Medical Policy: 02.04.44
Original Effective Date: August 2013
Reviewed: April 2020
Revised: April 2020
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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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 variants (SNVs), 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 a number SNVs 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 this type of test is to identify those individuals at increased risk who may benefit from more intensive surveillance.
Single-gene variants conferring a high risk of breast cancer have been linked to hereditary breast cancer syndromes. Examples are variants in BRCA1 and BRCA2. These, and a few other genes, account for less than 25% of inherited breast cancer. Moderate risk alleles, such as variants in the CHEK2 gene, appear to at least moderately increase the risk of breast cancer.
In contrast, several common single nucleotide variants (SNVs) 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, and the increased breast cancer risk associated with each is very small relative to the general population risk. Some have suggested that these common-risk SNVs 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 has recommended that women at high risk (>20% lifetime risk) should undergo breast magnetic resonance imaging and a mammogram every year, and those at moderately increased risk (15%-20% lifetime risk) should talk with their doctors about the benefits and limitations of adding magnetic resonance imaging screening to their yearly mammogram.
The purpose of genetic testing in asymptomatic individuals is to predict the risk of disease occurrence. The criteria under which prognostic testing may be considered clinically useful are as follows:
The relevant population of interest is individuals who have not been identified as being at high risk of breast cancer. This population would include individuals who do not have a family member who had breast cancer (non-familial).
The intervention of interest is testing for common single nucleotide variants (SNVs) associated with a small increase in the risk of breast cancer. Patients who are asymptomatic and at average risk of breast cancer by clinical criteria are actively managed by internists in an outpatient clinical setting.
The following practice is currently being used to predict the risk of breast cancer: standard clinical risk prediction without testing for common SNVs associated with risk of breast cancer.
The outcomes of interest are a reclassification of individuals from normal risk and evidence of a change in management (eg, preventive or screening strategies) that results in improved health outcomes.
Follow-up over 5 to 10 years is needed to monitor the occurrence of breast cancer.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Genome-wide association studies (GWAS) examine the entire genome of thousands of subjects for SNVs at semi-regular intervals and attempt to associate SNV alleles with particular diseases. Several case-control GWAS, primarily in white women, have investigated common-risk markers of breast cancer. A number of SNVs associated with breast cancer have been reported at a high level of statistical significance and have been validated in 2 or more large, independent studies.
A number of systematic reviews and meta-analyses have investigated the association between breast cancer and individual SNVs. Meta-analyses of case control studies have indicated that specific SNVs are associated with increased or decreased breast cancer risk (see below table). Other meta-analyses have revealed the interaction between the environment (e.g. obesity, age at menarche) or ethnicity and breast cancer risk conferred by certain SNVs. Meta-analyses of genome-wide association studies (GWAS) have identified SNVs at new breast cancer susceptibility loci. All of these markers are considered to be in an investigational phase of development.
|8q24 [G-allele of rs13281615]||X|
|8q24 [homozygous A-alleles of rs13281615]||X|
|ATR-CHEK1 checkpoint pathway genes||X|
|CYP1A2 1F [A-allele of rs762551]||X|
|Fibroblast growth factor receptor genes||X|
|MAP3K1 [C-allele of rs889312 and G-allele of rs 16886165||X|
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.
One potential use of SNV testing is to evaluate the risk of breast cancer for chemoprevention. In 2017, Cuzick et al assessed whether a panel of 88 SNPs could improve risk prediction over traditional risk stratification using data from 2 randomized tamoxifen prevention trials. The study included 359 cases and 636 controls, with the 88 SNPs assessed on an Illumina OncoArray that evaluated approximately half a million SNPs. The primary outcome was breast cancer or ductal carcinoma in situ. The 88 SNP score improved discriminability above the Tyrer-Cuzick risk evaluator; however, there was modest improvement in the percentage of women who were classified as high risk. The percentage of women with a 10-year risk of recurrence of 8% or more was estimated to be 18% for Tyrer-Cuzick and 21% when the 88 SNP score was added. The SNP score did not predict which women would benefit from tamoxifen.
The number of common low-penetrance single nucleotide variants (SNVs) associated with breast cancer is rapidly increasing. No studies were identified that provide direct evidence that use of SNV-based risk assessment has any impact on health care outcomes. Indirect evidence from an improvement in risk prediction with an 88 SNV panel has been reported, although the improvement in risk prediction is modest.
