Expanded Genetic Panels to Assess Cancer Risk

• Notice
• Benefit Application
• Description
• Prior Approval
• Policy
• Procedure Codes
• Selected References
• Policy History

Medical Policy: 02.04.64 

Original Effective Date: November 2016 

Reviewed: November 2020 

Revised: May 2021 

Notice:

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.

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:

Numerous genetic mutations are associated with inherited cancer syndromes. Patients may have a personal and/or family history of cancer that suggests that the cancer is syndrome related. Some patients may meet clinical criteria for 1 or more hereditary cancer syndromes, and it has been proposed that mutation testing using next-generation sequencing technology to analyze multiple genes at 1 time (panel testing) can optimize testing in these patients compared to testing for individual mutations.

For individuals who have a personal and/or family history suggesting an inherited cancer syndrome who receive sequencing panel, the evidence includes mainly reports describing the frequency of detecting mutations in patients referred for panel testing. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Published data on analytic validity is lacking, but it has been reported to be high, approaching that of direct sequencing of individual genes. Clinical validity studies have generally reported the results of the frequency with which mutations are identified using large panels, and occasionally have reported the variant of unknown significance rate. Published data on clinical utility is lacking, and it is unknown whether use of these panels improves health outcomes. Many panels include mutations that are considered to be of moderate or low penetrance, and management guidelines are not well-defined in these patients, leading to the potential for harm in identifying one of these non-highly penetrant mutations. The evidence is insufficient to determine the effects of the technology on health outcomes.

Commercially available cancer susceptibility mutation panels can test for multiple mutations associated with a specific type of cancer or can include mutations associated with a wide variety of cancers. Mutations included in these panels are associated with varying levels of risk of developing cancer, and only some mutations included on panels are associated with a high risk of developing a well-defined cancer syndrome for which there are established clinical management guidelines. Clinical management recommendations for the inherited conditions associated with low-to-moderate penetrance are not standardized, and the clinical utility of genetic testing for these mutations is uncertain and could lead to harm. In addition, high rates of variants of uncertain significance have been reported with these panels.  In large panels, many of the genes assessed are relatively newly identified. Pathogenic variants in these genes are rare, cancer risks are not well characterized, there are no guidelines for medical management, and the role of predictive testing for family members is uncertain.

For individuals who have a personal and/or family history suggesting an inherited cancer syndrome who receive testing with a next-generation sequencing panel, the evidence includes mainly reports describing the frequency of detecting mutations in patients referred for panel testing. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Published data on analytic validity is lacking, but it has been reported to be high, approaching that of direct sequencing of individual genes. Clinical validity studies have generally reported the results of the frequency with which mutations are identified using large panels, and occasionally have reported the variant of unknown significance rate. Published data on clinical utility is lacking, and it is unknown whether use of these panels improves health outcomes. Many panels include mutations that are considered to be of moderate or low penetrance, and management guidelines are not well-defined, leading to the potential for harm in identifying one of these non-highly penetrant mutations. The evidence is insufficient to determine the effects of the technology on health outcomes.

The following criteria can be used to evaluate the clinical utility of cancer susceptibility panel testing:

• Does panel testing offer substantial advantages in efficiency compared with sequential analysis of individual genes?
• Is decision making based on potential results of panel testing well-defined?
• Do positive results on panel testing result in changes in cancer susceptibility that are clinically important?
• Does this change in cancer susceptibility lead to changes in management that result in health outcome benefits for the patient being tested?
• Is the impact of ancillary information provided by panel testing well-defined?
• What is the probability that ancillary information leads to further testing or management changes that may have either a positive or a negative impact on the patient being tested?

 Note: This policy does not apply to the individual markers that have demonstrated efficacy in certain types of cancer.

