Medical Policy: 02.04.63
Original Effective Date: September 2016
Reviewed: November 2020
Revised: November 2020
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Molecular (genetic) panel testing of tumor tissue (frequently referred to as tumor profiling) offers the potential to evaluate large numbers of genetic markers at a single time to identify treatments that target specific biological “pathways” defined at the molecular level. They may also identify variants and biomarkers to identify potential clinical trials for solid tumors and hematological malignancies. Targeted cancer treatment identifies genetic abnormalities that are present in the cancer of a specific individual and the use of drugs that target the specific genetic abnormality. The focus of this policy is on the “expanded” panel testing that includes a wide variety of genetic markers in cancer tumor tissue without regard for demonstrated benefits of a specific targeted treatment.
There were no published studies identified that evaluated the analytic validity of these panels. The panels are performed primarily by next-generation sequencing, which has a high analytic validity. Some panels supplement the next-generation sequencing with additional testing methods, such as polymerase chain reaction (PCR), for intronic regions that are included as components of the panel. PCR is generally considered to have an analytic validity of more than 95%.
The clinical validity of panels as a whole cannot be determined because of the many different mutations and the large number of potential cancers in which it can be used. Clinical validity would need to be reported for each specific mutation for a particular type of cancer. Because there are many hundreds of different mutations included in the panels and dozens of different cancer types, evaluation of the individual clinical validity for each pairing is beyond the scope of this review.
To demonstrate clinical utility, controlled trials are required in which a strategy of cancer mutation testing followed by targeted treatment based on mutation analysis is compared with standard treatment without mutation testing. Randomized trials will be necessary to control for selection bias in treatment decisions, because clinicians may select candidates for mutation testing based on clinical, demographic and other factors. Outcomes of these trials would be the morbidity and mortality associated with cancer and cancer treatment. Overall survival is most important; cancer-related survival and/or progression-free survival may be acceptable surrogates. Quality-of-life measurement may also be important if study design allows for treatments with different toxicities in the experimental and control groups. There are currently no published randomized controlled trials (RCTs) with this type of design.
The FoundationOne™ test (Foundation Medicine Inc., Cambridge, MA) is a targeted mutation panel intended for use with solid tumors. It analyzes 236 cancer-related genes and 47 introns from an additional 19 genes using next-generation sequencing technology. The test identifies a number of types of mutations, including base substitutions, duplications/deletions, copy number variations, and rearrangements. The test can be performed on a surgical biopsy or a needle biopsy of a solid tumor that contains at least 40 μm of tissue, 20% of which must be malignant material.
FoundationOne CDx™ is a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. The test is intended as a companion diagnostic to identify patients who may benefit from treatment with targeted therapies.
FoundationOne Heme test (Foundation Medicine Inc., Cambridge, MA) is a similar panel that is intended for use in hematologic malignancies. It analyzes 405 cancer-related genes and selected introns from an additional 31 genes. In addition, RNA sequencing of 265 genes is done to test for common rearrangements resulting from gene fusion.
OnkoMatch (GenPath Diagnostics) is a polymerase chain reaction (PCR)â€’based gene panel that detects 68 mutations (single nucleotide polymorphisms) in 14 oncogenes and tumor suppressor genes that are associated with solid tumors (AKT1, APC, BRAF, CTNNB1 [beta-catenin], EGFR, IDH1, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, PTEN, TP53). The product brochure (available on the manufacturer website) states that OnkoMatch is intended for use in patients with lung, breast, colon, gastrointestinal, pancreatic, head and neck, ovarian, or thyroid cancers, or melanoma. Test developers recommend its use “to support diagnostic and treatment decisions and to facilitate clinical trial enrollment.” GenPath also lists OnkoMatch Plus for Lung and OnkoMatch Plus for ALK-Negative Lung is part of the test catalog.
The GeneTrails Solid Tumor Panel (Knight Diagnostic Labs, Portland OR) consists of 37 genes that areknown to have mutations in solid tumors. Of the 37 mutations, 20 have known targetable treatmentsbased on the presence or absence of mutations, and 17 have mutations that might indicate eligibility forongoing clinical trials. According to the manufacturer, this test is intended toward patients with adenocarcinomas (colon, small intestine, stomach, esophagus), squamous cell carcinomas (lung, head, neck, esophagus, cervix), BRAF-negative melanomas, cholangiocarcinoma, and carcinomas of the endometrium, ovaries, salivary glands, urothelium, and adrenal cortices.
