Medical Policy: 02.04.63 

Original Effective Date: September 2016 

Reviewed: September 2018 

Revised: September 2018 

 

Benefit Application:

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.

 

Description:

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. 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.

 

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 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)‒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:

  • Illumina Inc. (San Diego, CA) offers several cancer panels. The TruSeq® Amplicon Panel analyzes 48 cancer-related genes by next-generation sequencing. The Illumina TruSight™ Tumor panel analyzes 26 cancer-related genes associated with solid tumors.
  • Life Technologies Inc. offers several variations of their Ion AmpliSeq™ panels intended for use in cancer. The Ion AmpliSeq Comprehensive Cancer Panel analyzes more than 400 cancer-related genes and tumor suppressor genes. The Ion AmpliSeq Cancer Hotspot Panel v2 analyzes the “hotspot” regions of 50 cancer-related and tumor suppressor genes.

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.

 

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.

 

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 (C-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.

 

Some examples of recommendations for testing of common solid tumors are listed below:

 

  • Breast cancer 
    • HER2 testing, when specific criteria are met. 
  • Colon cancer 
    • KRAS, NRAS, and BRAF testing for patients with metastatic colon cancer.
  • Non-small-cell lung cancer
    • KRAS, EGFR [epidermal growth factor receptor], and ALK [anaplastic lymphoma kinase] testing for patients with metastatic adenocarcinoma 
    • Consider EGFR and ALK testing especially in never smokers, mixed histology, or small biopsy specimen 
    • Strongly endorses broader molecular profiling to identify rare driver mutations (HER2, BRAF V600E, ROS1, and RET gene rearrangements, and MET amplification or MET exon skipping)
  •  Melanoma
    • BRAF V600 testing for patients with metastatic disease 
    • Activating C-KIT variants for patients with metastatic disease
  • Ovarian cancer
    • BRCA
  •  Chronic myelogenous leukemia
    • BCR-ACL
  •  Gastrointestinal stromal tumors
    • C-KIT

 

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.

 

For additional information on testing for circulating tumor DNA (ctDNA) see policy 02.04.16 Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsies)

 

Prior Approval:

 

Not applicable

 

Policy:

See related medical policy 02.04.16 Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsies)

 

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:

  • The FoundationOne™ test
  • FoundationOne CDx™
  • FoundationOne Heme test
  • OnkoMatch
  • Tumor profiling service (Caris Molecular Intelligence through Caris Life Sciences)
  • SmartGenomics (PathGroup)
  • Paradigm Cancer Diagnostic (PcDx) Panel
  • Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
  • TruSeq® Panels
  • Illumina TruSight™ Tumor
  • Ion AmpliSeq Comprehensive Cancer Panel
  • Ion AmpliSeq Cancer Hotspot Panel v2
  • GeneTrails® Solid Tumor Panel
  • OmniSeq Target™

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.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81445 Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed
  • 81450 Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed
  • 81455 Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed
  • 81479 Unlisted molecular pathology procedure
  • 0037U Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
  • 0048U Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)
  • 0057U Oncology (solid organ neoplasia), mRNA, gene expression profiling by massively parallel sequencing for analysis of 51 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a normalized percentile rank

 

Selected References:

