Use of Common Genetic Variants (Single Nucleotide Polymorphisms) to Predict Risk of Non-familial Breast Cancer

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» Description» Selected References
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» Policy
 

Medical Policy: 02.04.44 
Original Effective Date: August 2013 
Reviewed: April 2016 
Revised: April 2016 


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: 

Several single-nucleotide polymorphisms (SNPs), which are single base-pair variations in the DNA sequence of the genome, have been found to be associated with breast cancer and are common in the population, but confer only small increases in risk. Commercially available assays test for several SNPs to predict an individual's risk of breast cancer relative to the general population. The intent of both types of tests is to identify those at increased risk who may benefit from more intensive surveillance.

 

Rare, single gene variants conferring a high risk of breast cancer have been linked to hereditary breast cancer syndromes. Examples are mutations in BRCA1 and BRCA2. These, and a few others, account for less than 25% of inherited breast cancer.  Moderate risk alleles, such as variants in the CHEK2 gene, are also relatively rare and apparently explain very little of genetic risk.


In contrast, several common SNPs associated with breast cancer have been identified primarily through genome-wide association studies (GWAS) of very large case-control populations. These alleles occur with high frequency in the general population, although the increased breast cancer risk associated with each is very small relative to the general population risk. Some have suggested that these common risk SNPs could be combined for individualized risk prediction either alone or in combination with traditional predictors; personalized breast cancer screening programs could than vary by starting age and intensity according to risk.

 

Several meta-analyses have investigated the association between breast cancer and various SNPs. Meta-analyses of case control studies have indicated that specific SNPs are associated with increased or decreased breast cancer risk. Other meta-analysis have revealed the interaction between environment (e.g. obesity, age at menarche) or ethnicity and breast cancer risk conferred by certain SNPs. Breast cancer risk associated with SNPs in microRNAs in commonly modified by ethnicity. Meta-analyses of GWAS have identified SNPs at new breast cancer susceptibility loci. All of these markers are considered to be in an investigational phase of development.  

 
SNPs Studied in Association with Breast Cancer

 

SNPs Studied in with Breast Cancer Risk

2q35 [rs13387042]

8q24 [G-allele of rs13281615]

8q24 [homozygous A-alleles of rs13281615]

AKAP9 [M463I]

ATR-CHEK1 checkpoint pathway genes

ATXN7 [K264R]

Chemotactic cytokines

COMT [V158M]

COX2 [rs20417]

COX2 [rs689466]

COX2 [rs5275]

COX11 [rs6504950]

CYP1A1 [T3801C]

CYP1A2 1F [A-allele of rs762551]

CYP19 [rs10046]

Fibroblast growth factor receptor genes

IL-10 [rs1800871]

IRS1 [rs1801278]

MAP3K1 [C-allele of rs889312 and G-allele of rs 16886165

MDM2 [rs2279744]

MDR1 [C3435T]

MTR [A(2756G]

PON1 [L55M]

STK15 [F31I]

STK15 [V571I]

TCF7L2 [rs7903146]

VDR [rs731236]

VDR [rs2228570]

VEGF [C936T]

XRCC2 [R188H]

XRCC3 [A17893G]

XRCC3 [T241M]

 

SNP Panel Tests 

  
Estimates of breast cancer risk, based on SNPs derived from large GWAS and/or from SNPs in other genes known to be associated with breast cancer, are available as laboratory-developed test services from different companies. The literature on these associations is growing although information about the risk models is proprietary. Independent determination of clinical validity in an intended-use population to demonstrate clinical validity has not been performed. There are also no studies to suggest that use of SNP-based risk assessment has any impact on health outcomes. No peer-reviewed reports have been published in which commercially available breast cancer risk estimators have been compared to each other to determine if they report similar results on the same individuals, specifically for breast cancer. 

 

Clinical Genetic Tests


Two companies currently offer risk assessment based on SNP panel testing and clinical information. Neither is provided as a DTC (direct-to-consumer) test. Only BREVEGen is currently listed in the Genetic Testing Registry of the National Center for Biotechnology Information.  

 

OncoVue®

 

The OncoVue® Breast Cancer Risk Test (InterGenetics™, Oklahoma City, OK) is a proprietary test that evaluates multiple, low risk SNPs associated with breast cancer. Results are combined with personal history measures to determine breast cancer risk at different times during adulthood. The test does not detect known high risk genetic factors such as BRCA mutations associated with hereditary breast and ovarian cancer. OncoVue® synthesizes various genetic and medical history risk measures into a personalized single-risk estimate for premenopause, perimenopause and postmenopause for each patient, with comparison to the average population risk at each of these life stages. 