There is insufficient evidence to determine whether using SNVs for breast cancer risk in asymptomatic individuals changes management decisions and improves patient outcomes.
The OncoVue Breast Cancer Risk Test (InterGenetics Inc., Oklahoma City, OK) is a proprietary test that evaluates multiple, low risk single nucleotide variants (SNVs) associated with breast cancer. The 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 ri and 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 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 member centers 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. Participating centers located throughout the United States are listed on the OncoVue website. OncoVue is not listed in the Genetic Testing Registry of the National Center for Biotechnology Information.
On October 6, 2014 Phenogen Sciences, Inc. Charlotte, NC, announced the availability of BREVAGenplus. This test is an enhancement of the company’s first generation product BREVAGen that included 7 single nucleotide variants (SNVs). BREVAGenplus includes a greatly expanded SNV panel (over 70) 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 single nucleotide variants (SNVs) 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, and having first degree relatives with breast cancer (if any)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 BREVAGenplus. If a state does not have a provider listed they advise to contact BREVAGen to find out how the physician can order BREVAGenplus.
Based on review of the peer reviewed medical literature the available data suggests that BREVAGenplus may add predictive accuracy to the Gail model, however, the degree of improved risk prediction may be modest and clinical implications are unclear. Other panel tests have fewer data to support conclusion about their clinical validity and clinical utility. Use of such risk panels for individual patient care or population screening programs is premature because performance of these panels in the intended-use population is uncertain and most genetic breast cancer risk has yet to be explained by undiscovered gene variants and SNVs.
For individuals who are asymptomatic and at average risk of breast cancer by clinical criteria (no family history) who receive testing for single nucleotide variants (SNVs) associated with a small increase in the risk of breast cancer no studies were identified that provide direct evidence that use of SNV-based risk assessment has any impact on net health care outcomes. Long-term prospective studies with large sample sizes are needed to determine the clinical validity and utility of SNV-based models for use in predicting breast cancer risk. The NCCN guideline Breast Cancer Risk Reduction Version 1.2019 includes, for women not considered to be at risk for familial/hereditary breast cancer, an evaluation of elements of risk that contribute to increased breast cancer risk is recommended and include: demographics factors such as female gender, age, ethnicity/race, life-style factors such as lack of exercise and alcohol consumption, BMI, individuals receiving early thoracic irradiation to the chest and breast areas before age 30 and reproductive history include nulliparity, prolonged interval between menarche and age at first live birth (e.g. early menarche or late age at first live birth), onset of menarche at a younger age, onset of menopause at older age. All women should be counseled regarding healthy lifestyle recommendations to decrease breast cancer risk and to avoid lifestyle that would adversely impact their chance of developing the disease. The modified Gail model is a computer-based, multivariate, logistic regression model that uses age, race, age at menarche, age at first live birth or nulliparity, number of first degree relatives with breast cancer, number of previous biopsies, and histology of breast biopsies to produce actuarial estimates of future breast cancer risk. Women with a life expectancy ≥ 10 years and no diagnosis/history of breast cancer who are considered to be at increased risk for breast cancer based on any of the above-mentioned assessments, should receive counseling and should undergo breast screening in the NCCN Guidelines for Breast Cancer Screening and Diagnosis. If life expectancy is < 10 years there is probably minimal if any benefit to risk-reduction therapy or screening. The evidence is insufficient to determine the effects of the technology on health outcomes.
In 2017, the American College of Obstetricians and Gynecologists issued a practice bulletin (number 179, replaces practice bulletin number 122 August 2011), regarding breast cancer risk assessment and screening in average risk women which states the following:
Clinical Considerations and Recommendations:
For women not considered to be at risk for familial/hereditary breast cancer, an evaluation of elements of risk that contribute to increased breast cancer risk is recommended. These include demographics factors such as female gender, age, and ethnicity/race. There is an increased incidence of BRCA 1/2 mutation reported in women of Ashkenazi Jewish decent.
Reproductive history is another factor to consider. Risk factors linked to reproductive history include nulliparity, prolonged interval between menarche and age at first live birth (e.g. early menarche or late age at first live birth), onset of menarche at a younger age, onset of menopause at older age.
Body mass index (BMI) is an independent risk factor for breast cancer, especially in Caucasian women. This increase in risk has been attributed to increase in circulating endogenous estrogen levels from fat tissue. In addition, the association between BMI and risk for postmenopausal breast cancer is stronger for hormone receptor positive tumors. Lifestyle factors such as current or prior hormone therapy (HT), alcohol consumption, and to a lesser extent, smoking also contribute to the risk of developing breast cancer.
