MEDICAL POLICY

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APPENDIX
HISTORY

Genetic Testing for Hereditary Breast and/or Ovarian Cancer

Number 12.04.504

Effective Date January 13, 2014

Revision Date(s) 01/13/14; 08/12/13; 06/10/13; 10/15/12; 05/08/12; 05/10/11; 04/13/10; 12/08/09; 06/10/08; 05/08/07; 03/13/07; 02/13/07; 02/14/06; 02/08/05

Replaces 2.04.504 and 2.04.02

Policy

Genetic testing for a BRCA1 or BRCA2 mutation, associated with genetic counseling, may be considered medically necessary when the ANY of the following criteria are met:

Personal History of Breast Cancer

Persons WITH breast cancer who have ANY of the following:

  • Two or more first or second degree relatives (related through a single lineage) with breast or pancreatic cancer;
  • One first or second degree relative (related through a single lineage) with breast cancer diagnosed at an early age (e.g. < 50 years);
  • One first or second degree relative (related through a single lineage) with ovarian/fallopian tube/primary peritoneal cancer diagnosed at any age;
  • One first-degree relative with bilateral breast cancer
  • Persons (themselves) with breast cancer diagnosed at an early age (e.g. <50 years);
  • Persons (themselves) with breast cancer with multiple primary breast cancers or bilateral disease;
  • Persons (themselves) with breast cancer AND who are from an ethnic background, e.g., Ashkenazi Jewish descent, associated with deleterious founder mutations (see Policy Guidelines);
  • Persons (themselves) with breast AND ovarian/fallopian tube/primary peritoneal cancer, even if not simultaneous; or
  • Persons (themselves) with a triple negative breast cancer (estrogen receptor-negative, progesterone receptor-negative and HER2-negative),diagnosed age<60 years
  • Men (themselves) who develop breast cancer at any age.

Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer

  • Persons WITH epithelial ovarian/fallopian tube/primary peritoneal cancer at any age.

Personal history of pancreatic cancer

  • Persons WITH pancreatic cancer at any age with 2 or more first or second degree relatives with breast and/or pancreatic cancer at any age.

No Personal History/Family History Only

Persons WITHOUT breast, ovarian/fallopian tube/primary peritoneal or pancreatic cancer who have ANY of the following:

  • Two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 or younger.
  • A combination of 3 or more first- or second-degree relatives with breast cancer, regardless of age of diagnosis;
  • At least one first- or second-degree relative with breast cancer and at least one first- or second-degree relative with ovarian/fallopian tube/primary peritoneal cancer;
  • One first-degree relative with bilateral breast cancer;
  • A combination of 2 or more first- or second-degree relatives with ovarian/fallopian tube/primary peritoneal cancer, regardless of age of diagnosis;
  • One first- or second-degree relative with both breast and ovarian/fallopian tube/primary peritoneal cancer, at any age;
  • A history of breast cancer in a first degree male relative;
  • For women who are from an ethnic background , e.g., Ashkenazi Jewish heritage, associated with a high prevalence of deleterious founder mutations (see Policy Guidelines), and who have one or more first-degree relatives (or 2 second-degree relatives, related through a single lineage) with breast or ovarian/fallopian tube/primary peritoneal cancer at any age; or
  • Individuals (male or female) from families with a known BRCA1 or BRCA2 mutation.

Not meeting criteria of either “Personal History” or “No Personal History” section

Testing of unaffected individuals not meeting the criteria in either section may be considered medically necessary when all of the following three criteria are met:

  • History of:
  • First- or second-degree blood relative meeting any of the criteria in the Personal History section or
  • Third degree blood relative with breast cancer and/or ovarian cancer with 2 or greater close blood relatives with breast cancer (at least one with breast cancer age 50 or younger) and/or ovarian cancer; AND
  • The affected family member is unavailable for testing (see below); AND
  • There are very few individuals (fewer than 2 first- or second-degree female relatives or female relatives surviving beyond 45 years in either lineage) in which to observe the manifestation of the gene.

Testing of the affected family member not covered by the Plan may be considered medically necessary to provide the medical information necessary for decision-making for the unaffected Premera member only when all of the following criteria are met:

  • The information is needed to adequately assess risk in the Plan member: AND
  • The information will be used in the immediate care plan of the Plan member; AND
  • The non-Plan member’s benefit plan (if any) will not cover the test. A copy of the denial letter from the non-Plan member’s benefit plan must be provided.

Testing for genomic rearrangements of the BRCA1 and BRCA2 genes (also known as BART) may be considered medically necessary in patients who meet criteria for BRCA testing and whose testing for point mutations is negative.

Testing for CHEK2 genetic abnormalities (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer irrespective of the family history.

Unless they meet the criteria above, genetic testing either for those affected by breast, ovarian, fallopian tube, or primary peritoneal cancer or for unaffected individuals, including those with a family history of pancreatic cancer, is considered investigational.

Related Policies

12.04.57

Non-BRCA Breast Cancer Risk Assessment (OncoVue®)

12.04.63

Use of Common Genetic Variants to Predict Risk of Non-Familial Breast Cancer

12.04.91

General Approach to Genetic Testing

12.04.93

Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

Policy Guidelines

Families at high risk for harboring a BRCA1 or BRCA2 mutation are those in which the incidence of breast or ovarian cancer in first- or second-degree relatives suggests an autosomal dominant inheritance, i.e., about half the family members are affected. However, this criterion identifies only a subset of mutation carriers, and may not adequately cover the possibility of paternal transmission of a BRCA1 or BRCA2 mutation. Men rarely develop breast cancer and thus there may not be an affected first-degree relative, and the size of the family may not permit analysis of possible autosomal dominant inheritance. Moreover, a recent study in the Ashkenazi Jewish population (see Rationale), in which 2% of women have a founder BRCA mutation, showed that approximately 50% of mutation carriers came from families in which the incidence of cancer is low and not suggestive of hereditary breast cancer.

Definition: Early age at diagnosis refers to diagnosis at a premenopausal age; an exact cutoff for testing affected individuals without known family history but with cancer diagnosis at an early age has not been established, although guidelines of the American College of Medical Genetics suggest age 45 or younger and the US Preventive Task Force guidelines suggest age < 50. The decision to test an affected individual based on age at diagnosis in the absence of family history will depend on the risk estimate for the individual patient (e.g., from widely available risk assessment computer programs) and the patient tolerance for risk.