Professional Guidelines and Position Statements

American Society of Clinical Oncology (ASCO)

American Society of Clinical Oncology (ASCO) recognizes that concurrent multigene testing (ie, panel testing) may be efficient in circumstances that require evaluation of multiple high-penetrance genes of established clinical utility as possible explanations for a patient’s personal or family history of cancer. Depending on the specific genes included on the panel employed, panel testing may also identify mutations in genes associated with moderate or low cancer risks and mutations in high-penetrance genes that would not have been evaluated on the basis of the presenting personal or family history. Multigene panel testing will also identify variants of uncertain significance (VUS) in a substantial proportion of patient cases. ASCO affirms that it is sufficient for cancer risk assessment to evaluate genes of established clinical utility that are suggested by the patient’s personal and/or family history.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer and susceptibility genes (BRCA1 or BRCA2). Women with a positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing (grade B recommendation, 2013). The use of genetic cancer susceptibility panels is not specifically mentioned.

National Comprehensive Cancer Network (NCCN)

National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer (v.1.2021) state that, regarding multigene testing:

• "Patients who have a personal or family history suggestive of a single inherited cancer syndrome are most appropriately managed by genetic testing for that specific syndrome. When more than one gene can explain an inherited cancer syndrome, then multi-gene testing may be more efficient and/or cost effective."

The NCCN notes certain cons associated with panel testing, such as higher chance of identifying variants of unknown significance, unactionable variants, or variants that do not have a clear course of treatment. The NCCN also identifies two examples of clinical scenarios in which multi- gene testing should not be considered: “an individual from a family with a known pathogenic variant and no other reason for multi-gene testing, and as first-line testing when the family history is strongly suggestive of a known hereditary syndrome.”

Overall, the NCCN acknowledges the significant benefits of panel testing, such as value compared to single gene sequencing, as well as providing more information for causes of illnesses, but states that choice of panel and testing is critical.

The Centers for Disease Control and Prevention (CDC)

The Centers for Disease Control and Prevention (CDC) Office of Public Health Genomics helped to establish and support the ACCE Model Project, which has become the standard for evaluating scientific data on new genetic tests. The ACCE Model System* for Collecting, Analyzing and Disseminating Information on Genetic Tests provides an evaluation framework that is applicable to a variety of genetic tests. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) used the ACCE framework and established this process as a way of evaluating an evidence-based method for assessing genetic tests and other types of genomic technology as it has transitioned from the research arena to the practice arena. The ACCE evaluation framework examines:

• Analytical validity: Measures the specific genotypic test performance characteristics and whether the test accurately and reliably detects the gene marker(s) of interest. This refers to how well a test performs in the laboratory and how well the test measures the property or characteristic it is intended to measure. If the test does what its makers claim, it must produce the same results repeatedly and in different laboratories given the same set of procedures.
• Clinical validity: Refers to the associations of the test result(s) with patient outcomes of interest, and may be expressed as clinical sensitivity, specificity, and predictive value for the outcome. Evidence is usually retrospective. This component refers to the accuracy with which a test predicts the presence or absence of a clinical condition or predisposition. Initially, the test has to be conducted on individuals who are known to have the condition (as well as those who do not) to determine its success rate.
• Clinical utility: Clinical utility determines whether the use of genetic testing to modify medical management decisions improves patient outcomes. Best evidence is prospective, from randomized clinical trials of standard management procedures versus genetic test--directed management. Evidence may also be derived using banked samples from already completed clinical trials, or by constructing an indirect chain of evidence linking test results to clinical outcome. If a test has utility, it means that the result (positive or negative) provides information that can be used in the formulation of an effective treatment or preventive strategy.
• Ethical, Legal, and Social Implications: Determines what, if any, ethical, legal, or social implications may arise from the use of this test and its results

Collaborative Group of the Americas on Inherited Gastrointestinal Cancer

In 2020, the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer published a position statement on multigene panel testing for patients with gastrointestinal cancer.  Recommendations were based on the evidence, professional society recommendations endorsing testing of a given gene, and opinion of the expert panel. The group noted the variability in genes included in commercially available panels and recommended that multigene panels include a minimum of 11 specific genes associated with defective mismatch repair (Lynch syndrome) and polyposis syndromes. Additional genes to be considered had low to moderately increased risk, had limited data of colorectal cancer risk, or causation for colorectal cancer was not proven.