 

For women without a strong family history of breast cancer and at average risk before testing, OncoVue® purports to estimate a woman’s individual risk and place her in standard, moderate or high risk groups. The results are intended to help a woman and her physician decide if more frequent exams and/or more sophisticated surveillance techniques are indicated. For women already known to be at high risk based on a family history consistent with hereditary breast cancer, the test is represented as having added value by indicating greater or lesser risk at different life stages.  

 
OncoVue® is available only through the Breast Cancer Risk Testing Network (BCRTN), described as a network of Breast Care Centers engaged in frontline genetic identification of breast cancer risk levels in their patients. BCRTN member centers will provide genetic breast cancer risk testing their patients using OncoVue® as part of a comprehensive education program to help OncoVue® “at risk” women understand their risk level and intervention strategies. BCRTN members will be selected for the network based on number of criteria, including quality standards of care, level of breast cancer surveillance technology, and the capacity to provide patient education on genetic testing and future risk management protocols.

 

BREVAGen™/BREVAGenplus™  

 
BREVAGen™ (Phenogen Sciences, Charlotte, NC)

BREVAGen™ evaluates 7 breast cancer-associated SNPs identified in genome-wide association studies (GWAS). Risk is calculated by multiplying the product of the individual SNP risk by the Gail model risk. BREVAGen™ has been evaluated for use in Caucasian women of European descent age 35 years and older. Like OncoVue®,  BREVAGen™ does not detect know high risk mutations, e.g. in BRCA. Suitable candidates for testing include women with a Gail lifetime risk of 15% or greater; with high lifetime estrogen exposure (e.g. early menarche and late menopause); or with relatives diagnosed with breast cancer. BREVAGen™ is not suitable for women with previous diagnoses of lobular carcinoma in situ, ductal carcinoma in situ, or breast cancer.


BREVAGenplus™ (Phenogen Sciences, Charlotte, NC)


On October 6, 2014 Phenogen Sciences, Inc. announced the availability of BREVAGenplus™. This test is an enhancement of the company’s first generation product BREVAGenplus™.  BREVAGenplus™ includes a greatly expanded SNP panel and is applicable for additional ethnicities African-American, Caucasian and Hispanic.

 
BREVAGenplus™ predictive risk test is performed in a physician’s office using a simple, non-invasive cheek swab. The test combines information from the patient’s genetic markers (SNPs) known to be associated with sporadic breast cancer, with their clinical risk score which includes factors such as the patient’s current age, age at menarche, age at first live birth, race/ethnicity, etc, to calculate their risk of developing sporadic breast cancer. This clinical risk score is determined by the National Cancer Institute Breast Cancer Risk Assessment Tool (BCRAT), also known as the Gail model. The test provides five year and lifetime predictive risk assessments to more accurately determine the patient’s risk of developing breast cancer during those time frames. This assists the physician in developing a personalized breast cancer risk management plan by putting the appropriate surveillance measures in place.

 
Suitable candidates for BREVAGenplus™ testing include African American, Caucasian and Hispanic women aged 35 years and older; women with an above average clinical risk score (Gail lifetime risk) of 15% or greater; women with one or more clinical risk factors for sporadic breast cancer; women who do not qualify for a BRCA test or who have had a negative BRCA result; women concerned about their breast cancer risk. This testing is not suitable for woman who have had a previous diagnosis of breast cancer, lobular carcinoma in situ (LCIS) or ductal carcinoma in situ (DCIS).  

 

Phenogen Sciences maintains on its website a list of physicians by state who have been trained to use BREVAGen™/BREVAGenplus™.  If a state does not have a provider listed they advise to contact BREVAGen™ to find out how the physician can order BREVAGenplus™.

 

Summary  

   

Common SNPs have been shown in primary studies and meta-analyses to be significantly associated with breast cancer risk; some SNPs convey slightly elevated risk compared with the general population risk. Panels of SNPs are commercially available, with results synthesized into breast cancer risk estimates. These have not been clinically validated and clinical utility has not been demonstrated. Non-U.S. tests are commercially available as direct-to-consumer tests. Use of such risk panels for individual patient care or for population screening programs is premature because (1) performance of these panels in the intended-use populations is uncertain, and (2) most genetic breast cancer risk has yet to be explained by undiscovered gene variants and SNPs. Long-term prospective studies with large sample sizes are needed to determine the clinical validity and utility of SNP-based models for use in predicting breast cancer risk. The discrimination offered by the limited genetic factors currently known is insufficient to inform clinical practice.

