95% CI, 31.0% to 56.7%). Median rPFS duration was 9.0 months (95% CI, 8.3 to 13.5). Anemia was the most frequent grade 3 or higher adverse event (25.2%). A key limitation of this trial is its lack of a control group. Continued approval for this indication for rucaparib may be contingent upon verification of progression-free survival in the ongoing confirmatory TRITON3 trial (NCT02975934), which is a randomized, controlled phase 3 trial evaluating rucaparib 600 mg twice daily versus physician’s choice of treatment in patients with mCRPC and a deleterious germline or somatic
BRCA1, BRCA2, or ATM mutation.
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 solid tumors, 6 of whom had prostate cancer. In the full cohort, the ORR was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival (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 Metastatic Prostate Cancer
The purpose of tumor mutational burden (TMB) testing in individuals with advanced prostate 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 prostate 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%; 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 prostate 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.
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 prostate 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 with prostate cancer.
Biomarker Testing with Circulating Tumor DNA (Liquid Biopsy) to Guide Treatment in Prostate Cancer
One purpose of liquid biopsy testing of patients who have advanced prostate cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment). 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.
Olaparib
FoundationOne Liquid is an FDA-approved companion diagnostic to detect
BRCA1, BRCA2, or ATM alterations in mCRPC patients who may benefit from treatment with olaparib (FDA, 2020). Approval was based on a retrospective analysis of data from participants enrolled in cohort A of the PROfound trial (i.e., patients who had a BRCA1, BRCA2, or ATM tumor variant). The sponsor conducted a clinical bridging study to demonstrate the concordance between variant status by the clinical trial assay used for enrollment and the FoundationOne Liquid CDx, and the effectiveness of olaparib in patients identified with a variant by the liquid test. The point estimates of PPA and NPA between FoundationOne® Liquid CDx and the F1 LDT CTA assay and the corresponding 95% confidence intervals were: PPA, 79.9% (72.2% to 86.2%); NPA, 91.8% (87.0, 95.2). Estimated radiological PFS HR and the corresponding 95% confidence intervals were 0.33 [0.21, 0.53] for the FoundationOne Liquid CDx ATM/BRCA1/BRCA2 positive and F1 LDT CTA ATM/BRCA1/BRCA2 positive population, which were comparable with the observed radiological PFS hazard ratio and the corresponding 95% confidence intervals of 0.34 [0.25, 0.47] for the F1 LDT CTA
ATM/BRCA1/BRCA2 positive population.
Rucaparib
FoundationOne Liquid is an FDA-approved companion diagnostic to identify patients with
BRCA1/2 alterations eligible for rucaparib treatment in prostate cancer (FDA, 2020).,There are no FDA-approved tissue-based companion diagnostic alternatives for this indication. Approval was based on results of the TRITON2 clinical trial (NCT02952534). The ORR in the primary efficacy population was 46.3% (95% CI, 30.7% to 62.6%) in
BRCA-positive patients determined by FoundationOne Liquid CDx, which was comparable to the ORR of 43.5% (31.0% to 56.7%) in patients identified by the clinical trial assay (central plasma, central tissue, or local testing). Loehr et al reported confirmed ORR by enrollment assay in 62 evaluable participants with measurable disease and found overlapping confidence intervals for all 3 estimates (Loehr, 2021). Those enrolled by central tissue testing had an ORR of 55.0% (95% CI, 31.5% to 76.9%; 11/20), compared with 31.3% (95% CI, 11.0% to 58.7%; 5/16) in patients enrolled by central plasma test and 42.3% (95% CI, 23.4 to 63.1; 11/26) in patients enrolled by local test.
Clinical trials have evaluated the effectiveness of PARP inhibitor drugs in individuals with prostate cancer confirmed to have
BRCA1, BRCA2, or ATM alterations as determined by FoundationOne Liquid.
American Society of Clinical Oncology
In 2022, the American Society of Clinical Oncology (ASCO) 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 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-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).
National Comprehensive Cancer Network
Germline Testing
The current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer are version 4.2022 (NCCN, 2022). Guidelines are updated frequently; refer to the source for the most current recommendations.
The Principles of Genetics section (PROS-B) provides appropriate scenarios for germline genetic testing in individuals with a personal history of prostate cancer.
Germline testing is recommended in patients with a personal history of prostate cancer in the following scenarios related to the tumor: metastatic, regional (node-positive), very-high risk localized, high-risk localized prostate cancer.
Germline testing may be considered in patients with a personal history of prostate cancer in the following scenarios: intermediate-risk prostate cancer with intraductal/cribriform histology
Somatic Testing
Tumor testing for alterations in homologous recombination DNA repair genes, such as
BRCA1, BRCA2, ATM, PALB2, FANCA,
RAD51D, CHEK2, and CDK12, is recommended in patients with metastatic prostate cancer. This testing can be considered in patients with regional prostate cancer.
Tumor testing for microsatellite instability-high (MSI-H) or dMMR is recommended in patients with metastatic castration-resistant prostate cancer and may be considered in patients with regional or castration-naïve metastatic prostate cancer.
TMB testing may be considered in patients with metastatic castration-resistant prostate cancer.
Tumor Specimen and Assay Considerations
The panel strongly recommends a metastatic biopsy for histologic and molecular evaluation. When unsafe or unfeasible, plasma ctDNA assay is an option, preferably collected during biochemical (PSA) and/or radiographic progression in order to maximize diagnostic yield. Caution is needed when interpreting ctDNA-only evaluation due to potential interference from clonal hematopoiesis of indeterminate potential (CHIP), which can result in a false-positive biomarker signal.
