LCD L36715: BRCA1 and BRCA2 Genetic Testing

Notice: It is not appropriate to bill Medicare for services that are not covered (as described by this entire LCD) as if they are covered. When billing for non-covered services, use the appropriate modifier.

Compliance with the provisions in this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

Cancer may be the result of genetic alterations which often result in the deregulation of pathways that are important for various cellular functions including growth, maintenance of DNA integrity, cell cycle progression, and apoptosis (programmed cell death), among others. Among women in the United States, breast cancer is the most common cancer diagnosis, excluding squamous and basal cell skin cancers. Breast cancer is the second leading cause of cancer deaths among women, after lung cancer. Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and the fifth most common cause of cancer mortality in women. Epithelial ovarian cancer comprises the majority of malignant ovarian neoplasms.

While most breast cancers are considered sporadic, up to 10% are due to specific mutations in single genes that are passed down in families. Similar rates are reported for ovarian cancer. Specific patterns of breast and ovarian cancer are linked to the BRCA1 and BRCA2 genes, which cause BRCA-related breast and ovarian cancer syndrome. BRCA-related breast and ovarian cancer syndrome is an inherited cancer-susceptibility syndrome characterized by the following:

• Multiple BRCA-related breast and ovarian cancer syndrome related cancers within a family (e.g., invasive ductal carcinoma, ductal carcinoma in situ, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, melanoma, prostate cancer with Gleason score greater than or equal to 7, pancreatic cancer and melanoma);

• Cancers typically occur at an earlier age than in sporadic cases (i.e, cancers not associated with inherited genetic risk);

• Two or more primary cancers in a single individual. This could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancers of different types related to BRCA-related breast or ovarian cancer (e.g., breast and ovarian);

• Cases of male breast cancer.

Mutations in the BRCA1 and BRCA2 genes are passed down in families through an autosomal dominant inheritance pattern meaning that the associated cancer predisposition can be inherited through either the mother’s or father’s side of the family and transmitted by a male or female. When a parent carries a BRCA mutation, there is a 50% chance of passing down the gene mutation with every pregnancy. Although the risk of inheriting the predisposition from a parent who carries a mutation is 50%, not everyone with an inherited mutation will develop cancer. The likelihood that a woman with a mutation will develop a related cancer (i.e., penetrance of a BRCA mutation) is estimated between 41% and 90% and is much lower for men. The risk of developing cancer depends on numerous variables, including the penetrance of the specific mutation, the genetic makeup of the individual, environmental risk factors, the sex of the individual, and their age.

In addition, there are some histopathologic features that have been noted to occur more frequently in breast cancers that are associated with BRCA1 or BRCA2 mutations. Multiple studies have demonstrated that BRCA1 breast cancer is more likely to be characterized as estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) negative, also referred to as triple negative breast cancer. Studies indicate BRCA1 mutations are identified in 9% to 28% of patients with triple negative breast cancer.

BRCA1 and BRCA2 Testing Overview

Germline genetic testing of BRCA1 and BRCA2 is available to identify individuals at increased risk for breast and ovarian cancers, as individuals with an inherited cancer syndrome may benefit from screening and prevention strategies to reduce their risk. The prevalence of BRCA mutations in the population is estimated between 1 in 300 and 1 in 800; however, specific mutations known as “founder mutations” occur more often in populations founded by a small ancestral group, including Ashkenazi (Eastern European) Jews, French Canadians, and Icelanders. The prevalence of BRCA mutations in the Ashkenazi Jewish population is approximately 1 in 40. Three recurrent BRCA1 and BRCA2 mutations have been identified in Ashkenazi Jewish individuals (i.e., a genetically distinct population of Jewish people of eastern and central European ancestry) and make up the vast majority of BRCA mutations that occur in this population.

Rearrangements, such as large genomic alterations including translocations, inversions, large deletions and insertions are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less common in BRCA2 and in individuals of Ashkenazi Jewish descent. The National Comprehensive Cancer Network (NCCN) guidelines note that comprehensive genetic testing includes full sequencing of BRCA1/BRCA2 and the detection of large genomic rearrangements. The NCCN recommends that since certain large genomic rearrangements are not detectable by a primary sequencing assay, additional testing may be needed in some cases.

Evidence in the published, peer-reviewed scientific literature indicates that BRCA1 and BRCA2 genetic testing is appropriate for a specific subset of adult individuals who have been identified to be at high risk for hereditary breast and ovarian cancers. Furthermore, several specialty organizations, including NCCN, American College of Medical Genetics (ACMG), and American Society of Clinical Oncology (ASCO), have issued statements recognizing the role of pre- and post-test genetic counseling and BRCA testing in the management of at-risk patients. The U.S. Preventive Services Task Force (USPSTF) has published recommendations regarding genetic risk assessment, genetic counseling and BRCA mutation testing for breast and ovarian cancer susceptibility. Based on this USPSTF recommendation, the Patient Protection and Affordable Care Act requires that private group and individual health plans provide coverage for genetic counseling and, if appropriate, genetic testing for women at risk for BRCA-related breast or ovarian cancer syndrome as a preventive service with no out-of-pocket expense.

