Medical Policy: 02.04.63
Original Effective Date: September 2016
Reviewed: September 2017
Revised: September 2017
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
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 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. 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 cancers without regard for demonstrated benefits of a specific targeted treatment.
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.
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 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 in its 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 Guardant360 panel (GuardantHealth, Redwood City, CA) analyzes 68 genes associated with solid tumors. It is intended to be used for a wide variety of solid tumors. This panel uses novel technology of analyzing cell-free DNA present in the circulating blood rather than analyzing a tumor sample. The manufacturer’s website refers to “digital sequencing” using information technology, but there is a lack of published studies that evaluate the analytic validity of this technique.
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:
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.
Note: This policy does not apply to the individual markers that have demonstrated efficacy in certain types of cancer. The National Comprehensive Cancer Network (NCCN) guidelines in 2011 reported the following markers demonstrated effectiveness in predicting treatment response to targeted therapies for specific cancers: Breast cancer (HER2, ERBB2), Colon cancer (KRAS and BRAF), Non-small-cell lung cancer (EGFR, ALK/ROS1), Metastatic melanoma (BRAF v600), Chronic myeloid leukemia (BRC-ABL) and Gastrointestinal stromal tumors (KIT).
The National Comprehensive Cancer Network (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.
Clinical practice guidelines state that while there is diagnostic benefit of gene expression profiling assays, a clinical benefit has not been demonstrated (category 2B). (NCCN, 2016).
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.
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. 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.
No published literature was identified on the clinical validity of the GPS Cancer test. In addition, search of studies did not identify any data on clinical validity of the test.
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Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc. They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.
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