Published peer-reviewed evidence and professional society/organizational consensus guidelines support testing for certain tumor markers for the screening, staging, diagnosis and management of some types of cancer. However, for other tumor markers there is insufficient evidence to establish clinical utility for informing on improvement of health outcomes. To have clinical utility the specific gene or gene biomarker for which testing has been requested, or gene expression classifier assay should be demonstrated in the published, peer-reviewed scientific literature in the form of prospective clinical trial data to improve the diagnosis, management, or clinical outcomes for the individual’s tumor type or disease. Data is lacking for the clinical utility of multigene panels for inherited cancer susceptibility panels. There are management guidelines for syndromes with high penetrance, which have clinical utility in that they inform clinical decision making and result in the prevention of adverse health outcomes. Clinical management recommendations for the inherited conditions associated with low-to-moderate penetrance are not standardized, and the clinical utility of genetic testing for these mutations is uncertain. Variants of uncertain significance are generally not clinically actionable, and most are re-classified as benign.

Prior Approval:

Not applicable

Policy:

Genetic cancer susceptibility panels to assess cancer risk using next generation sequencing (NGS), including but not limited to the following, are considered investigational.

Testing for a large number of genes that have no certain link to risk status or disease development lacks clinical value. Only some variants included on panels are associated with a high risk of developing a well-defined cancer syndrome for which there are established clinical management guidelines. Often, abnormal findings in large gene panels are described as variants of uncertain significance. This means that although mutations/variants may be found in these genes, there are no actionable results. Change in clinical treatment or surveillance is not impacted by results. There is insufficient evidence in the medical literature to show the expanded panel of genetic testing improves net health outcomes. 

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 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
• 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
• 81599 Unlisted multianalyte assay with algorithmic analysis
• 0101U Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (15 genes [sequencing and deletion/duplication], EPCAM and GREM1 [deletion/duplication only])
• 0102U Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (17 genes [sequencing and deletion/duplication])
• 0103U Hereditary ovarian cancer (eg, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (24 genes [sequencing and deletion/duplication], EPCAM [deletion/duplication only])
• 0130U Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis), targeted mRNA sequence analysis panel (APC, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, and TP53) (List separately in addition to code for primary procedure)
• 0131U Hereditary breast cancer–related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (13 genes) (List separately in addition to code for primary procedure)
• 0132U Hereditary ovarian cancer–related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (17 genes) (List separately in addition to code for primary procedure)
• 0133U Hereditary prostate cancer–related disorders, targeted mRNA sequence analysis panel (11 genes) (List separately in addition to code for primary procedure)
• 0134U Hereditary pan cancer (eg, hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (18 genes) (List separately in addition to code for primary procedure)
• 0135U Hereditary gynecological cancer (eg, hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (12 genes) (List separately in addition to code for primary procedure)
• 0136U ATM (ataxia telangiectasia mutated) (eg, ataxia telangiectasia) mRNA sequence analysis (List separately in addition to code for primary procedure)
• 0137U PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) mRNA sequence analysis (List separately in addition to code for primary procedure)
• 0138U BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) mRNA sequence analysis (List separately in addition to code for primary procedure)
• 0163U Oncology (colorectal) screening, biochemical enzyme-linked immunosorbent assay (ELISA) of 3 plasma or serum proteins (teratocarcinoma derived growth factor-1 (TDGF-1, Cripto-1), carcinoembryonic antigen (CEA), extracellular matrix protein [EMP]), with demographic data (age, gender, CRC screening compliance) using a proprietary algorithm and reported as likelihood of CRC or advanced adenomas

Selected References:

