Hereditary Cancer Syndrome Multigene Panels · Hereditary cancer syndrome multi-gene panels include a wide variety of genes and may be focused on the genetic causes of a particular
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Lab Management Guidelines V1.0.2020
Hereditary Cancer Syndrome Multigene Panels
MOL.TS.182.Av1.0.2020
Introduction
Hereditary cancer syndrome multigene panel testing is addressed by this guideline.
Procedures addressed
The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements.
Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2,CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53
81432
Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analyses for BRCA1, BRCA2, MLH1, MSH2, and STK11
81433
Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11
81435
Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes, including MLH1, MSH2, EPCAM, SMAD4, and STK11
81436
Hereditary neuroendocrine tumor disorders (eg, medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); genomic sequence analysis panel, must include sequencing of at least 6 genes, including MAX, SDHB, SDHC, SDHD, TMEM127, and VHL
A hereditary cancer syndrome is when a mutation in a single gene causes a significantly increased risk for certain cancers. Hereditary cancer syndromes are usually characterized by a pattern of specific cancer types occurring together in the same family, younger ages of cancer diagnosis than usual, or other co-existing non-cancer conditions.
Prevalence
Most cancer is sporadic and believed to be caused by a mix of behavioral or lifestyle, environmental, and inherited risk factors. However, about 5-10% of cancers are believed to have a major inherited component.1
Hereditary cancer syndromes
There are at least 50 hereditary cancer syndromes.1 This table lists some of the most common along with associated cancers.2
Syndrome Associated cancers
Hereditary breast and ovarian cancer syndrome (HBOC)
• breast
• ovarian, fallopian tube, or primary peritoneal cancer
Peutz-Jeghers syndrome • polyps (hamartomas) in the stomach
• small intestine and colon
• pancreas
• lung
• breast
• uterine
• ovarian
Overlapping clinical findings
Many hereditary cancer syndromes can include the same types of cancer and therefore have overlapping clinical findings. For example, breast cancer is a feature of HBOC caused by BRCA mutations, Li Fraumeni syndrome, Cowden syndrome, and others. Sometimes, the pattern of cancers in the family or pathognomonic features makes the underlying syndrome clear. However, in many cases it can be difficult to reliably diagnose hereditary cancer syndromes based on clinical and family history alone.
Test information
Introduction
Testing for hereditary cancer syndromes may include multigene panel testing.
Sanger Sequencing
Until recently, most sequencing tests used the Sanger sequencing methodology that was originally developed in the 1970s. Sanger sequencing is labor intensive and did not lend itself to high-throughput applications.
Next-generation sequencing (NGS)
NGS, which is also sometimes called massively parallel sequencing, has been developing since about 2005 to allow larger scale and more efficient gene sequencing. NGS relies on sequencing many copies of small pieces of DNA simultaneously and using bioinformatics to assemble the sequence.
The efficiency of NGS has led to an increasing number of large, multi-gene testing panels. NGS panels that test several genes at once are particularly well-suited to conditions caused by more than one gene or where there is considerable clinical overlap between conditions making it difficult to reliably narrow down likely causes. As
a result, several laboratories have begun to combine genes involved in causing various hereditary cancer syndromes, which often have both of those characteristics.
Detection rate of NGS
NGS may not perform as well as Sanger sequencing in some applications. Results may also be obtained that cannot be adequately interpreted based on the current knowledgebase.
o When a sequence variation is identified that has not been previously characterized or shown to cause the disorder in question, it is called a variant of uncertain significance (VUS). VUSs are relatively common findings when sequencing large amounts of DNA with NGS.
o Under certain circumstances, technologies used in multi-gene testing may fail to identify mutations that might be identifiable through single-gene testing. If high clinical suspicion remains for a particular syndrome after negative multi-gene test results, consultation with the testing lab, additional targeted genetic testing, or both may be warranted.
Hereditary cancer syndrome multi-gene panels
Hereditary cancer syndrome multi-gene panels include a wide variety of genes and may be focused on the genetic causes of a particular cancer type or broad detection of common hereditary cancer syndromes.
Multi-gene tests vary in technical specifications. For example, different labs may have different depth of coverage, extent of Intron/Exon Boundary analysis, or methodology of large Deletion/Duplication Analysis.
Because genes can be easily added or removed from multi-gene tests over time by a given lab, medical records must document
the genes included in the specific multi-gene test used from each patient, and
the labs that performed the panels.
Moderate risk genes
Panels may also include genes believed to be associated with cancer, but with a more modest impact on risk than recognized hereditary cancer syndromes. Results for such genes are of less clear value because there often are not clear management recommendation for mutation-positive individuals.
This section includes relevant guidelines and evidence pertaining to hereditary cancer syndrome panel testing.
