BRCA1 and BRCA2 Genetic Testing

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for BRCA1 and BRCA2 Genetic Testing. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for BRCA1 and BRCA2 Genetic Testing and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site.

Internet Only Manual (IOM) Citations:

• CMS IOM Publication 100-03 Medicare National Coverage Determinations (NCD) Manual,
  • Chapter 1, Part 2, Section 90.2 Next Generation Sequencing (NGS) for Patients with Advanced Cancer
• CMS IOM Publication 100-02 Medicare Benefit Policy Manual,
  • Chapter 15, Section 80.1 Clinical Laboratory Services
• CMS IOM Publication 100-04, Medicare Claims Processing Manual,
  • Chapter 16 Laboratory Services
  • Chapter 23, Section 10 Reporting ICD Diagnosis and Procedure Codes 
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
  • Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD 

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury. 
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations. 

Federal Register References:

• 42 Code of Federal Regulations (CFR) Section 410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

History/Background and/or General Information

Cancer is the result of genetic alterations that 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.^19,27 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.^19,27 Epithelial ovarian cancer comprises the majority of malignant ovarian neoplasms.²⁰

While most breast cancers are considered sporadic, up to 10% are due to specific mutations in single genes that are passed down in families.^{16, 24} Similar rates are reported for ovarian cancer.²⁰ Specific patterns of breast and ovarian cancer are linked to the BRCA1 and BRCA2 genes, which cause hereditary breast and ovarian cancer syndrome HBOC.⁷ HBOC is an inherited cancer-susceptibility syndrome characterized by the following: ^{1, 27}

• Multiple HBOC related cancers within a family (i.e., invasive ductal carcinoma, ductal carcinoma in situ, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, melanoma, prostate cancer with Gleason score =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 HBOC (e.g., breast and ovarian);
• Cases of male breast cancer.

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.^{20, 33, 32} Studies indicate BRCA1 mutations are identified in 9% to 28% of patients with triple negative breast cancer.²⁰

Recently, germline genetic testing of BRCA1 and BRCA2 has been shown to be informative for treatment considerations in patients with ovarian cancer.² Specifically, olaparib, a poly (ADPribose) 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.

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.^1,20 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.^12,17,1,20 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.^12,17

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.^{23, 26, 30, 21} The 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.²⁰

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.^{25,8,10,5,15,13,9,6,20} 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 posttest 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.^28,29 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 HBOC as a preventive service with no out-of-pocket expense.

Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor approved by the FDA as monotherapy 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. Testing of ovarian cancer patients in this clinical scenario is indicated to guide treatment.²

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%²⁰ 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 gender of the individual and their age.

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.^{18, 14,20,28,29} Post-genetic testing counseling is also strongly recommended. The NCCN guidelines [2015] state that genetic counseling is a critical component of the cancer risk assessment process. In addition, the guidelines state that pretest 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.²⁰ Per the guidelines, posttest 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.²⁰

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 members is not a covered Medicare services. However, 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.^5,9,20,10,13 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.^17,20 Nonetheless, Medicare does not cover testing for patients without signs and symptoms of breast or ovarian cancer.

Multigene Panel Testing

Multigene panels for hereditary ovarian and breast cancer (HBOC) syndromes are available. In general, these panels test simultaneously for several genes associated with inherited breast and/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 hereditary cancer syndrome. All genes included in the test should be relevant to the personal and family history for the individual being tested.

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 fullsized protein or that is known to interfere with protein function in other ways and is associated with increased cancer risks.

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.²⁰ 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 CA125 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 Olaparib is recommended.^{2, 11}

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).²⁰

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.²⁰ Results are considered inconclusive if the individual is a carrier of an alteration that currently has no known clinical significance (variant of uncertain significance).²⁰

Covered Indications

This is a limited coverage LCD for BRCA1 and BRCA2 genetic testing. BRCA1 and BRCA2 genetic testing has been found to be reasonable and necessary in the following instances.

1. Personal History of Female Breast Cancer

BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer is covered in adults as medically reasonable and necessary when there is a personal history of breast cancer (invasive breast cancer or ductal carcinoma in situ) and ANY of the following indications:

• Diagnosed at age 45 or younger;
• Diagnosed at age 50 or younger with at least one close blood relative* with breast cancer at any age;
• Diagnosed with two breast primaries (includes bilateral disease or cases where there are two or more clearly separate ipsilateral primary tumors) when the first breast cancer diagnosis occurred prior to age 50;
• Diagnosed at age 60 or younger with a triple negative breast cancer (estrogen receptor [ER] negative, progesterone receptor [PR] negative, and human epidermal growth factor receptor 2 [HER2] negative);
• Diagnosed at any age and there are at least two close blood relatives* with pancreatic cancer or prostate cancer with Gleason score >7 at any age;
• Diagnosed at age 50 or younger with a limited family history (e.g., fewer than two first or second degree female relatives or female relatives surviving beyond 45 years in the relevant maternal and/or paternal lineage);
• Diagnosed at any age and there are at least two close blood relatives* with breast cancer at any age;
• Diagnosed at any age with at least one close blood relative* with breast cancer at age 50 or younger;
• Diagnosed at any age with at least one close blood relative* with epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer;
• Close male blood relative* with breast cancer;
• Individual of Ashkenazi Jewish descent (begin testing with Ashkenazi Jewish founder specific mutations). If negative, complete analysis may be considered if ancestry also includes non-Ashkenazi Jewish relatives or other criteria for BRCA1/BRCA2 genetic testing are met.

