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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 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.
Various companies now offer such SNP-derived risk estimates. For example, deCODE (Reykjavik, Iceland) offers the deCODE BreastCancer™ test, based on a panel of 7 SNPs identified primarily in genome-wide association studies. The website, 23andme.com, which offers direct-to-consumer (DTC) testing, includes 3 SNPs in known genes in their “Health Edition” test: 2 detect common polymorphisms in BRCA1 and BRCA2 genes associated with hereditary breast cancer in Ashkenazi Jewish populations, and one that detects a CHEK2 moderate risk variant. Navigenics (Foster City, CA) includes information on breast cancer risk in their overall DTC comprehensive genetic testing panel but does not appear to identify the individual SNPs used in their panel on their website. A comprehensive list of companies offering DTC genetic testing for various diseases including breast cancer is maintained and regularly updated by the Genetics and Public Policy Center.
Tests combining the results of SNPs to predict breast cancer risk are available either as a laboratory-developed service by physician order from a clinical laboratory licensed for high complexity testing under the Clinical Laboratory Improvement Amendments (CLIA); or as a DTC laboratory-developed service. In the latter case, it is not clear that the laboratory is necessarily CLIA-licensed although some states have chosen to regulate DTC laboratories in the same way as clinical laboratories (e.g., New York state). None of these tests have been cleared by the U.S. Food and Drug Administration.
As examples, but not inclusive of all available services, The deCODE BreastCancer™ test requires a physician order (however, the deCODEme Cancer Scan, which includes a breast cancer risk estimate, does not); 23andme and Navigenics accept direct consumer test orders; and all three companies either contract with or operate CLIA-licensed laboratories to do their genetic testing. The companies themselves mathematically combine single marker results into risk estimates and provide interpretations.
The OncoVue® Breast Cancer Risk Test (InterGenetics, Inc.) is a proprietary test for which the status of multiple single nucleotide polymorphisms (SNPs) is evaluated and the results incorporated along 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. OncoVue synthesizes the various 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. 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.
The OncoVue test 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 members will provide genetic breast cancer risk testing for 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 a number of criteria, including quality standards of care, level of breast cancer surveillance technology, and the capability of providing patient education on genetic testing and future risk management protocols.
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 risks 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 known high-risk mutations, e.g., BRCA. According to the BREVAGen website, “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, 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 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.
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 BREVAGen™ 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 service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
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.
SOURCESBlue Cross Blue Shield Association Policy # 2.04.57 and 2.04.63
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.