National Comprehensive Cancer Network (NCCN)
The National Comprehensive Cancer Network (NCCN) makes the following general recommendations for using multi-gene panels in evaluating risk for breast and ovarian cancer and now includes this option in some management algorithms:3 ,4
“Because of their complexity, multi-gene testing is ideally offered in the context of professional genetic expertise for pre- and post-test counseling.”
“Testing of an individual without a cancer diagnosis should only be considered when an appropriate affected family member is unavailable for testing.”
“When more than one gene can explain an inherited cancer syndrome, then multi-gene testing may be more efficient and/or cost effective. As commercially available tests differ in the specific genes analyzed (as well as classification of variants and many other factors), choosing the specific laboratory and test panel is important. Multi-gene testing can include ‘intermediate’ penetrant (moderate-risk) genes. For many of these genes, there is limited data on the degree of cancer risk and there are no clear guidelines on risk management for carriers of mutations. Not all genes included on available multi-gene tests are necessarily clinically actionable.” If a moderate risk gene mutation is identified, “gene carriers should be encouraged to participate in clinical trials or genetic registries.”
“As is the case with high-risk genes, it is possible that the risks associated with moderate-risk genes may not be entirely due to that gene alone, but may be influenced by gene/gene or gene/environment interactions. In addition, certain pathogenic/likely pathogenic variant in genes may post higher or lower risk than other pathogenic/likely pathogenic variants in that same gene. Therefore, it may be difficult to use a known pathogenic/likely pathogenic variant alone to assign risk for relatives."
“Mutations in many breast cancer susceptibility genes involved in DNA repair may be associated with the rare autosomal recessive condition, Fanconi anemia.” Therefore, multi-gene testing may unexpectedly reveal that an individual and their family are at an increased risk for this condition.
“There is an increased likelihood of finding variants of unknown significance when testing for mutations in multiple genes.”
American Society of Breast Surgeons
The American Society of Breast Surgeons (2019) published a consensus guideline on genetic testing for hereditary breast cancer. They state the following:
“Breast surgeons, genetic counselors, and other medical professionals knowledgeable in genetic testing can provide patient education and counseling and make recommendations to their patients regarding genetic testing and arrange testing. When the patient’s history and/or test results are complex, referral to a certified genetic counselor or genetics professional may be useful. Genetic testing is increasingly provided through multi-gene panels. There are a wide variety of panels available, with different genes on different panels. There is a lack of consensus among experts regarding which genes should be tested in different clinical scenarios. There is also variation in the degree of consensus regarding the understanding of risk and appropriate clinical management of mutations in some genes.”
“Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data support that genetic testing should be offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations (surgery and potentially radiation) and systemic therapy. Additionally, family members may subsequently be offered testing and tailored risk reduction strategies.”
“Genetic testing should be made available to all patients with a personal history of breast cancer. Every patient being seen by a breast surgeon, who had genetic testing in the past and no pathogenic variant was identified, should be re-evaluated and updated testing considered. In particular, a patient who had negative germline BRCA1 and 2 testing, who is from a family with no pathogenic variants, should be considered for additional testing.1 Genetic testing performed prior to 2014 most likely would not have had PALB2 or other potentially relevant genes included and may not have included testing for large genomic rearrangements in BRCA1 or BRCA2.”
“Genetic testing should be made available to patients without a history of breast cancer who meet NCCN guidelines. Unaffected patients should be informed that testing an affected relative first, whenever possible, is more informative than undergoing testing themselves. When it is not feasible to test the affected relative first, then the unaffected family member should be considered for testing if they are interested, with careful pre-test counseling to explain the limited value of “uninformative negative” results. It is also reasonable to order a multi-gene panel if the family history is incomplete (i.e., a case of adoption, patient is uncertain of exact type of cancer affecting family members, among others) or other cancers are found in the family history, as described above.”
American College of Medical Genetics
The American College of Medical Genetics has a policy statement that offers general guidance on the clinical application of large-scale sequencing focusing primarily on whole exome and whole genome testing. However, some of the recommendations
regarding counseling around unexpected results, variants of unknown significance, and minimum requirements for reporting apply to many NGS applications.5
Criteria
Introduction
Requests for hereditary cancer syndrome panel testing are reviewed using these criteria.
Criteria
This guideline applies to all hereditary cancer syndrome panels, which are defined as assays that simultaneously test for more than one hereditary cancer syndrome. This guideline does not apply when testing more than one gene related to the same hereditary cancer syndrome (e.g., Lynch syndrome).
Medical necessity coverage generally relies on criteria established for testing individual hereditary cancer syndromes. See the Coverage Guidance table for examples of genes known to be included in currently available hereditary cancer syndrome multi-gene panels with coverage guidance. This is not intended to be a complete list of available genes as these panels are evolving rapidly.