Definition: Close blood relative typically refers to first-degree (parent, full sibling, or offspring) and second-degree (grandparent, grandchild, uncle, aunt, niece, nephew, or half-sibling) relatives in diseases associated with high penetrance gene mutations such as BRCA1 and BRCA2 mutations. Accommodation may be made to include third-degree relatives (first cousin, great grandparent or great grandchild) in some cases, e.g., limited family history, particularly in tracing hereditary breast and ovarian and related cancers in the paternal lineage. Certified genetic counselors or other qualified genetics professionals are best able to assess exceptional cases.

Testing Unaffected Individuals

  • As the majority of test results will be negative and uninformative in unaffected family members of potential BRCA mutation families,an affected family member must be tested first whenever possible to adequately interpret the test. Should a BRCA mutation be found in an affected family member(s), the DNA from the unaffected family member can be tested specifically for the same mutation of the affected family member without having to sequence the entire gene.
  • Interpreting the testing results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result, but leads to difficulties in interpreting negative test results because the possibility of a BRCA mutation is not ruled out.
  • NCCN Guidelines caution:
  • The significant limitations of interpreting results for an unaffected individual should be discussed
  • Clinical judgment should be used to determine if the patient has reasonable likelihood of a mutation, considering the unaffected patient’s current age and the age of female unaffected relatives who link the patient with the affected relatives.

In patients with breast or ovarian cancer who are from high-risk families without a known BRCA1 or BRCA2 gene, and who are not from ethnic groups with known founder mutations, comprehensive BRCA mutation analysis should be performed.

Testing in eligible individuals who belong to ethnic populations in which there are well-characterized founder mutations should begin with tests specifically for these mutations. For example, founder mutations account for approximately three-quarters of the BRCA mutations found in Ashkenazi Jewish populations (see Rationale). When the testing for founder mutations is negative, comprehensive mutation analysis should then be performed.

Note: Founder mutations are associated with certain ethnic backgrounds and are not necessarily tied to specific countries. Requests for founder mutation testing other than Ashkenazi Jewish heritage will be considered on a case-by-case basis.

For this policy, cancer of the fallopian tube and primary peritoneal cancer are also considered BRCA-associated malignancies and are to be considered in assessing the family history.

Prostate Cancer

Patients with BRCA mutations have an increased risk of prostate cancer, and patients with known BRCA mutations may therefore consider more aggressive screening approaches for prostate cancer. However, the presence of prostate cancer in an individual, or in a family, is not itself felt to be sufficient justification for BRCA testing.

Description

Several genetic syndromes with an autosomal dominant pattern of inheritance that feature breast cancer have been identified. Of these, hereditary breast and ovarian cancer (HBOC) and some cases of hereditary site-specific breast cancer have in common causative mutations in BRCA genes. Families suspected of having HBOC syndrome are characterized by an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, and ovarian cancer at any age. Other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, laryngeal cancer, occur more frequently in HBOC families. Hereditary site-specific breast cancer families are characterized by early onset breast cancer with or without male cases, but without ovarian cancer. For this policy, both will be referred to collectively as hereditary breast and/or ovarian cancer.

Germline mutations in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in the majority of HBOC families, especially if ovarian cancer or male breast cancer are features. However, in site-specific breast cancer, BRCA mutations are responsible for only a proportion of affected families, and research to date has not yet identified other moderate or high-penetrance gene mutations that account for disease in these families. BRCA gene mutations are inherited in an autosomal dominant fashion through either the maternal or paternal lineage. It is possible to test for abnormalities in BRCA1 and BRCA2 genes to identify the specific mutation in cancer cases, and to identify family members with increased cancer risk. Family members without existing cancer who are found to have BRCA mutations can consider preventive interventions for reducing risk and mortality.

BART

In August 2006, the BRAC Analysis Rearrangement Test (BART) was introduced. This refinement of the BRAC test detects rare, large rearrangements of the DNA in the BRCA1 and BRCA2 genes and is performed for women with exceptionally high risk who have tested negative for sequence mutations and the common large rearrangements already included in Myriad’s test. Myriad will conduct the BART on patient samples where the individual’s personal and family history is indicative of an exceptionally high level of risk, but the sample tests negative for BRAC analysis.

CHEK2

CHEK2 (cell cycle checkpoint kinase2) is also involved with DNA repair and human cancer predisposition like BRCA1 and BRCA2. CHEK2 is normally activated in response to DNA double-stranded breaks.

CHEK2 regulates the function of BRCA1 protein in DNA repair and also exerts critical roles in cell cycle control and apoptosis. The CHEK2 mutation, 1100delC in exon 10 has been associated with familial breast cancers.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply.

Benefit Application

The U.S. Food and Drug Administration (FDA) has not regulated these tests because to date they have been offered as laboratory-developed services, subject only to the general laboratory operational regulation under the Clinical Laboratory Improvement Amendments (CLIA) of 1988. Laboratories performing clinical tests must be certified for high complexity testing under CLIA.

The USPSTF recommends that women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. (Grade B recommendation)

Consistent with federal mandates, these services are covered as preventive care (without cost sharing) when the member’s contract is subject to those mandates, and when the member meets the medical necessity criteria outlined in this policy. The medical necessity criteria listed here are congruent with USPSTF evidence review and guidelines.

Note: The U.S. Preventive Services Task Force (USPSTF) recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene (BRCA) testing for women whose family history is not associated with an increased risk for deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2). (Grade D recommendation)

The Company interprets this recommendation as supportive of a medical necessity review prior to coverage of BRCA testing in the general population.

Rationale

2004 Update

Articles published since the TEC Assessment and last policy update were reviewed for information regarding professional guidelines for BRCA testing, testing of unaffected family members, and testing of high-risk ethnic populations. In addition, Web sites for relevant professional organizations were consulted for posted guidelines.

The American Society of Clinical Oncology (ASCO) recommends that cancer predisposition testing be offered when: 1) the person has a strong family history of cancer or very early age of onset of disease; 2) the test can be adequately interpreted; and 3) the results will influence the medical management of the patient or family member.