Caris Life Sciences (Irving, TX) offers tumor profiling services that allow analysis of up to 56 tumor associated genes. According to the manufacturer’s website, panels with specific genes are not listed, but customized panels are available according to the patients’ clinical information and cancer type. The panels use a variety of technologies, including NGS, immunohistochemistry, fluorescence in situ hybridization, Sanger sequencing, pyrosequencing, quantitative PCR, and fragmentation analysis.
SmartGenomics (PathGroup, Brentwood TN) offers testing of up to 62 cancer-associated genes using a combination of NGS, cytogenomic array and other technologies. It is intended for use in a wide variety of solid and hematologic tumors to identify targeted treatments and also to assess eligibility for clinical trials.
The Paradigm Cancer Diagnostic (PcDx) Panel (Paradigm, Ann Arbor, MI) is a NGS-based panel that evaluates more than 500 genetic “targets.” Targets include point mutations, deletions, CNVs, fusions, mRNA expression, and protein expression. The test is intended for patients with a wide variety of cancers refractory to standard care.
The Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) consists of 341 cancer associated genes. It is a hybridization capture-based NGS assay that detects mutations, CNVs, and structural rearrangements. This test offers paired analysis of tumor tissue with matched normal tissue to determine whether mutations are truly somatic cancer mutations.
A number of other targeted panels appear to be primarily marketed to researchers. Some of these are listed next:
OmniSeq Target™ is a multi-analyte test platform developed by the Center for Personalized Medicine at Roswell Park Cancer Institute (RPCI) to determine the presence or absence of relevant tumor genomic alterations The OmniSeq Comprehensive panel test is a next-generation molecular sequencing assay that tests tumor DNA and RNA, identifying somatic variants in 144 genes said to guide cancer therapeutic management.
The GPS Cancer™ test is a commercially available proteogenomic test intended for patients with cancer. The test includes whole genome sequencing (20,000 genes, 3 billion base pairs), whole transcriptome (RNA) sequencing, and quantitative proteomics by mass spectrometry. The test is intended to inform personalized treatment decisions for cancer, and treatment options are listed when available, although treatment recommendations are not made. Treatment options may include Food and Drug Administration approved targeted drugs with potential for clinical benefit, active clinical trials of drugs with potential for clinical benefit, and/or available drugs to which the cancer may be resistant.
No published literature was identified on the clinical validity of the GPS Cancer test. In addition, search of selected websites did not identify any data on clinical validity of the test. The general published literature on the clinical validity of proteogenomics includes the following types of studies: proteomic biomarkers as prognostic markers, molecular characterization, and monitoring quantitative protein levels.
The GeneTrails Solid Tumor Panel (Knight Diagnostic Labs, Portland OR) consists of 37 genes that are known to have mutations in solid tumors. Of the 37 mutations, 20 have known targetable treatments based on the presence or absence of mutations, and 17 have mutations that might indicate eligibility for ongoing clinical trials. According to the manufacturer, this test is intended toward patients with adenocarcinomas (colon, small intestine, stomach, esophagus), squamous cell carcinomas (lung, head and neck, esophagus, cervix), BRAF-negative melanomas, cholangiocarcinoma, and carcinomas of the endometrium, ovaries, salivary glands, urothelium, and adrenal cortices.
The DarwinOncoTarget™ and DarwinOncoTreat™ tests analyze whole transcriptome sequencing (RNASeq) of a patient-derived tumor sample to identify aberrantly activated proteins for which a clinically relevant targeted inhibitor already exists and to match tumor-specific dependencies with clinically-relevant drugs.
The National Society of Genetic Counselors (NSGC) endorses the use of multigene panel tests when clinically warranted and appropriately applied. These tests can provide a comprehensive and efficient route to identifying the genetic causes of disease. Before ordering a multi-gene panel test, providers should thoroughly evaluate the analytic and clinical validity of the test, as well as its clinical utility. Additional factors to consider include, but are not limited to: clinical and family history information, gene content of the panel, limitations of the sequencing and informatics technologies, and variant interpretation and reporting practices.