DNA analysis for MSI and immunohistochemistry (IHC) for MMR are different assays measuring different biological effects caused by dMMR function. If MSI is used, testing using a next-generation sequencing (NGS) assay validated for prostate cancer is preferred.
The preferred method of selecting patients for rucaparib treatment is somatic analysis of
BRCA1 and BRCA2 using a ctDNA sample.
Post-Test Considerations
Post-test genetic counseling is recommended if pathogenic/likely pathogenic variant (mutation) identified in any gene that has clinical implications if also identified in germline (e.g.,
BRCA1, BRCA2, ATM, PALB2, CHEK2,
MLH1, MSH2, MSH6, PMS2). Post-test genetic counseling to assess for the possibility of Lynch syndrome is recommended if MSI-H or dMMR is found.
Ongoing and Unpublished Clinical Trials
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 2023, the American Urological Association and the Society of Urologic Oncology published amended guidelines on advanced prostate cancer (Lowrance, 2023). The guidelines included the following relevant recommendation (level of evidence) on the treatment of mCRPC:
The current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer are version 3.2023 (NCCN, 2023). Guidelines are updated frequently; refer to the source for the most current recommendations.
The guidelines include the following relevant recommendations:
Targeted Therapy
Germline Testing
The Principles of Genetics section (PROS-B) provides appropriate scenarios for germline genetic testing in individuals with a personal history of prostate cancer.
Germline testing is recommended in patients with a personal history of prostate cancer in the following scenarios related to the tumor: metastatic, regional (node-positive), very-high risk localized, high-risk localized prostate cancer.
Germline testing may be considered in patients with a personal history of prostate cancer in the following scenarios related to the tumor: intermediate-risk prostate cancer with intraductal/cribriform histology; or a prior personal history any of the following cancers: of exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, and small intestinal.
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.
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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| References: |
Abida W, Patnaik A, Campbell D, et al.(2020) Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol. Nov 10 2020; 38(32): 3763-3772. PMID 32795228
Agarwal N, Azad AA, Carles J, et al.(2023) Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. Jul 22 2023; 402(10398): 291-303. PMID 37285865 Bonneville R, Krook MA, Chen HZ, et al.(2022) Detection of Microsatellite Instability Biomarkers via Next-Generation Sequencing. Methods Mol Biol. 2020; 2055: 119-132. PMID 31502149 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 Chi KN, Rathkopf D, Smith MR, et al.(2023) Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. Jun 20 2023; 41(18): 3339-3351. PMID 36952634 Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Oya M, Shore N, Loredo E, Procopio G, et al for the PROpel Investigators.(2022) Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evid 2022;1(9). https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043. Accessed August 24, 2023 Desai AV, Robinson GW, Gauvain K, et al.(2022) Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. Oct 03 2022; 24(10): 1776-1789. PMID 35395680 Doebele RC, Drilon A, Paz-Ares L, et al.(2020) Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. Feb 2020; 21(2): 271-282. PMID 31838007 Drilon A, Siena S, Ou SI, et al.(2017) Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. Apr 2017; 7(4): 400-409. PMID 28183697 Fizazi K, Piulats JM, Reaume MN, et al.(2023) Rucaparib or Physician's Choice in Metastatic Prostate Cancer. N Engl J Med. Feb 23 2023; 388(8): 719-732. PMID 36795891 Food and Drug Administration (FDA).(2020) 2020. FoundationOne Liquid CDx. Summary of Safety and Effectiveness Data. PMA Number P200016. https://www.accessdata.fda.gov/cdrh_docs/pdf20/P200016B.pdf. Accessed August 26, 2022. Food and Drug Administration (FDA).(2020) FoundationOne Liquid CDx. Summary of Safety and Effectiveness Data. 2020. PMA Number P190032. https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190032B.pdf. Accessed August 27, 2022. Food and Drug Administration (FDA).(2022) 2022. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed August 28, 2022. Food and Drug Administration (FDA).(2022) 2022. 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. Accessed August 29, 2022. Food and Drug Administration (FDA).(2024) 2024. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed August 7, 2025. Food and Drug Administration (FDA).(2024) 2024. 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. Accessed August 7, 2025. Hong DS, DuBois SG, Kummar S, et al.(2020) Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. Apr 2020; 21(4): 531-540. PMID 32105622 Hussain M, Mateo J, Fizazi K, et al.(2020) Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. Dec 10 2020; 383(24): 2345-2357. PMID 32955174 Loehr A, Patnaik A, Campbell D, et al.(2021) Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study. Clin Cancer Res. Dec 15 2021; 27(24): 6677-6686. PMID 34598946 Lowrance W, Dreicer R, Jarrard DF, et al.(2023) Updates to Advanced Prostate Cancer: AUA/SUO Guideline (2023). J Urol. Jun 2023; 209(6): 1082-1090. PMID 37096583 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 Mateo J, Boysen G, Barbieri CE, et al.(2017) DNA Repair in Prostate Cancer: Biology and Clinical Implications. Eur Urol. Mar 2017; 71(3): 417-425. PMID 27590317 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 National Comprehensive Cancer Network (NCCN).(2022) Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2022. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed August 25, 2022. National Comprehensive Cancer Network (NCCN).(2023) Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 3.2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed August 25, 2023. National Comprehensive Cancer Network (NCCN).(2025) National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Prostate Cancer. Verson 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed August 7, 2025. Stewart MD, Merino Vega D, Arend RC, et al.(2022) Homologous Recombination Deficiency: Concepts, Definitions, and Assays. Oncologist. Mar 11 2022; 27(3): 167-174. PMID 35274707 TRK Fusion Cancer.(2025) TRK Fusion Cancer (Testing). https://trkcancer.com/testing. Accessed August 7, 2025. |
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| Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants. | |
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