Recently, germline genetic testing of BRCA1 and BRCA2 has been shown to be informative for treatment considerations in patients with ovarian cancer. Specifically, Lynparza, a poly (ADP-ribose) polymerase (PARP) inhibitor has been FDA approved for use as monotherapy in patients with ovarian cancer and with deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, who have been treated with three or more prior lines of chemotherapy.

Several national evidence-based and expert opinion guidelines and accrediting bodies recommend that genetic testing should be undertaken only in conjunction with independent pretest genetic counseling services in order to assist patients in complex clinical decision making. Post-genetic testing counseling is also strongly recommended. The NCCN guidelines state that genetic counseling is a critical component of the cancer risk assessment process. In addition, the guidelines state that pre-test counseling should include a discussion of why the test is being offered and how test results may impact medical management, cancer risks associated with the genes being tested, the significance of possible test results for the individual and family, the likelihood of a positive result, technical aspects and accuracy of the test, and economic considerations. Per the guidelines, post-test counseling includes disclosure of results, discussion of the significance of the results for the individual and relevant family members, a discussion of the impact of the results on psychosocial aspects and on the medical management of the individual, and how and where the patient will receive follow-up care and access to additional resources. (Genetic counseling is not a specified Medicare benefit category therefore is not a mandatory item for coverage.)

Multigene Panel Testing

Multigene panels for BRCA-related ovarian and breast cancer syndromes are available. In general, these panels test simultaneously for several genes associated with inherited breast or ovarian cancer, including but not limited to the BRCA1 and BRCA2 genes. The genes included and the methods used in multigene panels vary by laboratory. Some cancer susceptibility testing panels include genes that have not been associated with hereditary breast or ovarian cancer and, in some cases, are not clinically actionable. Testing with a targeted panel may be indicated as a cost-effective strategy when the individual’s symptoms or family history meet testing criteria for more than one BRCA-related cancer syndrome. All genes included in the test should be relevant to the personal and family history for the individual being tested. An increased likelihood of finding variants of unknown significance exists when testing for mutations in multiple genes. This is among the many reasons multigene testing is ideally offered in the context of professional genetic expertise.

Management of breast or ovarian cancer may be aided by genetic testing. For example, per NCCN Guidelines, a breast MRI may be recommended when the following gene tests indicate more than a 20% risk of breast cancer: ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53. A risk-reducing mastectomy may be an option based on gene or risk level of the following tests: BRCA1, BRCA2, CDH1, PTEN, TP53, or PALB2 or a risk-reducing salpingo-oophorectomy may be considered based on the following: BRCA1, BRCA2, Lynch syndrome, BRIP1, RAD51C, or RAD51D. Even with insufficient evidence from the following tests, intervention may still be warranted based on family history or other clinical factors: BRIP1, ATM, CHEK2, STK11, or PALB2.

Test Results and Management

A positive BRCA test result reveals the presence of a mutation in either the BRCA1 or BRCA2 gene that prevents the translation of the full-sized protein or that is known to interfere with protein function in other ways and is associated with increased cancer risks.

A negative BRCA test result is interpreted within the context of a patient's individual and family cancer history, notably regarding whether any family member has previously been identified as carrying a mutation or not. An affected individual who has tested negative for a BRCA mutation may still have an inherited predisposing mutation in one of the BRCA genes that was not identified by testing, or a mutation in another gene that predisposes to breast or ovarian cancer. An individual in whom testing reveals they do not carry a BRCA1 or BRCA2 mutation that has been positively identified in another family member is considered to have a true negative result (i.e., they have not inherited the BRCA mutation nor associated increased cancer risks identified in other family members).

A person is considered to have an indeterminate result if that person is not a carrier of a known cancer-predisposing gene mutation and the carrier status of all other biologic family members is either also negative or unknown. Results are considered inconclusive if the individual is a carrier of an alteration that currently has no known clinical significance (variant of uncertain significance).

