Expanded Genetic Panels to Assess Cancer Risk

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

 

Medical Policy: 02.04.64 

Original Effective Date: November 2016 

Reviewed: November 2018 

Revised: November 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:

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.

 

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 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 following list contains some (but not all) examples of expanded genetic panels commercially available at this time:

 

Although genetic cancer susceptibility panels using next-generation sequencing are considered investigational, there may be individual components of the panel that are medically necessary.

 

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

 

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.1.2019) 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 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

 

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 are considered investigational.

 

Although multigene genetic cancer susceptibility panels are considered investigational, there may be individual components of the panel that are medically necessary.

 

The following genes are recommended in the presence of genetic/familial high-risk assessment for breast cancer: (v2.2019)

• ATM
• BARD1
• BRCA1/BRCA2
• CHEK2
• NBN
• NF1
• PALB2
• PTEN
• STK11
• TP53

 

The following genes are recommended in the presence of genetic/familial high-risk assessment for ovarian cancer (v2.2019)

• BRCA1/BRCA2
• BRIP1
• RAD51C
• RAD51D
• STK11

 

The following are recommended and considered well-established in the presence of genetic/familial high-risk assessment for colorectal cancer (v1.2018)

• APC
• BMPR1A
• EPCAM
• GREM1
• MLH1
• MSH2
• MLH6
• MUTYH
• PMS2
• PTEN
• SMAD4
• STK11
• TP53

 

The following are recommended and considered well-established in the presence of Lynch Syndrome (Colorectal: Version 1.2018)

• MLH1
• MSH2
• MSH6
• PMS2

 

The evidence base is insufficient to demonstrate how comprehensive test results from all genes and/or gene mutations included in the panels listed below may be used to manage treatment decisions (i.e., clinical utility) and improve net health outcomes. Panel testing is similar to population testing with minimal value seen in genetic testing for information not effecting treatment. The following below, but not limited to these genetic panels are considered investigational to determine cancer risk.

 

 

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

 

Selected References:

• Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17:505-7. PMID: 25764213
• Castera L, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014. 22(11):1305-13.
• 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
• Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. Jan 1 2015;121(1):25-33. PMID 25186627
• Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. Nov 1 2015;33(31):3660-3667. PMID 26324357
• Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. Jul 1 2014;32(19):2001-2009. PMID 24733792
• LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. Nov 2014;16(11):830-837. PMID 24763289
• Chong HK, Wang T, Lu HM, et al. The validation and clinical implementation of BRCAplus: a comprehensive high-risk breast cancer diagnostic assay. PLoS One. 2014;9(5):e97408. PMID 24830819
• Judkins T, Leclair B, Bowles K, et al. Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk. BMC Cancer. 2015;15:215. PMID 25886519
• National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancers (v.1.2019).
• Walsh T, Lee MK, Casadei S, Thornton AM, Stray SM, Pennil C, Nord AS, Mandell JB, Swisher EM, King MC. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. PNAS (2010) 107:12629-33.
• Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King MC, Swisher EM. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. PNAS (2011) 108:18032-7. 
• Nord AS, Lee M, King MC, Walsh T. Accurate and exact CNV identification from targeted high-throughput sequence data. BMC Genomics. (2011) 12:184.
• Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet. (2010) 11:31-46.
• 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
• Bertolotto C, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011. 480(7375):94-8.
• Yokoyama S, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011. 480(7375):99-103.
• Eng C, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996. 276(19):1575-9.
• Carney JA and Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002. 108(2):132-9.
• Ricketts C, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 2008. 100(17):1260-2.
• Vanharanta S, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet. 2004. 74(1):153-9.
• Ricketts CJ, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010. 31(1):41-51.
• Baysal BE. Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors. Biochim Biophys Acta. 2013. 1827(5):573-7.
• Hao HX, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009. 325(5944):1139-42.
• Kunst HP, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011. 17(2):247-54.
• Ni Y, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008. 83(2):261-8.
• 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.
• NCCN Guidelines Version 4.2016. Non-small cell lung cancer 2016.
• The American Congress of Obstetrics and Gynecology Committee on Genetics. Committee Opinion No. 634: Hereditary cancer syndromes and risk assessment. Obstet Gynecol. 2015. 125(6):1538-43
• Boyar, S., Shapiro, C., Reasy, fire, aim,: Addressing issues associated with multigene panel testing for cancer susceptibility. Oncology 2016 Sept:800-807.
• Raman G, Avendano EE, Chen M. Update on Emerging Genetic Tests Currently Available for Clinical Use in Common Cancers. Evidence Report/Technology Assessment. No. . (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I.) Rockville, MD: Agency for Healthcare Research and Quality. July 2013.
• 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
• O'Leary E, Iacoboni D, Holle J, et al. Expanded gene panel use for women with breast cancer: identification and intervention beyond breast cancer risk. Ann Surg Oncol. Aug 01 2017. PMID 28766213
• American Society of Colon and Rectal Surgeons. Hereditary Colorectal Cancer Expanded Version. n.d.
• 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.1.2018).
• 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.

 

Policy History:

 

• November 2018 - Annual Review, Policy Revised
• December 2017 - Annual Review, Policy Revised
• November 2016 - New Policy

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