**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.