In 1999, the American College of Medical Genetics (ACMG) published guidelines for BRCA testing under the auspices of a grant from the New York State Department of Health to the ACMG Foundation. The guidelines suggest that increased risk for a mutation in a known cancer susceptibility gene is evident if:

  • There are three or more affected first or second degree relatives on the same side of the family, regardless of age at diagnosis, or
  • There are fewer than three affected relatives, but:
  • The patient was diagnosed at 45 years of age or less;
  • A family member has been identified with a detectable mutation; or
  • There are one or more cases of ovarian cancer at any age, and one or more members on the same side of the family with breast cancer at any age; or
  • There are multiple primary or bilateral breast cancers in the patient or one family member; or
  • There is breast cancer in a male patient, or in a male relative; or
  • The patient is at increased risk for specific mutations(s) due to ethnic background (for instance: Ashkenazi Jewish descent) and has one or more relatives with breast cancer or ovarian cancer at any age.

“At present, it is not recommended that the health care provider initiate discussion of the testing option with unaffected Ashkenazi Jewish individuals unless additional factors are uncovered in the family or personal history (i.e., one or more relatives with breast and/or ovarian cancer). For that matter it, is not currently recommended that widespread screening of any subpopulation be initiated.”

Early estimates of lifetime risk of cancer for BRCA mutation carriers (penetrance), based on studies of families with extensive history of disease, have been as high as 85%. Because factors that influence risk may be present in families with extensive breast and ovarian cancer histories, early penetrance estimates may have been biased upward. Studies of founder mutations in ethnic populations (e.g., Ashkenazi Jewish, Polish, and Icelandic populations) unselected for family history indicate lower penetrance estimates, in the range of 40%-60% for BRCA1 and 25%-40% for BRCA2. However, a recent genotyping study of Ashkenazi Jewish women with incident, invasive breast cancer, selected regardless of family history of cancer, and their family members resulted in an 82% lifetime risk of breast cancer for carriers of any of 3 BRCA founder mutations. Importantly, the risk of cancer in mutation carriers from families with little history of cancer (~50% of all carriers) was not significantly different. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Women with a history of breast cancer and a BRCA mutation have a significant risk of contralateral breast cancer; in 1 study the risk was 29.5% at 10 years for women with initially stage I or II disease.

Thus, the risk of cancer in a BRCA mutation carrier is significant, and knowledge of mutation status in individuals at potentially increased risk of a BRCA mutation may impact healthcare decisions to reduce risk. Risk-reducing options include intensive surveillance, prophylactic mastectomy, or prophylactic oophorectomy. Prophylactic mastectomy reduces the risk of breast cancer in high-risk women (based on family history) by 90% or more but is invasive and disfiguring. Prophylactic oophorectomy significantly reduces the risk of ovarian cancer to less than 10% and reduces the risk of breast cancer by approximately 50%. In women who have already had breast cancer, prophylactic oophorectomy reduces the risk of cancer relapse. Studies indicate that genotyping results significantly influence treatment choices.

BRCA mutation-associated cancers may have biologically different properties. In 1 study, 5-year survival was reported as poorer in women with BCRA1-associated breast cancer compared to non-carriers (63% vs. 91%). Conversely, in another study BRCA mutation carrier vs. non-carrier median survival of ovarian cancer was 53.4 vs. 37.8 months. However, there is no clear indication that cancer treatment should be modified based on BRCA status.

The prevalence of BRCA mutations is approximately 0.1%-0.2% in general population. Prevalence may be much higher for particular ethnic groups with characterized founder mutations (e.g., 2%-3% in the Ashkenazi Jewish population). Family history of breast and ovarian cancer is an important risk factor for BRCA mutation. Age and, in some cases, ethnic background can also be independent risk factors.

Young age of onset of breast cancer, even in the absence of family history, has been demonstrated to be a risk factor for BRCA1 mutations. Winchester estimated that hereditary breast cancer accounts for 36%-85% of patients diagnosed under age 30. In several studies, BRCA mutations are independently predicted by early age at onset, being present in 6%-10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (ages 35-50 years). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 mutations is in the 40s. In the Ashkenazi Jewish population, Frank et al. reported that 13% of 248 cases with no known family history and diagnosed before 50 years of age had BRCA mutations. In a similar study, 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA mutations. Additional studies indicate that early age of breast cancer diagnosis is a significant predictor of BRCA mutations in the absence of family history in this population.

As in the general population, family history of breast or ovarian cancer, particularly of early age onset, is a significant risk factor for a BRCA mutation in ethnic populations characterized by founder mutations. For example, in unaffected individuals of Ashkenazi Jewish descent, 12%-31% will have a BRCA mutation depending on the extent and nature of the family history. Several other studies document the significant influence of family history.

Unaffected individuals with a known family history but unknown family mutation may obtain interpretable results in most cases of a positive test. Most BRCA1 and BRCA2 mutations reported to date consist of frameshift deletions, insertions, or nonsense mutations leading to premature truncation of protein transcription. These are invariably deleterious and thus are informative in the absence of an established family genotype. In addition, specific missense mutations and noncoding intervening sequence mutations may be interpreted on the basis of accumulated data or from specific functional or biochemical studies. However, some mutations may have uncertain significance in the absence of a family study, and negative results offer no useful information, i.e., the patient may still be at increased risk of a mutation.

2006 Update

Articles published since the 2005 update were reviewed for information that might affect the policy statements or relevant background information in this document. However, nothing was found that would prompt reconsideration of the policy statements. Nor did any new publications contradict or substantially add to the background information. Guidelines published by the American Society of Clinical Oncology and the American College of Medical Genetics have not been updated since 2004.

2007 Update

Walsh and colleagues reported on the failure of BRCA1 and BRCA2 testing in approximately 12% of breast cancer patients (n=300) who were referred prior to their diagnosis from genetic testing because they were members of a family with at least 4 cases of breast cancer and/or ovarian cancer. In this study, researchers retested participants for carrier status of genetic mutations known to influence risk for development of breast cancer using a molecular method not currently cleared for market in the United States known as multiplex ligation-dependent probe amplification (MLPA). Prior to enrollment, all participants had received a negative result of BRCA1 and BRCA2 testing. The results of the MLPA analysis indicated that of the 300 families, 52 (17%) were, in fact, carriers of breast cancer genetic mutations and 12% had alterations of BRCA1 and BRCA2. The authors concluded that among patients with breast cancer and severe family histories of cancer who test negative for BRCA1 and BRCA2, effective methods for identifying these rare mutations should be made available to women at high risk. The clinical implications of these findings cannot be generalized to other populations, but results strongly suggest that improved methods for determining breast cancer risk are needed for individuals with strong family histories of breast cancer.

