**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 gender 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:

  1. An individual with ovarian* cancer  
  

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

  3. 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  
  

  4. 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  
  

  5. 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.

    1. Personal history of ovarian* carcinoma  
  

    2. Personal history of male breast cancer  
  

    3. Individual from a family with a known deleterious BRCA1/BRCA2 gene pathogenic mutation  
  

    4. Personal history of breast cancer and one or more of the following indications:  

      * Diagnosed at 45 years of age or less;
      * Diagnosed at 50 years of age or less with:  

        * An additional breast cancer primary at any age;
        * at least 1 close blood relative** with breast cancer at any age;
        * An unknown or limited family history;
      * Diagnosed at 60 years of age or less 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 with:  

        * at least 1 close blood relative** with breast cancer diagnosed at 50 years of age or less; or
        * at least 1 close blood relative** with ovarian* cancer; or
        * at least 1 close blood relative** with pancreatic cancer; or
        * at least 1 close blood relative** with prostate cancer (Gleason score greater than or equal to 7 or metastatic); or
        * at least 1 close male blood relative** with breast cancer; or
        * at least 2 additional diagnoses of breast cancer in patient and/or in close blood relative(s) at any age;
      * Individual of ethnicity associated with higher pathogenic mutation frequency (e.g. Ashkenazi Jewish)  
  

    5. Personal history of pancreatic cancer   
  

    6. Personal history of prostate cancer (Gleason score greater than or equal to 7) at any age with
      * at least 1 close blood relative** with ovarian* cancer, pancreatic cancer, or metastatic*** prostate cancer at any age or breast cancer (at 50 years of age or less); or
      * at least 2 close blood relatives with breast cancer, or prostate cancer (any grade) at any age; or
      * Ashkenazi Jewish ancestry  
  

    7. Personal history of metastatic*** prostate cancer  
  

    8. BRCA1/2 pathogenic mutation detected by tumor profiling on any tumor type in the absence of germline pathogenic mutation analysis   
  

    9. Personal history of cancer types listed above with a family history only (significant limitations of interpreting test results for an unaffected individual exists and therefore are not a covered benefit):  

      * First- or second-degree blood relative** meeting any of the above criteria
      * Third-degree blood relative* who has breast cancer or ovarian* carcinoma and who has at least 2 close blood relatives** with breast cancer (at least one with breast cancer at 50 years of age or less) or ovarian* carcinoma

Similar to all testing, the following situations require explanation of
medical necessity for BRCA testing in the patient's medical record:

  * Individuals with little known family health history,
  * Individuals who come from small families, and
  * In the case of sex-specific conditions, individuals who have few female/male relatives at risk of developing a particular condition.
  * 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 pathogenic 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.

**Multigene Panels Indications******

  * NCD 90.2 Section B 2. describes specific coverage criteria for nationally covered NGS as a diagnostic laboratory test for patients with germline (inherited) cancer. Section 90.2 D 2. 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:
    * All genes in the panel are relevant to the personal and family history for the individual being tested (panels with genes that are not relevant to the individual's personal and family history are not reasonable and necessary);
    * Criteria listed above in Indications for BRCA1 and BRCA2 Testing #4, #5, #6, or #7 are met.
    * Individual also meets criteria for at least ONE BRCA-related cancer syndrome for which NCCN guidelines provide clear testing criteria and management recommendations, including but not limited to BRCA-related breast or ovarian** cancer syndrome, Li-Fraumeni Syndrome, Cowden Syndrome, or Lynch Syndrome.

*Includes fallopian tube, and primary peritoneal cancers. BRCA-related ovarian cancers are associated with epithelial non-mucinous histology.

**NCCN defines close or 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 (either maternal or paternal) of the family.

*** Biopsy-proven and/or with radiographic evidence. It is not a biochemical
recurrence.

**** 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 or an Advanced Practice Nurse
in Genetics 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**  
  
 **Testing of an unaffected Medicare eligible individual or family member is
considered not reasonable and necessary.**  
  
BRCA1/BRCA2 genetic testing is considered not reasonable and necessary, thus
it is non-covered, for the following indications:

    1. Genetic screening in the general population or
    2. **_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 BRCA 1 and BRCA 2 testing for individuals without signs and symptoms of breast, ovarian* or other BRCA-related cancer syndromes as indicated in this policy.
    3. Testing of individuals less than 18 years of age.
    4. If a patient has been previously tested for BRCA1 and BRCA2, repeat testing prior to Lynparza therapy is not reasonable and necessary and will not be covered by Medicare.

For frequency limitations please refer to the Utilization Guidelines section
below.  
  
**Notice:** Services performed for any given diagnosis must meet all of the
indications and limitations stated in this policy, the general requirements
for medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.