Panels magnify the complexities of genetic testing and underscore the value of experts, such as genetic counselors, who can educate stakeholders about appropriate utilization of the technology to mitigate risks of patient harm and unnecessary costs to the healthcare system. NSGC supports straightforward and transparent pricing so that patients, providers, laboratories, and health plans can easily weigh the value of genetic testing in light of its cost.
NCCN guidelines do not contain recommendations for the general strategy of testing a tumor for a wide range of mutations. The guidelines do contain recommendations for specific genetic testing for individual cancers, based on situations where there is a known mutation-drug combination that has demonstrated benefits for that specific tumor type.
Some examples of recommendations for testing of common solid tumors are listed below:
The clinical validity of the panels as a whole cannot be determined because of the many different mutations and the large number of potential cancers for which they can be used. Clinical validity would need to be reported for each specific mutation for a particular type of cancer. Because there are hundreds of different mutations included in the panels and dozens of different cancer types, evaluation of the individual clinical validity for each pairing is beyond the scope of this review. A major concern with clinical validity is differentiating mutations that drive cancer growth from genetic variants that are not clinically important. It is expected that variants of uncertain significance will be very frequent with use of panels that include several hundred markers.
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.
The FDA has approved more than 50 companion diagnostic devices to detect mutations in 12 different genes for the targeted treatment of cancer. Methodologies include immunohistochemistry, real-time or multiplex PCR, FISH, and next generation sequencing.
The FDA has also approved additional nucleic acid based tests for cancer, not specifically as companion diagnostics. The U.S. Food and Drug Administration (FDA) currently do not require approval for any expanded genetic panels tests. Because of the large number of mutations contained in expanded panels, it is not possible to determine clinical validity for the panels as a whole.
On June 22, 2017 the FDA approved the Oncomine™ Dx Target Test (Thermo Fisher Scientific) as a next generation sequencing (NGS) test to detect multiple gene mutations for lung cancer in a single test from a single tissue specimen. This test detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations in tumor tissue of patients with NSCLC. This test can be used to select patients with NSCLC with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib.
On June 30, 2017 the FDA approved the Praxis Extended RAS Panel as a qualitative in vitro diagnostic test using targeted high throughput parallel sequencing for the detection of 56 specific mutations in RAS genes [KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4)] in DNA extracted from formalin-fixed, paraffin-embedded (FFPE) colorectal cancer (CRC) tissue samples. The Praxis™ Extended RAS Panel is indicated to aid in the identification of patients with colorectal cancer for treatment with Vectibix® (panitumumab) based on a no mutation detected test result. The test is intended to be used on the Illumina MiSeqDx® instrument.
In November 2017 the FDA approved the marketing of the MSK-IMPACT assay as a qualitative in vitro diagnostic test that uses targeted next generation sequencing of formalin-fixed paraffin-embedded tumor tissue matched with normal specimens from patients with solid malignant neoplasms to detect tumor gene alterations in a broad multi gene panel. The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product. MSK-IMPACT is a single-site assay performed at Memorial Sloan Kettering Cancer Center.
On November 30, 2017 the FDA approved FoundationOne CDx™ (F1CDx) as a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. The test is intended as a companion diagnostic to identify patients who may benefit from treatment with the targeted therapies in accordance with the approved therapeutic product labeling. Additionally, F1CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms. The F1CDx assay is a single-site assay performed at Foundation Medicine, Inc.
See related medical policies:
This policy does not apply to testing in non-small cell lung cancer, see appropriate related medical policy for information regarding panel testing for this oncologic indication.
Molecular panel testing of cancers to identify targeted therapy is considered investigational for all indications.
Tests available are including but not limited to the following:
Although the analytic validity of these panels is likely to be high when next generation sequencing is used, the clinical validity of the individual mutations for particular types of cancer is not easily obtained from the available published literature. The large number of mutations and many different types of cancer preclude determination of clinical validity for the panels as a whole. Only a handful of clinical genes have impactful meaning at this time, panel testing as described above does not result in each gene having impactful meaning for treatment. The change in clinical management, or the clinical utility, with these genetic panel test results is unproven. The clinical utility has not been substantiated in the medical literature to change net health outcomes.
Proteogenomic testing in multigene panels of patients with cancer (including, but not limited to the GPS Cancer test) is considered investigational for all indications.
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