2008 Update

This policy was updated with a literature review using MEDLINE in January 2008. While the ASCO and ACMG guidelines noted above have not been updated, new guidelines for breast and ovarian cancer susceptibility have been published by the U.S. Preventive Services Task Force and the National Comprehensive Cancer Network. Table 3 in the USPSTF review includes a summary of criteria from various groups on genetic testing in this situation. These guidelines help to better define families where there is a “high risk of a mutation” and also provide information about testing both for men with breast cancer and for women with ovarian cancer.

A clinical approach to these patients was recently published by Robson and Offit. Phillips reported that while uptake of prophylactic surgery and screening was associated with knowing one’s mutation status, in their cohort of 70 unaffected female mutation carriers who had chosen to receive results, the minority utilized risk-reducing surgery (11% had bilateral mastectomy and 29% bilateral oophorectomy) or chemoprevention. Rennert and colleagues reported that breast cancer-specific rates of death among Israeli women were similar for carriers of a BRCA founder mutation and noncarriers. Malone and colleagues reported on racial and ethnic differences in the prevalence of BRCA1 and BRCA2 in American women. Among their cases, 2.4% and 2.3% carried deleterious mutations in BRCA1 and BRCA2, respectively. BRCA1 mutations were significantly more common in “white” (2.9%) versus “black” (1.4%) cases and in Jewish (10.2%) versus non-Jewish (2.0%) cases; BRCA2 mutations were slightly more frequent in “black” (2.6%) versus “white” (2.1%) cases.

Using information from the USPSTF, a family at high risk of having a mutation is determined by having any of the following characteristics: 3 or more first- or second-degree relatives with breast cancer regardless of age at diagnosis; or 2 first-degree relatives with breast cancer, one of whom was diagnosed at age 50 years or younger; or combination of both breast and ovarian cancer among first- and second-degree relatives; or first-degree relative with bilateral breast cancer; or a combination of 2 or more first- or second-degree relatives with ovarian cancer regardless of age at diagnosis; or a first- or second-degree relative with both breast and ovarian cancer at any age; or a history of breast cancer in a male relative. In addition, based on information in the NCCN guidelines and in recognition of changes in management (including mammography) that can occur in males with, or at high risk for, breast cancer, testing males affected by breast cancer was added to the policy statement.

In applying this policy, an accurate family history is a key component in deciding which patients will be tested. In interpreting this history, it is important to evaluate the maternal and paternal lineage separately.

Other Cancers

BRCA1 mutations are also associated with increased risks of other malignancies, including prostate and colorectal cancer, although these risks are ill defined. Couch et al. studied familial pancreatic cancer and noted that BRCA2 mutations accounted for 6% of moderate and high-risk pancreatic cancer families.

However, current evidence-based guidelines from leading medical professional organizations have not recommended BRCA testing for assessment of risk of prostate cancer, pancreatic cancer, colon cancer or other non-breast cancers.

2009 Update

A literature search for the period of July 2008 through October 2009 found no studies which would alter the policy statement; therefore, the policy statement is unchanged.

2010 Update

Testing for Large BRCA Rearrangements (BART)

Over the past few years, a number of studies have shown that a significant percentage of women with a strong family history of breast cancer and negative tests for BRCA mutations have large genomic rearrangements (including deletions or duplications) in one of these genes. For example, in 2006 Walsh and colleagues reported on probands from 300 US families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic tests for BRCA1 and BRCA2. These patients underwent screening with additional multiple DNA-based and RNA-based methods. Of these 300 patients, 17% carried previously undetected mutations, including 35 (12%) with genomic rearrangement of BRCA1 or BRCA2.

A more recent study evaluated 251 patients with an estimated BRCA mutation using the Myriad II model of 10% or greater. In the 136 non-Ashkenazi Jewish probands, 36 (26%) had BRCA point mutations and 8 (6%) had genomic rearrangements, 7 in BRCA1 and 1 in BRCA2. No genomic rearrangements were identified in the 115 Ashkenazi Jewish probands, but 47 of the 115 (40%) had point mutations. In this population genomic rearrangements constituted 18% of all identified BRCA mutations. The authors also indicated that the estimated prevalence of a mutation was not predictive of the presence of a genomic rearrangement.

Thus, based on these published studies, testing for genomic rearrangements of BRCA1 and BRCA2 may be considered medically necessary when testing for standard mutations is negative in familial breast cancer when (1) there are 4 or more family members (one lineage) affected with breast and/or ovarian cancer or (2) in individuals with a risk of a BRCA mutation of at least 10%.

Commercial laboratories began this expanded testing in August 2006. Thus, BRCA testing done before this starting time would have had analysis for genomic rearrangement. Subsequent to that, based on information available from the laboratory, this additional testing is conducted on the subset of patients whose likelihood of a BRCA mutation is 30% or greater. When the likelihood of a BRCA mutation is between 10% and 30%, the test for genomic rearrangement must be ordered separately.

CHEK2 Mutations

A number of publications have also described the association of CHEK2 (cell cycle checkpoint kinase 2) mutations with hereditary breast cancer. The prevalence of this finding varies greatly by geographic regions, being most common in northern and eastern Europe. It has been detected in 4% of early breast cancer patients in the Netherlands, in 2.3% of such patients in Germany, but has been noted to be rare in these patients in Spain or Australia. In the US, this mutation is much less common than BRCA mutations and BRCA rearrangements. For example, in the study by Walsh cited above, 14 (4.7%) of the 300 patients with a positive family history of breast cancer (4 affected relatives) who were negative by standard BRCA testing, were positive for CHECK2 mutations. The low frequency makes evaluation of risk and treatment implications less precise. In general, the risk of breast cancer associated with this mutation is less that that associated with either BRCA1 or BRCA2.