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• 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.
• Washington Uo. BROCA -- Cancer Risk Panel
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• National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancers (v.1.2019).
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• Kunst HP, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011. 17(2):247-54.
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• Neumann HP, et al. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab. 2011. 96(8):E1279-82.
• Sancak O, et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur J Hum Genet. 2005. 13(6):731-41.
• Borkowska J, et al. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011. 50(1):13-20.
• Hoogeveen-Westerveld M, et al. Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. Hum Mutat. 2012. 33(3):476-9.
• Rodrigues DA, Gomes CM, Costa IM. Tuberous sclerosis complex. An Bras Dermatol. 2012. 87(2):184-96.
• Sasongko TH, et al. Novel mutations in 21 patients with tuberous sclerosis complex and variation of tandem splice-acceptor sites in TSC1 exon 14. Kobe J Med Sci. 2008. 54(1):E73-81.
• Lonser RR, et al. von Hippel-Lindau disease. Lancet. 2003. 361(9374):2059-67.
• 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.
• Song et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015. 33 (26): 2901-7.
• Ramus et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015. 107(11).
• Norquist BM, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2015 Dec 30:1-9. [Epub ahead of print].
• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians. 2016;66(1):7-30.
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• Rubinstein WS, Maglott DR, Lee JM, Kattman BL, Malheiro AJ, Ovetsky M et al. The NIH genetic testing registry: a new, centralized database of genetic tests to enable access to comprehensive information and improve transparency. Nucleic Acids Res. 2013;41:D925-D935.
• Cheng DT, Prasad M, Chekaluk Y, et al. Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing. BMC Med Genomics. May 19 2017;10(1):33. PMID 28526081
• Mu W, Lu HM, Chen J, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. Nov 2016;18(6):923-932. PMID 27720647
• Vysotskaia VS, Hogan GJ, Gould GM, et al. Development and validation of a 36-gene sequencing assay for hereditary cancer risk assessment. PeerJ. Feb 2017;5:e3046. PMID 28243543
• Balmana J, Digiovanni L, Gaddam P, et al. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. J Clin Oncol. Dec 2016;34(34):4071-4078. PMID 27621404
• Buys SS, Sandbach JF, Gammon A, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer. May 15 2017;123(10):1721-1730. PMID 28085182
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• American Society of Breast Surgeons. (2017). Consensus guideline on hereditary genetic testing for patients with and without breast cancer. Columbia, MD: American Society of Breast Surgeons.
• National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment: Colorectal Cancer v.1.2021).
• Phillips, K. A., Deverka, P. A., Trosman, J. R., Douglas, M. P., Chambers, J. D., Weldon, C. B., & Dervan, A. P. (2017). Payer coverage policies for multigene tests. Nature biotechnology, 35(7), 614-617
• Evolving Payer Coverage Policies on Genomic Sequencing Tests: Beginning of the End or End of the Beginning?. JAMA. 2018;319(23):2379-2380.
• U. S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA- related cancer in women: recommendation statement. Am Fam Physician. Jan 15 2015;91(2):Online. PMID 25591222.
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• Dy, G. K., Nesline, M. K., Papanicolau-Sengos, A., DePietro, P., LeVea, C. M., Early, A., Chen, H., Grand’Maison, A., Boland, P., Ernstoff, M. S., Edge, S., Akers, S., Opyrchal, M., Chatta, G., Odunsi, K., Pabla, S., Conroy, J. M., Glenn, S. T., DeFedericis, H. T., … Morrison, C. (2019). Treatment recommendations to cancer patients in the context of FDA guidance for next generation sequencing. BMC Medical Informatics and Decision Making, 19(1), 14.
• Food and Drug Administration Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS) – Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases Guidance for Stakeholders and Food and Drug Administration Staff. April 13, 2018

Policy History:

• May 2021 - Interim Review, Policy Revised
• November 2020 - Annual Review, Policy Revised
• January 2020 - Interim Review, Policy Revised
• November 2019 - Annual Review, Policy Revised
• October 2019 - New Coding Update, Policy Revised
• November 2018 - Annual Review, Policy Revised
• December 2017 - Annual Review, Policy Revised
• November 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.