However, this guideline takes into account the efficiency gains from simultaneously testing multiple candidate genes. Therefore, coverage requirements rely to some degree on how the panel will be billed. Panels may be billed in a variety of ways:
Gene sequencing portion:
o A separate CPT code for sequencing each gene studied or a subset (e.g., 81201, 81294, 81297, etc.)
o A single CPT code developed specifically for a particular type of panel (e.g., 81432, 81435, 81437)
o A single unlisted CPT code (e.g., 81479)
Deletion/duplication analysis portion:
o A separate CPT code for deletion/duplication analysis of each gene studied or a subset (e.g., 81203, 81292, 81294, 81404, 81479, etc.)
o A single CPT code developed specifically for a particular type of panel (e.g., 81433, 81436, 81438)
o Microarray analysis (e.g., 81228 or 81229)
o Part of a single unlisted CPT code for the sequencing and deletion/duplication portions of the panel (e.g., 81479)
Hereditary cancer syndrome multi-gene panels will be reimbursed when the following criteria are met:
Panel will be billed with separate procedure codes for each gene analyzed (however, please note that the billed amount should not exceed the list price of the test).
o The medical necessity of each billed procedure will be assessed independently. See the Coverage Guidance table for gene-specific policy guidance.
When a patient meets medical necessity criteria for any hereditary cancer syndrome gene(s) included in a multi-gene panel, genetic testing for the clinically indicated gene(s) will be reimbursed. This includes the sequencing and deletion/duplication† components.
Any genes that are included in a multi-gene panel but do NOT meet medical necessity criteria will NOT be reimbursed. It will be at the laboratory, provider, and patient’s discretion to determine if a multi-gene panel remains the preferred testing option.
o Sequencing and/or deletion/duplication analysis† of any hereditary cancer syndrome gene(s) should only be performed once per lifetime and will therefore only be reimbursed once per lifetime. If gene testing was previously performed, and is now being included in a panel, such testing will not be separately reimbursable regardless of whether clinical coverage criteria are met, OR
Panel will be billed with a single procedure code to represent all genes being sequenced, with or without another single procedure code representing the deletion/duplication analysis† portion. Code(s) may be specific to that panel or an unlisted code, such as 81479.
o No previous hereditary cancer syndrome testing has been performed
Medical necessity must be established for at least two conditions included in the panel (e.g., hereditary breast and ovarian cancer and Li Fraumeni syndrome). Note that this is two conditions and not two genes (i.e., meeting criteria for only Lynch syndrome, which is caused by mutations in at least 5 genes, would not fulfill criteria alone).
Although not a complete list, the following are considered separate conditions: Hereditary breast cancer - this includes both BRCA1/2 and PALB2.
o Testing for one condition was performed and billed separately. A multi-gene panel is now being considered as a reflex and will be billed at a rate comparable to single syndrome pricing (e.g., myRisk update).
Medical necessity must be established for at least one condition included in the panel in addition to the already tested condition (e.g., hereditary breast and ovarian cancer was already performed, but Lynch syndrome criteria are also met).
Note that if BRCA1/2 testing was already performed and PALB2 criteria are now met, PALB2 testing alone would be reimbursable and not a reflex panel test (e.g. myRisk Update).
† When deletion/duplication testing is not part of a single panel CPT code being billed, deletion/duplication testing should be billed in only one of the following ways:
A separate CPT code for deletion/duplication analysis of each individual gene (may include non-specific molecular pathology tier 2 codes or unlisted code 81479), or
A single CPT code specific to the performed deletion/duplication analysis panel, or
A single microarray procedure
Procedure codes representing multiple methods for deletion/duplication testing will not be reimbursable for the same panel (e.g., test-specific deletion/duplication procedure codes and microarray will not both be reimbursable for the same panel).
Coverage guidance
The following table describes coverage guidance for genes associated with hereditary cancer syndromes.
Coverage Guidance for Genes Included in Hereditary Cancer Syndrome Multi-Gene Panels
Gene testing is not reimbursed strictly for hereditary cancer indications. In general, this category applies to genes that have only a low to moderate impact on cancer risk (compared to high penetrance cancer syndrome-causing genes) and no clear management guidelines associated with identifying a mutation.
1. National Cancer Institute. Fact Sheets: Genetic Testing for Hereditary Cancer Syndromes (Reviewed March 15, 2019). Available at: http://www.cancer.gov/about-cancer/causes-prevention/genetics/genetic-testing-fact-sheet
2. Hampel H et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1):70-87. Available at: https://www.acmg.net/docs/gim2014147a.pdf
3. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Available at: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf
4. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
5. The American Society of Breast Surgeons. Official Statement: Consensus guideline on genetic testing for hereditary breast cancer. 2019. Available at: https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf
6. ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet Med. 2012 Aug;14(8):759-61.