A meta-analysis by Weischer concluded that for familial breast cancer, the cumulative risk at age 70 years for CHEK2*1100delC mutation was 37% (confidence interval 26% to 56%). This risk is lower than cumulative risk at age 70 of 57% for BRCA1 and 49% for BRCA2. In an accompanying editorial, Offit and Garber raise a number of questions about potential use of this assay. In particular, they raise questions about the breast cancer risk estimates presented in the Weischer study; a number of the questions relate to the variable methods of ascertainment used in the studies in this meta-analysis. They also note that other mutations, such as CHEK2*S428F, are observed in other populations. The varying frequency is mentioned, with the mutation noted in 0.5 – 1.0% of the population in northern and eastern Europe compared with 0.2 – 0.3% in the US. Finally, they raise concerns about the implications of the low penetrance of this mutation. They concluded that on the basis of data available at this time, there is not compelling evidence to justify routine clinical testing for CHECK2 to guide the management of families affected with breast cancer. Thus, based on a number of concerns, testing for CHEK2 mutations is considered investigational because the impact on net health outcome is uncertain.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

In response to requests, input was received through 3 Physician Specialty Societies (5 reviews) and 3 Academic Medical Centers (5 reviews) while this policy was under review for January 2010. While the various Physician Specialty Societies and Academic Medical Centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the Physician Specialty Societies or Academic Medical Centers, unless otherwise noted. Those providing input were in general agreement with the policy statements considering testing for genomic rearrangements of BRCA1 and BRCA2 as medically necessary, and CHEK2 testing as investigational.

2011 Update

The National Cancer Institute updated their statement “Low Penetrance Predisposition To Breast and Ovarian Cancer” in February 2011. Regarding CHEK2 and four other low-penetrance polymorphisms, they state:

“There is a very large literature grouping of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.”

2012 Update

Triple Negative Breast Cancer

In patients with breast cancer that is “triple-negative”, i.e., negative for expression of estrogen and progesterone receptors and for overexpression of HER2 receptors, there is an increased incidence of BRCA mutations. Pathophysiologic research has suggested that the physiologic pathway for development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer. In 200 randomly selected patients with triple-negative breast cancer from a tertiary care center, there was a greater than 3-fold increase in the expected rate of BRCA mutations. BRCA1 mutations were found in 39.1% of patients and BRCA2 mutations in 8.7%. Young et al. studied 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing. A total of 6 BRCA mutations, 5 BRCA1 and 1 BRCA2, were found for a mutation rate of 11%. Finally, in a study of 77 patients with triple-negative breast cancer, 15 patients (19.5%) had BRCA mutations: 12 in BRCA1 and 3 in BRCA2.

Pancreatic and Ovarian Cancer

Unaffected individuals may also be at high risk due to other patterns of non-breast cancer malignancies. A personal history of pancreatic cancer is estimated to raise the risk of a BRCA mutation by 3.5-10-fold over the general population. Couch et al. reported on screening for BRCA in 2 cohorts of families at high risk for pancreatic cancer. In the first cohort of high-risk families, there were a total of 5 BRCA mutations in 151 probands, and in the second cohort, there were another 5 BRCA mutations in 29 probands. The combined BRCA mutation rate for these 2 cohorts was 6% (10/180). Ferrone et al. tested 187 Ashkenasi Jewish patients with pancreatic cancer for BRCA mutations and found that 5.5% (8/187) had a BRCA mutation.

Women with a personal history of ovarian cancer also have an increased rate of BRCA mutations. In a systematic review of 23 studies, Trainer et al. estimated the rate of BRCA mutations for women with ovarian cancer to be in the range of 3-15%. In this review, there were 3 studies that were performed in the United States and tested for both BRCA1 and BRCA2. The incidence of BRCA mutations in these studies was 11.3%, 15.3%, and 9.5%. In a population-based study of 1,342 unselected patients with invasive ovarian cancer performed in Canada, there were 176 women with BRCA mutations, for a rate of 13.3%. The prevalence of mutations was higher for women in their 40s (24.0%) and in women with serous ovarian cancer (18.0%). Ethnicity was also an additional risk factor for BRCA, with higher rates seen in women of Italian (43.5%), Jewish (30.0%), and Indo-Pakistani origin (29.4%).

A clinical approach to these patients was recently published by Robson and Offit. Phillips et al. reported that while uptake of prophylactic surgery and screening was associated with knowing one’s mutation status, in their cohort of 70 unaffected female mutation carriers who had chosen to receive results, the minority utilized risk-reducing surgery (11% had bilateral mastectomy and 29% bilateral oophorectomy) or chemoprevention. Rennert and colleagues reported that breast cancer-specific rates of death among Israeli women were similar for carriers of a BRCA founder mutation and noncarriers. Malone and colleagues reported on racial and ethnic differences in the prevalence of BRCA1 and BRCA2 in American women. Among their cases, 2.4% and 2.3% carried deleterious mutations in BRCA1 and BRCA2, respectively. BRCA1 mutations were significantly more common in “white” (2.9%) versus “black” (1.4%) cases and in Jewish (10.2%) versus non-Jewish (2.0%) cases; BRCA2 mutations were slightly more frequent in “black” (2.6%) versus “white” (2.1%) cases. Couch et al. studied familial pancreatic cancer and noted that BRCA2 mutations accounted for 6% of moderate and high-risk pancreatic cancer families.

A recent publication described the high rate of occult fallopian tube cancers in at-risk women having prophylactic bilateral salpingo-oophorectomy. In this prospective series of 45 women, 4 (9%) were found to have fallopian tube malignancies. The authors noted that this supports other studies that have demonstrated the fimbrial end of the fallopian tube as an important site of cancer in those with BRCA1 or BRCA2 mutations. Similarly, the current NCCN guidelines for assessing high risk in breast and ovarian cancer (2) include both fallopian tube and primary peritoneal cancer as other malignancies that should be asked about when assessing family history to make a decision regarding testing for BRCA1 and BRCA2. Thus, these 2 conditions are added to the policy statements and Policy Guidelines.

CHEK2

Zhang et al. performed a systematic review of candidate-gene association studies, identifying more than 1,000 published articles. Meta-analysis was performed for a total of 279 genetic variants in 128 genes that were identified by at least 3 different researchers. Significant associations with the risk of breast cancer were found for 29 variants in 20 genes. The association was strong for 10 variants in 6 genes, 4 of which were located in the CHEK2 gene. There was also a strong association found for two variants of the ATM gene and an additional 4 genes that had a single variant with a strong association (CASP8, CTLA4, NBN, and TP53).

Peng et al. performed an overview of systematic reviews and pooled analyses on the association of genetic variants with breast cancer. A total of 87 analyses were identified, which examined 145 candidate gene variants and found that 46 variants were significantly associated with breast cancer. The odds ratios for these associations ranged from 0.66 to 3.13. Using the method of false-positive report probability, there were 10 associations in 7 genes that were noteworthy. These genes were CASP8, CHEK2, CTLA4, FGFR2, ILIB, LSP1, and MAP3K1.

2013 Update

NCCN Guidelines

These guidelines are included for information only and are not meant to replace the criteria in the Policy statement.