 

There is a lack of published detail regarding OncoVue®, BREVAGen® and BREVAGenplus® test validation, supportive data, and management implications. Available data suggest that OncoVue®, BREVAGen® and BREVAGenplus® may add predictive accuracy to the Gail model. However, the degree of improved risk prediction may be modest, and clinical implications are unclear. There is insufficient evidence to determine whether using breast cancer risk estimates from OncoVue®, BREVAGen® or BREVAGenplus® in asymptomatic individuals changes management decisions and improves patient outcomes.


Practice Guidelines and Position Statements

 

American Society of Clinical Oncology (ASCO)

 

The 2010 American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility:

 

Emergence of Tests for Low Penetrance Genetic Variants
GWAS have identified genetic variations called single nucleotide polymorphisms (SNPs) that, although strongly associated with disease in large case-control studies, are usually not the DNA variations that alter the function of relevant gene products. Instead, the SNPs are located in close proximity to as yet unidentified causative variants. Unlike high- and intermediate-penetrance mutations, SNPs associated with disease risk are generally common (allele frequencies of up to 50% in the populations studied) and confer a modest increase in risk (per-allele odds ratios of < 1.5), although penetrance can vary based on environmental and lifestyle factors. As many as 100 SNPs are currently associated with cancer risk.

 
Several commercial laboratories currently offer genomic risk assessment, a type of genetic testing for SNPs associated with disease risk. In genomic risk assessment, the SNPs in an individual's genomic profile are identified (or genotyped) and translated into absolute risk estimates through the use of various algorithms. To date, no published studies are known to have established whether these algorithms are well calibrated or whether the risk estimates provided through genomic risk assessment are accurate. Because these tests have uncertain clinical validity, they are not currently considered part of standard oncology or preventive care.

 

Clinical Utility of Genetic Testing
Genetic tests for intermediate-penetrance mutations and genomic profiles of SNPS linked to low penetrance variants (LPVs) are of uncertain clinical utility because the cancer risk associated with the mutation or SNP is generally too small to form an appropriate basis for clinical decision making.

 

Recommendation

ASCO recommends that genetic tests with uncertain clinical utility, including genomic risk assessment, be administered only in the context of clinical trials.

 

American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility

In 2015, the American Society of Clinical Oncology updated the policy statement regarding genetic and genomic testing for cancer susceptibility which states: “ASCO recognizes that concurrent multigene testing (i.e 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 (VUSs) in a substantial proportion of patient cases, simply as a result of the multiplicity of genes tested. 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. Because of the current uncertainties and knowledge gaps, providers with particular expertise in cancer risk assessment should be involved in the ordering and interpretation of multigene panels that include genes of uncertain clinical utility and genes not suggested by the patient’s personal and/or family history. ASCO encourages research to delineate the optimal use of panel-based testing, development of evidence-based practice guidelines as data emerges, and education of providers regarding challenges in the use of these tests.”

 

National Comprehensive Cancer Network (NCCN) Version 1.2015 Breast Cancer Risk Reduction

Next generation sequencing allows for the sequencing of multiple genes simultaneously. This is referred to as multi-gene testing.

 

A major dilemma regarding multi-gene testing is that there are limited data and a lack of clear guidelines regarding degree of cancer risk associated with some of the genes assessed in multi-gene testing, and how to communicate and manage risk for carriers of these genes. This issue is compounded by the low incidence rates of hereditary disease, leading to difficulty in conducting adequately powered studies. Some multi-gene tests may include moderate-penetrance genes, for which there are little available data regarding degree of cancer risk and guidelines for risk management.

 

Further it is possible that the risks associated with these genes may not entirely be due to that gene only, but may be influenced by gene/gene or gene/environment interactions. Also, certain mutations in a gene may be associated with a different degree of risk than other mutations in that gene. For example, the presence of certain ATM mutations is associated with an increased risk for early-onset breast cancer and frequent bilateral occurrence, but the association between other ATM genetic variants and breast cancer susceptibility is less clear.

 

As a result of these dilemmas, risk management following detection of a mutation for a moderate-risk gene, and how risk should best be communicated to relatives, is currently unknown. Further, the information gained from testing for moderate-penetrance genes may not change risk management recommendations significantly compared to that based on family history only.