Several strategies have been proposed for achieving the goal of reducing cancer risk for individuals with known BRCA mutations. The NCCN guidelines include detailed strategies and evidence review for at-risk patients. For women these strategies include breast self-exams (BSE), clinical breast exams (CBE), mammograms, breast magnetic resonance imaging (MRI), risk-reducing bilateral salpingo-oophorectomy, discussion of risk-reducing bilateral mastectomy, and use of trans-vaginal ultrasound and CA-125 in women who have not elected risk-reducing ovarian surgery. For men these include BSE and CBE starting at age 35 and consideration of mammography and prostate cancer screening starting at age 40. For both men and women recommendations include education regarding signs and symptoms of cancer(s), especially those associated with BRCA gene mutations, and screening may be individualized based on cancers observed in the family.

In patients with ovarian cancer with deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation who have been treated with three or more prior lines of chemotherapy, consideration of treatment with the PARP inhibitor Lynparza is recommended.

Once a mutation is identified in the family, Medicare eligible relatives with signs and symptoms of breast cancer are typically tested for that specific mutation only. For patients of Ashkenazi Jewish descent, initial testing is generally done for the three specific mutations that account for most hereditary breast and ovarian cancer in that population: 185delAG and 5382insC (also called 5385insC) in the BRCA1 gene and 6174delT in the BRCA2 gene. If the test results are negative, full analysis of the BRCA1 and BRCA2 genes is only considered if testing criteria for non-Jewish individuals are met.

Medicare is a defined benefit program and requires that testing is only performed on patients with signs and symptoms of disease. Testing of unaffected individuals or family member is not a covered Medicare service.

CRITERIA FOR FURTHER GENETIC RISK EVALUATION:

The patient must have a personal history of breast or ovarian cancer. Testing of unaffected individuals or family member is not a covered Medicare service therefore the NCCN risk evaluation that is performed must be applied to patients with the diagnosis confirmed of cancer of ovarian or breast origin if payment is to be considered by Novitas. This risk evaluation that follows is performed to determine if a formal risk assessment is necessary.

NCCN Criteria for further genetic risk evaluation include:

• An individual with ovarian* cancer

• An individual of Ashkenazi Jewish descent with breast cancer, ovarian* cancer, or pancreatic cancer at any age

• An individual with a personal or family history of three or more of the following (especially if early onset and can include multiple primary cancers in same individual):

• breast cancer,

• pancreatic cancer,

• prostate cancer (Gleason score greater than or equal to 7),

• melanoma,

• sarcoma,

• adrenocortical carcinoma,

• brain tumors,

• leukemia,

• diffuse gastric cancer,

• colon cancer,

• endometrial cancer,

• thyroid cancer,

• kidney cancer,

• dermatologic manifestations or macrocephaly,

• hamartomatous polyps of gastrointestinal (GI) tract

• An individual with a breast cancer diagnosis meeting any of the following:

• A known mutation in a cancer susceptibility gene within the family

• Early-age-onset breast cancer

• Triple negative (ER-, PR-, HER2-) breast cancer diagnosed at 60 years of age or less

• Two primary breast cancer primaries in a single individual

• Male breast cancer

• Breast cancer at any age and

• greater than or equal to 1 close blood relative** with breast cancer at 50 years of age or less, or

• greater than or equal to 1 close blood relative** with invasive ovarian* cancer at any age, or

• greater than or equal to 2 close blood relatives** with breast cancer or pancreatic cancer at any age, or

• From a population at increased risk

• An individual with personal history of cancer with one or more of the following:

• A close relative** with any of the following:

• A known mutation in a cancer susceptibility gene within the family

• greater than or equal to 2 breast cancer primaries in a single individual

• greater than or equal to 2 individuals with breast cancer primaries on the same side of family with at least one diagnosed at 50 years of age or less

• Ovarian* cancer

• Male breast cancer

• First- or second-degree relative** with breast cancer at 45 years of age or less

• Family history of three or more of the following (especially if early onset and can include multiple primary cancers in same individual):

• breast cancer,

• pancreatic cancer,

• prostate cancer (Gleason score greater than or equal to 7),

• melanoma,

• sarcoma,

• adrenocortical carcinoma,

• brain tumors,

• leukemia,

• diffuse gastric cancer,

• colon cancer,

• endometrial cancer,

• thyroid cancer,

• kidney cancer,

• dermatologic manifestations or macrocephaly,

• hamartomatous polyps of gastrointestinal (GI) tract

BRCA 1 and BRCA 2 testing consists of full sequence and duplication/deletion analysis. Genetic testing for a known mutation in a family may be limited to the known familial variant.

Coverage Indications, Limitations, and/or Medical Necessity

Covered Indications

INDICATIONS FOR BRCA 1 AND BRCA 2 TESTING

The following indications for BRCA 1 and BRCA 2 testing are covered by Medicare:

Personal history of breast, ovarian, pancreatic or prostate cancer with the following RISK Assessment (stratification) items (1-8 below) that are to be considered before testing in those patients with one of the four mentioned cancers that is suspected to be of hereditary origin.

N/A