The National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer were updated in 2013. Criteria for genetic testing for the hereditary breast and/or ovarian cancer syndrome included 3 factors: 1) there is a personal or family history suggesting genetic cancer susceptibility; 2) the test can be adequately interpreted; and 3) the results will aid in the diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer.

Note: Testing for Family History only:

  • NCCN emphasizes:
  • There are significant limitations of interpreting test results for an unaffected individual and
  • Testing of unaffected individuals should only be considered when an appropriate affected family member is unavailable for testing.

The NCCN definition of a personal or family history suggesting genetic cancer susceptibility requires at least one of the following criteria to be present:

  • Individual from a family with a known deleterious BRCA1/BRCA2 mutation.
  • Personal history of breast cancer plus one or more of the following:
  • Diagnosed at age <45 years
  • Two breast primaries when the first breast cancer diagnosis occurred at age 50 years or younger
  • Diagnosed age 50 years or younger with one or more close blood relative with breast cancer at any age or with a limited family history
  • Diagnosed age 60 years or younger with a triple negative breast cancer
  • Diagnosed at any age with one or more close blood relatives with breast cancer diagnosed age 50 years or younger
  • Diagnosed at any age, with two or more close blood relatives with breast cancer at any age
  • Diagnosed at any age with one or more close blood relatives with epithelial ovarian cancer
  • Diagnosed at any age with two or more close blood relatives with pancreatic cancer or aggressive prostate cancer (Gleason score 7 or greater)
  • Close male relative with breast cancer
  • For an individual of ethnicity associated with higher mutation frequency (e.g., Ashkenazi Jewish) no additional family history may be required
  • Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer
  • Personal history of male breast cancer
  • Personal history of pancreatic cancer or aggressive prostate cancer (Gleason score 7 or greater) at any age with 2 or more close blood relatives with breast and/or ovarian cancer at any age and/or pancreatic cancer or aggressive prostate cancer (Gleason score 7 or greater) at any age
  • Family history only (significant limitations of interpreting test results for an unaffected individual should be discussed):
  • Testing of unaffected individuals should only be considered when an appropriate affected family member is unavailable for testing.
  • Clinical judgment should be used to determine if the patient has reasonable likelihood of a mutation, considering the unaffected patient’s current age and the age of female unaffected relatives who link the patient with the affected relatives.
  • First- or second-degree blood relative meeting any of the above criteria.
  • Third-degree blood relative with breast cancer and/or ovarian/fallopian tube/primary peritoneal cancer with 2 or more close blood relatives with breast cancer (at least one with breast cancer at or less than 50 years) and/or ovarian cancer.

According to the NCCN guidelines, patients who meet the criteria for genetic testing should be tested for mutations in BRCA1 and BRCA2..

NCCN also states:

  • For the purposes of these guidelines, invasive and ductal carcinoma in situ breast cancers should be included.
  • Close blood relatives include first-, second-, and third-degree relatives on the same side of the family.

CHEK2

NCCN v3.2013 introduces a new page: “Additional Genetic Mutations Associated with Breast/Ovarian Cancer Risk”. This page addresses CHEK2 testing as part of a panel intended for individuals who have tested negative for high penetrance genes and for those whose family history is suggestive of more than one syndrome. NCCN says: “Limitations of these panels include an unknown percentage of variants of unknown significance, uncertainty of level of risk associated with most of these genes, and lack of clear guidelines on risk management of carriers of some of these mutations. Because of the complexity and limited data regarding their clinical utility, hereditary multigene cancer panels should only be ordered in consultation with a cancer genetics professional.”

Prostate cancer

A number of studies have indicated that BRCA mutations are associated with increased risk of prostate cancer in men. In a study of 832 Ashkenazi Jewish men diagnosed with localized prostate cancer, and 454 Ashkenazi Jewish men without prostate cancer, the presence of a BRCA2 mutation was associated with a more than 3-fold increased risk of prostate cancer (odds ratio [OR]: 3.18, 95% confidence interval [CI: 1.52-6.66). In a similar population of 251 Ashkenazi Jewish men with prostate cancer and 1,472 volunteers without prostate cancer, the presence of a BRCA mutation was associated with a 3.41 times higher risk of prostate cancer (95% CI: 1.64-7.06). When broken down by type of BRCA mutation, BRCA2 was associated with a 4.82 times increased risk (95% CI: 1.87-12.25), while BRCA1 mutations were not associated with an increased risk.

Other studies have looked at the results of prostate cancer screening in men with BRCA mutations. The IMPACT study evaluated the results of screening in 205 men 40-69 years of age who were BRCA mutation carriers and 95 control patients. At the baseline screen, biopsies were performed in 7.0% of patients with a prostate-specific antigen (PSA) greater than 3.0, and prostate cancer was identified in 3.3%. This resulted in a positive predictive value of 47.6%, which is considerably higher than that estimated for normal risk men. Also, the grade of tumor identified was intermediate in 67% of cancers and high in 11%. This differs from the expected distribution of cancer grade in average risk men, with more than 60% expected to have low-grade cancer.

2014 Update

USPSTF has issued an update to their 2005 recommendations.

Primary care providers and asymptomatic women: These recommendations are directed toward primary care providers who screen asymptomatic women to identify those with an increased family history risk for potentially harmful mutations in breast cancer susceptibility genes.

Genetic counseling: USPSTF emphasizes that if women have a positive screening result, they should be referred for genetic counseling. Genetic testing should only occur if it is indicated after genetic counseling.

The Grade D recommendation against BRCA genotyping in women without a high-risk family history is largely unchanged from 2005. However, the Grade B recommendation places a greater emphasis on the use of validated tools (e.g., Ontario Family History Assessment Tool [FHAT], Manchester scoring system, Referral Screening Tool [RST], Pedigree Assessment Tool [PAT], and FHS-7) for genetic risk assessment.