 

Multi-gene testing is a new and rapidly growing field, but there is currently a lack of evidence regarding proper procedures and risk management strategies that should follow testing, especially when mutations are found for moderate-penetrance genes and when a VUS is found. For this reason, the NCCN Panel recommends that multi-gene testing be offered in the content of professional genetic expertise, with pre- and post-test counseling being offered. Panel recommendations are in agreement with recommendations by ASCO, who issue an updated statement regarding genetic testing in 2015. Carriers of a genetic mutation should be encouraged to participate in clinical trials or genetic registries.    
 

Regulatory Status
No test combining the results of SNP analysis with clinical factors to predict breast cancer risk has been approved or cleared by the U.S. Food and Drug Administration (FDA). These are offered as laboratory-developed tests; that is, tests developed and used at a single testing site. Laboratory developed tests, as a matter of enforcement discretion, have not been traditionally regulated by FDA in the past. They do require oversight under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), and the development and use of laboratory developed tests is restricted to laboratories certified as high complexity under CLIA.

 

FDA has not yet developed specific rules for DTC genetic testing. On November 22, 2013, FDA issued a warning letter to 23andMe ordering the site to “immediately discontinue marketing the Saliva Collection Kit and Personal Genome Service until such time as it receives FDA marketing authorization for the device.” In February 2015, FDA granted marketing authorization to 23andMe for its Bloom syndrome DTC carrier test. 23andMe also provides “ancestry-related genetic reports and uninterpreted raw genetic data only.”

 

Under the current regulatory program, CLIA requires that laboratories demonstrate the analytical validity of the tests they offer. However, there is no requirement for a test to demonstrate either clinical validity or clinical utility.


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Prior Approval: 

 

Not applicable.


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Policy: 

Testing for one or more single nucleotide polymorphisms (SNPs) to predict an individual's risk of breast cancer is considered investigational.

 

The OncoVue® and BREVAGen® or BREVAGenplus® breast cancer risk tests are considered investigational for all indications, including but not limited to use as a method of estimating individual patient risk for developing breast cancer. 

 

There is a lack of published detail regarding OncoVue®, BREVAGen® and BREVAGenplus® test validation, supportive data, and management implications. Available data suggest that OncoVue®, BREVAGen® and BREVAGenplus® may add predictive accuracy to the Gail model. However, the degree of improved risk prediction may be modest, and clinical implications are unclear. There is insufficient evidence to determine whether using breast cancer risk estimates from OncoVue®, BREVAGen®   or BREVAGenplus® in asymptomatic individuals changes management decisions and improves patient outcomes.

 

No peer-reviewed reports have been published in which these commercially available breast cancer risk estimators have been compared to each other to determine if they report similar results on the same individuals specifically for breast cancer. Long-term prospective studies with large sample sizes are needed to determine the clinical validity and utility of SNP-based models for use in predicting the risk of breast cancer risk. Clinical-genetic tests may improve predictive accuracy of currently-used clinical risk predictors. However, the magnitude of improvement is small and clinical significance is uncertain. Whether potential harms of these tests due to false negative and false positive results are outweighed by potential benefit associated with improved risk assessment is unknown.  Therefore, the use of this testing is considered investigational.





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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.
  • 81479 Unlisted molecular pathology procedure
  • 81599 Unlisted multianalyte assay with algorithmic analysis

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Selected References: 

  • BREVEGen
  • OncoVue
  • National Comprehensive Caner Network (NCCN): NCCN Guidelines Version 1.2013 Breast Cancer Risk Reduction, Discussion
  • American Cancer Society Breast Cancer Genetics: Is Testing an Option?
  • American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility; Journal of Clinical Oncology, February 10, 2010 vol. 28 no 5 893-901
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  • National Comprehensive Cancer Network (NCCN),  Breast Cancer Risk Reduction Version 1.2015. Also available at www.nccn.org
  • National Comprehensive Cancer Network (NCCN), Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 2.2016. Also available at www.nccn.org
  • BREVAGenplus, also available at http://brevagen.com
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Policy History: 

 

Date                                        Reason                                Action

August 2013                                                                       New policy

June 2014                              Annual review                       Policy revised

May 2015                              Annual review                       Policy revised

April 2016                              Annual review                       Policy revised

 


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Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.

Contact Information
New information or technology that would be relevant for Wellmark to consider when this policy is next reviewed may be submitted to:
  Wellmark Blue Cross and Blue Shield
  Medical Policy Analyst
  P.O. Box 9232
  Des Moines, IA 50306-9232
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