Other factors to consider are number of breast biopsies, done with the intent to diagnose cancer.
Individuals receiving early thoracic irradiation encompassing the chest-breast areas before age 30 (e.g., to treat Hodgkin’s disease) is a significant risk factor for the development of breast cancer.
Change in breast density has been suggested as a risk factor for breast cancer. Dense breast tissue is measured by mammography is increasingly recognized as an important risk factor for breast cancer.
There are many elements that may reduce the risk of cancer. Breast feeding has been shown to have predictive effect in many studies.
Exercise has also been shown to reduce the risk of breast cancer, especially in post-menopausal women.
Oophorectomy before age 45 years and risk reduction therapy have a protective effective.
The modified Gail model is a computer-based, multivariate, logistic regression model that uses age, race, age at menarche, age at first live birth or nulliparity, number of first degree relatives with breast cancer, number of previous biopsies, and histology of breast biopsies to produce actuarial estimates of future breast cancer risk.
Women with a life expectancy ≥ 10 years and no diagnosis/history of breast cancer who are considered to be at increased risk for breast cancer based on any of the above-mentioned assessments, should receive counseling and should undergo breast screening in the NCCN Guidelines for Breast Cancer Screening and Diagnosis. Counseling should be tailored to the individual, to decrease breast cancer risk (e.g., risk-reduction surgery in BRCA 1/2 mutation carriers; therapy with risk-reduction agents in those without a contraindication to these agent(s).
If life expectancy is < 10 years there is probably minimal if any benefit to risk-reduction therapy or screening (see NCCN Guidelines for Breast Cancer Screening and Diagnosis and NCCN Guidelines for Breast Cancer).
Women with a diagnosis of DCI should be managed according to recommendations outlined in the NCCN Guidelines for Breast Cancer)
Evidence from studies indicate that in addition to family history and genetics, environmental factors play a significant role. As discussed under Other Elements of Risk, life-style factors such as lack of exercise and alcohol consumption are linked with risk for developing breast cancer and are some of the modifiable components.
Patients should be encouraged to maintain a healthy lifestyle and to remain up-to-date with recommendations for screening and surveillance.
Numerous studies have demonstrated that the intake of moderates amounts of alcohol (1-2 drinks per day) is associated with an increased risk for breast cancer. The consensus of the NCCN Breast Cancer Risk Reduction Panel is that alcohol consumption should be limited to ≤1 drink per day. The panel has defined one drink as 1 ounce of liquor, 6 ounces of wine, or 8 ounces of beer.
Increased levels of physical activity have been associated with a decreased risk for breast cancer.
As discussed under the section on Elements of Risk, there is a substantial amount of evidence indicating that overweight or obese women have a higher risk for postmenopausal breast cancer.
While there is no clear evidence that specific dietary components can effectively reduce breast cancer risk, weight gain and obesity in adulthood are risk factors for the development of postmenopausal breast cancer.
Counseling should also involve discussion of other factors that may have protective effect, if appropriate, such as planning first childbirth at a younger age and encouraging breastfeeding.
Breast cancer risk assessment provides a means of identifying healthy women without a history of personal breast cancer, who are at increased risk of future development of this disease. All women should be counseled regarding healthy lifestyle recommendations to decrease breast cancer risk and to avoid lifestyle that would adversely impact their chance of developing the disease. However, many of the risk factors for breast cancer are not modifiable.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. BREVAGenplus (Phenogen Sciences, a subsidiary of Genetic Technologies) and OncoVue Breast Cancer Risk Test (InterGenetics, Inc., Oklahoma City, OK) is available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this testing.
Testing for one or more single nucleotide variants (SNVs), including but not limited to the following, to predict an individual's risk of breast cancer is considered investigational as the evidence is insufficient to determine the effects of the technology on net health outcomes.
|Single Nucleotide Variants (SNVs)|
|8q24 [G-allele of rs13281615]|
|8q24 [homozygous A-alleles of rs13281615]|
|ATR-CHEK1 checkpoint pathway genes|
|CYP1A2 1F [A-allele of rs762551]|
|Fibroblast growth factor receptor genes|
|MAP3K1 [C-allele of rs889312 and G-allele of rs 16886165|
OncoVue 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 as the evidence is insufficient to determine the effects of the technology on net health outcomes.
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