  • The USPSTF recommends against routine genetic counseling or (BRCA) testing for women whose family history is not associated with an increased risk for potentially harmful mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2). (Grade D recommendation)
  • The USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in BRCA1 or BRCA2. Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing. (Grade B recommendation)

References

  1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic Testing for Inherited BRCA1 or BRCA2 Mutations. TEC Assessments 1997; Tab 4.
  2. The American Society of Clinical Oncology, Policy Statement Update: Genetic Testing for Cancer Susceptibility (posted online April 11, 2003) J Clin Oncol 2003; 21(12):1-10.
  3. The American College of Medical Genetics. Clinical Guidelines. Genetic Susceptibility to Breast and Ovarian Cancer: Assessment, Counseling and Testing Guidelines. 1999 (Retired). Last accessed January 10, 2014.
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  9. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302(5645):643-6.
  10. Metcalfe, K, Lynch HT, Ghadirian P et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22(12):2328-35.
  11. Hartmann LC, Schaid DJ, Woods JE et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999; 340(2):77-84.
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  14. Scheuer L, Kauff N, Robson M et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002; 20(5):1260-8.
  15. Olopade OI, Artioli G. Efficacy of risk-reducing salpingo-oophorectomy in women with BRCA-1 and BRCA-2 mutations. Breast J 2004; 10(suppl 1):S5-9.
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  17. Menkiszak J, Rzepka-Gorska I, Gorski B et al. Attitudes toward prevention oophorectomy among BRCA 1 mutation carriers in Poland. Eur J Gynaecol Oncol 2004; 25(1):93-5.
  18. Weitzel JN, McCaffrey SM, Nedelcu R et al. Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg 2003; 138(12):1323-8.
  19. Scheuer L, Kauff N, Robson M et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002; 20(5):1260-8.
  20. Ben David Y, Chetrit A, Hirsh-Yechezkel G et al. National Israeli Study of Ovarian Cancer. Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 2002; 20(2):463-6.
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  23. Malone KE, Daling JR, Thompson JD et al. BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 1998; 279(12):922-929.
  24. Frank TS Deffenbaugh AM, Reid JE et al. Clinical characteristics of individual with germline mutations in BRCA1 and BRCA2: Analysis of 10,000 individuals. J Clin Oncol 2002; 20(16):1480-90.
  25. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998; 62(3):676-689.
  26. Gershoni-Baruch R, Dagan E, Fried G et al. Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 2000; 36(8):983-6.
  27. Hodgson SV, Heap E, Cameron J et al. Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 1999; 36(5):369-73.
  28. Hartge P, Sturewing JP, Wacholder S et al. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 1999; 64(4):963-70.
  29. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004; 4(9):665-76.
  30. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 2006;295(12):1379-88.
  31. Nelson HD, Huffman, LH, Fu R et al. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2005; 143:362-79. Last accessed January 10, 2014.
  32. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Breast Cancer V.2.2011 and Ovarian Cancer. V.2.2011. Last accessed January 10, 2014.
  33. Robson M, Offit K. Management of an inherited predisposition to breast cancer. N Engl J Med 2007; 357:154-62.
  34. Phillips KA, Jenkins MA, Lindeman GJ et al. Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Clin Genet 2006; 70:198-206.
  35. Rennert G, Bisland-Naggan S, Barnett-Griness O et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 2007; 357:115-23.
  36. Malone KE, Daling JR, Doody DR et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population–based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 2006; 66:8297-308.
  37. Couch FJ, Johnson MR, Rabe KG et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2007; 16:342-6.
  38. Reviewed and recommended for adoption by Oncology Advisory Panel, May 22, 2008.
  39. Domchek SM, Gaudet MM, Stopfer JE et al. Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2. Breast Cancer Res Treat. 2009 Nov 3. [Epub ahead of print]
  40. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 2006; 295(12):1379-88.
  41. Palma MD, Domchjeck SM, Stopfer J et al. The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 2008; 68(17):7006-14.
  42. Myriad Website. https://www.myriadpro.com/hereditary-cancer-testing/hereditary-breast-and-ovarian-cancer-hboc-syndrome/bracanalysis-large-rearrangement-test-bart/ and http://d1izdzz43r5o67.cloudfront.net/brac/BART-table-faq.pdf. Last accessed January 10, 2014.
  43. Weischer M, Bojesen SE, Ellervik C et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 2008; 26(4):542-8.
  44. Offit K, Garger JE. Time to Check CHEK2 in Families with breast cancer? J Clin Oncol 2008; 26(4):519-20.
  45. National Cancer Institute (NCI). US National Institute of Health (NIH). Genetics of breast and ovarian cancer (PDQ®). Last Modified: February 2011. Last accessed January 10, 2014.
  46. Ferrone CR, Levine DA, Tang LH et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 2009; 27(3):433-8.
  47. Trainer AH, Meiser B, Watts K et al. Moving toward personalized medicine: treatment-focused genetic testing of women newly diagnosed with ovarian cancer. Int J Gynecol Cancer 2010; 20(5):704-16.
  48. Zhang S, Royer R, Li S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 2011; 121(2):353-7.
  49. Kleibl Z, Havranek O, Kormunda S et al. The AIB1 gene polyglutamine repeat length polymorphism and the risk of breast cancer development. J Cancer Res Clin Oncol 2011; 137(2):331-8.
  50. Osorio A, Milne RL, Alonso R et al. Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2. Br J Cancer 2011; 104(8):1356-61.
  51. Ramus SJ, Kartsonaki C, Gayther SA et al. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2011; 103(2):105-16.
  52. de Ruijter TC VJ, de Hoon JPJ, et al. Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol 2011; 137:183-92.
  53. Kandel MJ SD, Masciari S et al. Prevalence of BRCA1 mutations in triple negative breast cancer (BC). J Clin Onc 2006; 24(18S):508.
  54. Young SR, Pilarski RT, Donenberg T et al. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer. BMC Cancer 2009; 9:86.
  55. Gonzalez-Angulo AM, Timms KM, Liu S et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011; 17(5):1082-9.
  56. Genetic/Familial High-Risk Assessment: Breast and Ovarian (V.4.2013). National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf. Last accessed January 10, 2014.
  57. Blue Cross and Blue Shield Association.  Genetic Testing for Hereditary Breast and/or Ovarian Cancer. Medical Policy Reference Manual, Policy 2.04.02, Last review November 2011.
  58. Gallagher DJ, Gaudet MM, Pal P et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 2010; 16(7):2115-21.
  59. Kirchhoff T, Kauff ND, Mitra N et al. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 2004; 10(9):2918-21.
  60. Mitra AV, Bancroft EK, Barbachano Y et al. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int 2011; 107(1):28-39.Moyer VA. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013; doi: 10.7326/M13-2747. [Epub ahead of print] Last accessed January 10, 2014.