  • Febbo, P., Ladanyi, M., Aldape, K., Marzo, A., Hammond, M., Hayes, D., et. al. (2011, December) NCCN Task force report: evaluating the clinical utility of tumor markers in oncology. Journal of the National Comprehensive Cancer Network Vol. 9, Sup. 5.
  • Journal of the National Comprehensive Cancer Network (2011, December). NCCN molecular testing white paper: effectiveness, efficiency, and reimbursement. Retrieved June 5, 2014.
  • Raman, G., Avendano, E. E., Chen, M. (July, 2013). Update on emerging genetic tests currently available for clinical use in common cancers Evidence Report/Technology Assessment. Agency for Healthcare Research. Retrieved June 5, 2014.
  • Singh, R., Patel, K., Routbort, M., Aldape, K., Lu, X., Manekia, J., et. al., (2014, October) Clinical massively parallel next-generation sequencing analysis of 409 cancer-related genes for mutations and copy number variations in solid tumours. British Journal of Cancer. 111, 2014–2023.
  • Technology Evaluation Center. (2013, June). Special report: Multiple molecular testing of cancers to identify targeted therapies (Vol. 28, No. 1). BlueCross BlueShield Association.
  • Schwaederle M, Daniels GA, Piccioni DE, et al. On the Road to Precision Cancer Medicine: Analysis of Genomic Biomarker Actionability in 439 Patients. Mol Cancer Ther. Jun 2015;14(6):1488-1494. PMID 25852059
  • FoundationOne Web Site .About FoundationOne.2014
  • Oncology. G. OnkoMatch™ tumor genotyping 2014
  • GenPath®. Test catalog
  • Laboratories KD. GeneTrails Solid Tumor Genotyping Panel 2015
  • Sciences CL. Caris Molecular Intelligence 2015
  • SmartGenomics P. Advance Oncogenomic diagnostics 2015.
  • GuardantHealth I. Guardant360 test 2015
  • Paradigm Web Site. About PcDx
  • Cheng DT, Mitchell TN, Zehir A, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. May 2015;17(3):251-264. PMID 25801821
  • Illumina IWp. TruSeq Amplican - Cancer Panel 2014
  • Life Technologies. Cancer Genomics Data Analysis - Compendia Bioscience Products 2014
  • National Cancer Institute. Press Release: NCI launches trial to assess the utility of genetic sequencing to improve patient outcomes 1/30/2014. 2014;
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer, version 2.2016
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer, version 2.2016
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer, version 4.2016
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Melanoma, version 3.2016
  • National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 5.2017.
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians. 2016;66(1):7-30.
  • American Congress of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 634: Hereditary cancer syndromes and risk assessment. Obstet Gynecol. June 2015. 125(6):1538-1543.
  • Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, and Pritchard CC. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. (2016). epub PMID: 26845104
  • Sireci, AN, Aggarwal, VS, Turk, AT, Gindin, T, Mansukhani, MM, Hsiao, SJ. Clinical Genomic Profiling of a Diverse Array of Oncology Specimens at a Large Academic Cancer Center: Identification of Targetable Variants and Experience with Reimbursement. The Journal of molecular diagnostics : JMD. 2017 Mar;19(2):277-87. PMID: 28024947
  • Hermel, DJ, McKinnon, WC, Wood, ME, Greenblatt, MS. Multi-gene panel testing for hereditary cancer susceptibility in a rural Familial Cancer Program. Familial cancer. 2017 Jan;16(1):159-66. PMID: 27401692
  • Pritzlaff, M, Summerour, P, McFarland, R, et al. Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast cancer research and treatment. 2017 Feb;161(3):575-86. PMID: 28008555
  • Yadav, S, Reeves, A, Campian, S, Paine, A, Zakalik, D. Outcomes of retesting BRCA negative patients using multigene panels. Familial cancer. 2017 Jul;16(3):319-28. PMID: 27878467
  • Bunnell, AE, Garby, CA, Pearson, EJ, Walker, SA, Panos, LE, Blum, JL. The Clinical Utility of Next Generation Sequencing Results in a Community-Based Hereditary Cancer Risk Program. Journal of genetic counseling. 2017 Feb;26(1):105-12. PMID: 27276934
  • Li M. Statistical Methods for Clinical Validation of Follow-On Companion Diagnostic Devices via an External Concordance Study. Statistics in Biopharmaceutical Research 8, 355-363 (2016).
  • Knight Diagnostic Laboratories.(2015) GeneTrails Solid Tumor Genotyping Panel. 2015;
  • Wheler JJ, Janku F, Naing A, et al.(2016) Cancer Therapy Directed by Comprehensive Genomic Profiling: A Single Center Study. Cancer Res. Jul 1 2016;76(13):3690-3701. PMID 27197177
  • Au TH, et al. Personalized and precision medicine: integrating genomics into treatment decisions in gastrointestinal malignancies. J Gastrointest Oncol 2017;8(3):387-404.
  • Coyne G, et al. Defining precision: the precision medicine initiative trials NCI-IMPACT and NCI-MATCH. Curr Probl Cancer 2017; 41(3):182-194.
  • Hilal T, et al. Comprehensive genomic profiling in routine clinical practice leads to a low rate of benefit from genotype-directed therapy. BMC Cancer 2017 Aug 30;17(1):602.
  • Phillips KA, Deverka PA, Trosman JR, et al. Payer coverage policies for multigene tests. Nature biotechnology. 2017;35(7):614-617. doi:10.1038/nbt.3912.
  • Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
  • Okur V, Chung WK. The impact of hereditary cancer gene panels on clinical care and lessons learned. Cold Spring Harbor Molecular Case Studies. 2017;3(6):a002154. doi:10.1101/mcs.a002154

 

Policy History:

  • September 2018 - Annual Review, Policy Revised
  • September 2017 - Annual Review, Policy Revised
  • September 2016 - New Policy

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.

 

*CPT® is a registered trademark of the American Medical Association.