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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. Some of these incorporate clinical information into risk prediction algorithms. The intent of both types of test is to identify subjects 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 the 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 then vary by starting age and intensity according to risk. Along these lines, the American Cancer Society recommends that women at high risk (>20% lifetime risk) should undergo breast magnetic resonance imaging (MRI) and a mammogram every year, and those at moderately increased risk (15% to 20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their yearly mammogram.
SNP Panel Tests
Several companies, such as those listed in the table below, offer testing for breast cancer risk profiles using SNPs. Non-U.S. companies offer testing direct-to-consumers (DTCs). Algorithms or risk models for these tests are proprietary. When reported on company websites, panels range in number from 6 to 15 SNPs.
Tests for Breast Cancer Susceptibility Using SNP-Based Risk Panels (a)
DTC: direct-to-consumer; ND: not described; SNP: single nucleotide polymorphism
Clinical Genetic Tests
Two companies currently offer risk assessment based on SNP panel testing and clinical information. Neither is provided as a DTC test. Only BREVAGen is currently listed in the Genetic Testing Registry of the National Center for Biotechnology Information.
The OncoVue® Breast Cancer Risk Test (InterGenetics, Oklahoma City, OK) is a proprietary test that evaluates multiple, low-risk single nucleotide polymorphisms (SNPs) 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, see Genetic Testing for Hereditary Breast and/or Ovarian Cancer medical policy. 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 prior to testing, OncoVue® purports to estimate a woman’s individual risk and place her in standard-, moderate-, or high-risk groups. Results are intended to help a woman and her physician decide if more frequent exams and/or more sophisticated surveillance techniques are indicated.
BREVAGenplus® (Phenogen Sciences, Charlotte, NC) evaluates breast cancer-associated SNPs identified in genome-wide association studies (GWAS). The first-generation test, BREVAGen, included 7 SNPs. Per the company website, BREVAGenplus incorporates an “expanded panel” of SNPs. Risk is calculated by combining individual SNP risks with the Gail model risk. BREVAGenplus has been evaluated for use in African-American, Caucasian, and Hispanic patient samples age 35 years and older. Like OncoVue®, BREVAGenplus does not detect known high-risk mutations, e.g., in BRCA. According to the BREVAGenplus website, the test is best suited for women with a Gail lifetime risk of 15% or greater or with one or more clinical risk factors for sporadic breast cancer; or for women who do not qualify for a BRCA test or who have had a negative BRCA result and are concerned about their breast cancer risk. BREVAGenplus is not suitable for women with previous diagnoses of lobular carcinoma in situ, ductal carcinoma in situ, or breast cancer, since the Gail model cannot calculate breast cancer risk accurately for such women, or for women with an extensive family history of breast and ovarian cancer.
No SNP-based test to predict breast cancer risk has been approved or cleared by the U.S. Food and Drug Administration (FDA). These tests are offered as laboratory-developed tests under the Clinical Laboratory Improvement Amendments (CLIA) licensed laboratories. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratories offering such tests as a clinical service must meet general regulatory standards of CLIA and must be licensed by CLIA for high-complexity testing.
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 regulations, 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.
Genetic Testing for Hereditary Breast and/or Ovarian Cancer is addressed in a separate policy.
Testing for 1 or more single nucleotide polymorphisms (SNPs) to predict an individual’s risk of breast cancer is considered investigational.
The OncoVue® and 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.
POLICY GUIDELINESInvestigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member’s specific benefit plan language.
POLICY HISTORY10/13/2009: Policy added
11/19/2009: Approved by MPAC
11/17/2010: Policy reviewed; no changes.
10/05/2011: Policy reviewed; no changes.
09/27/2012: Policy reviewed; no changes.
10/22/2013: Policy description updated regarding BREVAGen™. Added BREVAGen™ to the policy statement as investigational. Deleted outdated references from the Sources section. Added CPT code 81479 to the Code Reference section.
10/30/2014: Non-BRCA Breast Cancer Risk Assessment medical policy combined into this policy with new title: "Use of Common Genetic Variants (Single Nucleotide Polymorphisms) to Predict Risk of Nonfamilial Breast Cancer." Policy description updated. Added policy statement that testing for 1 or more single nucleotide polymorphisms (SNPs) to predict an individual’s risk of breast cancer is considered investigational. Policy statement updated to state that the OncoVue® and BREVAGen™ tests are considered investigational for all indications.
07/23/2015: Code Reference section updated for ICD-10.
03/03/2016: Policy description updated regarding SNP panel tests and clinical genetic tests. Policy statement updated to change "BREVAGen" to "BREVAGenplus®." Investigative definition updated in policy guidelines section. Deleted outdated reference from the Sources section.
SOURCESBlue Cross Blue Shield Association Policy # 2.04.63
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.