Medical Policy: 02.04.44
Original Effective Date: August 2013
Reviewed: May 2015
Revised: May 2015
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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.
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. Some commercially available assays test for several SNPs and combine results to predict an individual's risk of breast cancer relative to the general population (using risk assessment tools such as Gail model/BCART). The intent of these assays is to identify those at increased risk of nonfamilial breast cancer who might 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.
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.
Clinical Genetic Tests
Two companies currently offer risk assessment based on SNP panel testing and clinical information, OncoVue® Breast Cancer Risk Test (InterGenetics™, Inc., Oklahoma City, OK) and BREVAGen™/BREVAGenplusTM (Phenogen Sciences, Charlotte, NC). Neither OncoVue® or BREVAGen™/BREVAGenplusTM is offered over the internet or directly to consumers. Patients may self-refer by finding the location of a participating member of the Breast Cancer Risk Testing Network, available on the InterGenetics website for OncoVue® or by using the BREVAGen™/BREVAGenplusTM doctor locator, available on the Phenogen Sciences website and making an appointment.
The OncoVue® Breast Cancer Risk Test (InterGenetics™, Inc., 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. The test is stated to be “an aid in the qualitative assessment of breast cancer risk, it is not intended as a stand-alone test for the determination of breast cancer risk in women.”
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™ (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™.
There is a lack of published literature regarding OncoVue® and BREVAGen™/BREVAGenplus™ test validation, supportive data, and management implications. The available data suggest that OncoVue® and BREVAGen™/BREVAGenplus™ may add predictive accuracy to the Gail Model. However, the degree of improved risk prediction may be modest, and the clinical implications are unclear. There is insufficient evidence to determine whether using breast cancer risk estimates from OncoVue® or BREVAGen™/BREVAGenplus™ in asymptomatic individuals changes management decisions and improves patient outcomes. Therefore, OncoVue® and BREVAGen™/BREVAGenplus™ testing for breast cancer risk assessment is are considered investigational.
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.
ASCO recommends that genetic tests with uncertain clinical utility, including genomic risk assessment, be administered only in the context of clinical trials.
National Comprehensive Cancer Network (NCCN) Version 1.2015 Breast Cancer Risk Reduction
Women > 35 years of age without a BRCA 1/2, TP53, or PTEN mutation; a strong family history or breast cancer; a history of thoracic radiation before age 30; or a history of LCIS should have their risk for breast cancer estimated according to the modified Gail model.
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.
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.
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.
Clinical utility of SNP panel tests and clinical genetic tests (e.g. OncoVue®, BREVAGen™/BREVAGenplus™) is unknown. Information about analytic performance (reproducibility) of marketed tests is lacking. Most tests are in an investigation phase of development, having demonstrated associations between the SNPs tested and breast cancer risk.
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.
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
- 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
- Assessment of Clinical Validity of a Breast Cancer Risk Modeling Combining Genetics and Clinical Information; Journal National Cancer Institute, 2010 Nov 3; 102(21): 1618-27
- Reeves GK, Travis RC, Green J et al. Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci JAMA 2010; 304(4):426-34
- Wacholder S, Hartge P, Prentice R et al. Performance of common genetic variants in breast-cancer risk models N Engl J Med 2010; 362(11):986-93
- Milne RL, Herranz J, Michailidou K et al. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium. Hum Mol Genet 2014; 23(7):1934-46.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines® in oncology: genetic/familial high-risk assessment: breast and ovarian, version 1.2014
- 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. Also available at www.nccn.org
- BREVAGenplus, also available at http://brevagen.com
- UpToDate. Risk Prediction Models for Breast Cancer Screening, Joann G. Elmore, M.D., MPH. Topic last updated October 28, 2014. Also available at www.uptodate.com
Date Reason Action
August 2013 New policy
June 2014 Annual review Policy revised
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.