*NCCN defines blood relative as first- (parents, siblings and children), second- (grandparents, aunts, uncles, nieces and nephews, grandchildren and half-siblings), and third degree-relatives (great-grandparents, great-aunts, great uncles, great grandchildren and first cousins) on same side of family.

Genetic testing for a known mutation in a family is a covered service for individuals with signs and/or symptoms of breast cancer. Testing of an unaffected Medicare eligible individual or family member is not a covered Medicare service.

2. Personal History of Other Cancer

BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer is covered in adults as medically necessary when there is a personal history of ANY of the following indications:

• Personal history of epithelial ovarian, fallopian tube, or primary peritoneal cancer;
• Personal history of male breast cancer;
• Personal history of pancreatic cancer or prostate cancer with Gleason score =7 at any age, =1 close blood relatives* with breast (=50 y), invasive ovarian, pancreatic cancer, or prostate cancer with Gleason score =7 at any age;
• Personal history of pancreatic cancer at any age with Ashkenazi Jewish ancestry (Begin testing with Ashkenazi Jewish founder specific mutations). If negative, complete analysis should be performed. Complete analysis may be considered if ancestry also includes non-Ashkenazi Jewish relatives and other criteria for BRCA1/BRCA2 genetic testing are met.

Genetic testing for a known mutation in a family is a covered service for individuals with signs and/or symptoms of another inheritable cancer. Testing of an unaffected Medicare eligible individual or family member is not a covered Medicare service.

Medicare will cover BRCA-testing for an adopted individual with breast or ovarian cancer diagnosed ≤ 45 y or ≤ 60 y with triple negative breast cancer, or has a personal history of an "other" cancer (see above) that is suspicious of being a BRCA-related cancer. Individuals with little known family health history, come from small families, and in the case of sex-specific conditions, have few female/male relatives at risk of developing a particular condition, may also be eligible for BRCA gene testing. Similar to all testing, these situations require explanation of medical necessity for BRCA testing in the patient's medical record, and documentation of genetic counseling prior to BRCA testing.

3. Multigene Panels

NCD 90.2 Section B 2. describes specific coverage criteria for nationally covered Next Generation Sequencing (NGS) as a diagnostic laboratory test for patients with germline (inherited) cancer. Section 90.2 D 1. permits coverage of other NGS as a diagnostic laboratory test for patients with germline (inherited) cancer when performed and ordered according to the requirements described in that section. As such, genetic testing for susceptibility to breast or ovarian cancer with multi-gene NGS panels (not otherwise covered under NCD 90.2 Section B 2) may be covered by this AB MAC as reasonable and necessary when ALL of the NCD criteria are met in addition to the following:

• Pretest genetic counseling by a cancer genetics professional independent of the laboratory has been performed and posttest genetic counseling by a cancer genetics professional independent of the laboratory is planned;
• All genes in the panel are relevant to the personal and family history for the individual being tested (large panels with genes that are not relevant to the individual’s personal and family history are not reasonable and necessary);
• Criteria listed under Section 1, Personal History of Female Breast Cancer and/or Section 2 Personal History of Other Cancer are met;
• Individual also meets criteria for at least ONE other hereditary cancer syndrome for which NCCN guidelines provide clear testing criteria and management recommendations, including but not limited to LiFraumeni Syndrome, Cowden Syndrome, or Lynch Syndrome.

*While not required for payment, NCCN Guidelines recommend referral to a cancer genetics professional with expertise and experience in cancer genetics prior to genetic testing and after genetic testing. Examples of cancer genetics professionals with expertise and experience in cancer genetics include: an American Board of Medical Genetics or American Board of Genetic Counseling certified or board eligible Clinical Geneticist, Medical Geneticist or Genetic Counselor not employed by a commercial genetic testing laboratory (excludes individuals employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory test itself as these individuals are also considered independent); medical oncologist, obstetrician-gynecologist or other physician trained in medical cancer genetics, a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory (excludes individuals employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory test itself as these individuals are also considered independent).

Limitations

BRCA testing is limited to once-in-a-lifetime. If a patient has been previously tested for BRCA1 and BRCA2, repeat testing prior to olaparib therapy is not reasonable and necessary and will not be covered by Medicare. 

Non-Covered Indications

BRCA1/BRCA2 genetic testing for susceptibility to breast or ovarian cancer is not covered for any other indication including any of the following because it is considered not medically reasonable and necessary for these indications:

• Genetic screening in the general population. Such testing is considered screening and is excluded by Medicare statute. An ABN must be obtained for BRCA1 and BRCA2 testing for individuals without signs and symptoms of breast, ovarian or other hereditary cancer syndromes as indicated in this LCD.
• Testing of individuals with no personal history of breast, ovarian, fallopian tube, primary peritoneal, pancreatic, or prostate cancer. Such testing is considered screening and is excluded by Medicare statute. An ABN must be obtained for BRCA1 and BRCA2 testing for individuals without signs and symptoms of breast, ovarian or other hereditary cancer syndromes as indicated in this LCD.
• Testing of individuals under 18 years of age.

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Documentation Requirements

Refer to the related Local Coverage Article: Billing and Coding: BRCA1 and BRCA2 Genetic Testing (A57449) for documentation requirements, utilization parameters and all coding information as applicable.

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