Coding

Codes

Number

Description

CPT

81211

BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis and common duplication/deletion variants in BRCA1 (i.e., exon 13 del 3.835kb, exon 13 dup 6kb, exon 14-20 del 26kb, exon 22 del 510bp, exon 8-9 del 7.1kb)

 

81212

BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants

 

81213

BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian cancer) gene analysis; uncommon duplication/deletion variants

 

81214

BRCA1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis and common duplication/deletion variants (ie, exon 13 del 3.835kb, exon 13 dup 6kb, exon 14-20 del 26kb, exon 22 del 510bp, exon 8-9 del 7.1kb)

 

81215

BRCA1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant

 

81216

BRCA2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis

 

81217

BRCA2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant

 

96040

Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family

ICD-9 Procedure

   

ICD-9 Diagnosis

   

ICD-10-CM
(effective 10/01/14)

   

ICD-10-PCS
(effective 10/01/14)

   

HCPCS

   

Type of Service

Medical

 

Place of Service

Outpatient

Physician’s Office

 

Appendix

N/A

History

Date

Reason

02/08/05

New PR Policy – PR.2.04.504 Add to Medicine Section – New Policy—replaces BC.2.04.02. Removed sentence in policy statement regarding BRCA1and BRCA2 testing in minors.

02/14/06

Replace Policy – Policy reviewed with literature search; no change to policy statement.

03/03/98

New BC Policy – BC.2.04.02Add to Medicine Section – New Policy—replaces PR.2.04.504

01/07/99

Coding Update – 1999 CPT Coding Release

03/11/03

Replace Policy – Revision of existing policy; candidates for genetic testing expanded to include those with early onset breast cancer and members of high-risk populations without an affected family member.

05/11/04

Replace Policy – Policy reviewed; no change to policy statement; new HCPC codes added.

02/08/05

New PR Policy – PR.2.04.504Replace Policy – Replace Policy-instituted. Replaces BC.2.04.02

02/14/06

Replace Policy – Policy reviewed with literature search; no change to policy statement.

02/22/06

Codes updated – No other changes, effective date unchanged.

06/30/06

Update Scope and Disclaimer – No other changes.

01/04/06

Replace Policy – Policy updated with literature review; reference added. No change in policy statement.

02/13/07

Replace Policy – Policy updated with literature review; references added. No change in policy statement.

03/13/07

Replace Policy – Explanation of BART test, as subset of BRCA, added to Policy Guidelines.

03/21/07

Codes Updated – No other changes.

05/08/07

Replace Policy – Policy statement clarified with substitution of ACMG criteria.

7/10/07

Cross Reference Update – No other changes.

06/10/08

Replace Policy – Policy updated with literature search. Policy statement modified to reflect USPTF guidelines: High risk age changed from <45 to <50, family history of ovarian cancer decreased from 3 to 2 relatives, Ashkenazi heritage added to criteria of those with breast or ovarian cancer. Revision of investigational statement to include assessment of risk of pancreatic, prostate and colon cancer. Rationale and References updated. Reviewed and recommended for adoption by Oncology Advisory Panel, May 22, 2008.

12/08/09

Replace Policy – Policy updated with literature search. Reference added. No change to the policy statement.

04/13/10

Replace Policy – Policy updated with literature search, references added, clinical input reviewed. Two policy statements added: one to indicate testing for genomic rearrangements (BART) may be considered medically necessary in specific situations and a second that testing for CHEK2 mutations in investigational. Fallopian tube and primary peritoneal cancer added to ovarian as additional cancers to consider in assessing risk. Reviewed by OAP on February 18, 2010.

02/17/2011

OAP Review – Reviewed by OAP with recommendation of changing CHEK2 from investigational to medically necessary

05/10/11

Replace Policy – Policy updated with literature search, references added, clinical input reviewed. No change to the policy statement.CHEK2 remains investigational.

01/24/12

CPT codes 81211 – 81217 added to policy.

04/16/12

Related Policies updated: 2.01.45 and 7.01.09 removed, as these have been archived.

05/08/12

Replace Policy. Policy updated with literature search, references added. Policy statement revised to indicate that BRCA testing may be considered medically necessary for women with a personal history of ovarian, fallopian tube, peritoneal cancer, triple negative breast cancer and pancreatic cancer when criteria are met. Also, BRCA testing may be considered medically necessary for women with breast cancer with a family history of 2 or more first degree relatives with pancreatic cancer. Clarification added to Guidelines regarding founder mutations.

05/24/12

Policy renumbered to 12.04.504 (previously 2.04.504) and reassigned to new Genetic Testing category. Related Policies updated; 2.04.57 renumbered to 12.04.57.

07/25/12

Update Related Policies – 12.04.63 has been added.

09/10/12

Update Coding Section – ICD-10 codes are now effective 10/01/2014.

10/15/12

Replace Policy. Two bullets in “No personal history” section of policy statement re-worded to clarify intent. No functional change to the policy statement.

01/14/13

Coding update. CPT codes 83890 – 83913 deleted as of 12/31/12; CPT codes 81200 – 81479 and 81599, effective 1/1/13, are added to the policy.

05/14/13

Update Related Policies. Add 12.04.91.

06/10/13

Interim update. Benefit Application section updated with federal preventative care mandate language which covers genetic counseling and evaluation for BRCA testing within the outlined patient population. No change in policy statements.

08/12/13

Replace policy. “One first degree relative with bilateral breast cancer” added to Personal History section for clarification of policy statement. Clarification added to Guidelines that the presence of prostate cancer alone does not justify BRCA testing. Prostate cancer studies added to Rationale. NCCN v4.2013 revisions to criteria for mutation testing and CHEK2 testing added to Rationale.

01/13/14

Replace policy. Policy statement revised to allow testing for unaffected individuals not meeting criteria in Personal History or No Personal History section when additional criteria are met. In limited circumstances, a non-Premera affected family member may qualify for BRCA testing. Notation added to indicate that NCCN guidelines are provided for informational purposes only and are not meant to replace the criteria in the policy statement. Definition of “close blood relative” added. Title changed, removing “BRCA1 and BRCA2 Mutations” to “Hereditary Breast and/or Ovarian Cancer”. USPSTF 2013 Recommendations added to Rationale. Deleted CPT codes 83890 – 83912 removed; 81479 and 81599 removed (they refer to a different policy); modifiers 0A and 0B removed, along with ICD-9 procedure code 99.99 (this policy is not auto adjucated); and deleted HCPCS codes S3818 - S3823 removed from policy.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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