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MP 2.04.02 Genetic Testing for Hereditary Breast and/or Ovarian Cancer

Medical Policy    
Section
Medicine
Original Policy Date
7/31/97
 
Last Review Status/Date
Reviewed with literature search/11:2012
Issue
11:2012
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

Hereditary breast and ovarian cancer (HBOC) syndrome describes the familial cancer syndromes that are related to mutations in the BRCA genes. Identification of patients with BRCA mutations may lead to enhanced screening and/or surveillance that could lead to improved outcomes.

Several genetic syndromes with an autosomal dominant pattern of inheritance that features 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, ovarian cancer at any age, as well as cancer of the fallopian tube and primary peritoneal cancer. 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.

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.


Policy

Genetic testing for BRCA1 and BRCA2 mutations in cancer-affected individuals may be considered medically necessary under any of the following circumstances:

  • Women who are affected with breast cancer or pancreatic cancer, and are from families with a high risk of BRCA1 or BRCA2 mutation as defined in the Policy Guidelines, OR;
  • Women who are affected with breast cancer or pancreatic cancer who are not from families with a high risk of BRCA1 or BRCA2 mutation, as defined in Policy Guidelines, but are affected with any one of the following:
    • early onset breast cancer;
    • two breast primary cancers with the first cancer diagnosis occurring prior to age 50 years;
    • triple negative breast cancer (neither express estrogen receptor and progesterone receptor, nor overexpress HER2) diagnosed at younger than age 60;
    • two or more close blood relatives with pancreatic cancer at any age
  • Women affected with epithelial ovarian cancer/fallopian tube /primary peritoneal cancer, OR;
  • Men affected with breast cancer at any age, OR;
  • Those affected with breast cancer who are from an ethnic background, e.g., Ashkenazi Jewish descent, associated with deleterious founder mutations.

Genetic testing for BRCA1 and BRCA2 mutations of unaffected adults may be considered medically necessary under any of the following circumstances:

  • Unaffected individuals (male or female) from families with a known BRCA1 or BRCA2 mutation, OR;
  • Unaffected individuals from families with a high risk of BRCA1 or BRCA2 mutation based on a family history (see Policy Guidelines), where it is not possible to test an affected family member for a mutation.
  • Unaffected individuals in populations at risk for specific founder mutations due to ethnic background, e.g., Ashkenazi Jewish descent, and with one or more relatives with breast, epithelial ovarian, fallopian tube, or primary peritoneal cancer at any age.

Further, the genetic testing should be performed in a setting that has suitably trained healthcare providers who can give appropriate pre- and post-test counseling and that has access to a Clinical Laboratory Improvement Amendments (CLIA)-licensed laboratory that offers comprehensive mutation analysis (see Policy Guidelines).

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

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

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

Genetic testing in minors for BRCA1 and BRCA2 mutations is investigational.


Policy Guidelines

In identifying families with a high risk of mutation in the BRCA1 or BRCA 2 gene, both maternal and paternal family histories are important, but each lineage must be considered separately. Any of the following scenarios indicates a high risk of BRCA1 or BRCA2 mutation. In assessing risk of a mutation for those affected with cancer, the overall family history (one lineage) including the affected person is considered. The following criteria for non-Ashkenazi Jewish women unaffected with cancer were derived by the USPSTF in 2005 after extensive literature review by the U.S. Preventive Services Task Force (USPSTF) (1):

  • Three or more first- or second-degree relatives with breast cancer regardless of age at diagnosis; or
  • Two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 years or younger; or
  • Combination of both breast and ovarian or fallopian tube or primary peritoneal cancer among first- and second-degree relatives; or
  • First-degree relative with bilateral breast cancer; or
  • A combination of two or more first- or second-degree relatives with ovarian or fallopian tube or primary peritoneal cancer regardless of age at diagnosis; or
  • A first- or second-degree relative with both breast and ovarian or fallopian tube or primary peritoneal cancer at any age; or
  • A history of breast cancer in a male relative.

More recent definitions of high-risk have been published, including the 2012 revised recommendations from National Comprehensive Cancer Network (NCCN). The following high-risk criteria largely represent NCCN hereditary breast and/or ovarian cancer syndrome testing criteria (2) with some modifications based on additional guidelines (3) and review of evidence.

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 an early age (see definition, following)
    • Diagnosed at age <50 years with at least one close blood relative (see definition, following) with breast cancer at age <50 years and/or at least one close blood relative with epithelial ovarian/fallopian tube/primary peritoneal cancer at any age
    • Two breast primaries when the first breast cancer diagnosis occurred prior to age 50 years
    • Diagnosed age <60 years with a triple negative breast cancer
    • Diagnosed age <50 years with a limited family history
    • Diagnosed at any age, with >2 close blood relatives with breast and/or epithelial ovarian/fallopian tube/primary peritoneal cancer at any age
    • 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 breast and/or ovarian cancer at any age with >2 close blood relatives with pancreatic cancer at any age
  • Personal history of pancreatic cancer at any age with >2 close blood relatives with breast and/or ovarian cancer and/or pancreatic cancer at any age
  • Family history only:
    • Close blood relative meeting any of the above criteria

Definition: Early age at diagnosis refers generally to diagnosis before age 40 to 45 years; 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 years or younger (see Rationale). 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, and the desire to inform the risk of family members.

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.

As the majority of test results will be negative and uninformative in unaffected family members of potential BRCA mutation families, it is strongly recommended that an affected family member 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 test results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result for an established disease-associated mutation but leads to difficulties in interpreting negative test results or mutations of uncertain significance because the possibility of a causative BRCA mutation is not ruled out.

In patients with breast cancer, ovarian cancer, cancer of the fallopian tube, or primary peritoneal 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.

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.

Comprehensive mutation analysis currently includes sequencing the coding regions and intron/exon splice sites, as well as tests to detect common large deletions and rearrangements that can be missed with sequence analysis alone. In addition, prior to August 2006, testing for large deletions and rearrangements was not performed, thus some patients with familial breast cancer who had negative BRCA testing prior to this time may consider repeat testing for the rearrangements (see Policy statement for criteria).

As noted above, cancers of the fallopian tube and primary peritoneal cancer are also considered BRCA-associated malignancies and are to be considered along with breast and ovarian cancer in assessing the family history.


Benefit Application

BlueCard/National Account Issues

Coverage for genetic testing for BRCA1 and BRCA2 is applicable only under those contracts or certificates of coverage that include benefits for preventive health services.

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. Per the geneclinics.org website, only 2 CLIA-certified laboratories currently offer comprehensive mutation analysis, and one is not in the U.S. (Note: it is possible for non-U.S.-based laboratories to obtain CLIA certification if they meet the same criteria applied to U.S.-based laboratories.) Several other laboratories offer targeted mutation analysis.


Rationale

This policy was developed following a 1997 TEC Assessment (4) and has been updated on a regular basis with literature searches for articles that contained information regarding professional guidelines for BRCA testing, testing of unaffected family members, and testing of high-risk ethnic populations. The most recent update covered the period of November 2010 through October 2011. In addition, relevant professional organizations were consulted for clinical guidelines.

Testing for BRCA1 and BRCA2 in High-risk Women

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 other factors that influence risk may be present in families with extensive breast and ovarian cancer histories, early penetrance estimates may have been biased upward. (5) Studies of founder mutations in ethnic populations (e.g., Ashkenazi Jewish, Polish, and Icelandic populations) unselected for family history indicated lower penetrance estimates, in the range of 40–60% for BRCA1 and 25–40% for BRCA2. (6-9) However, a 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.(10) 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 one study the risk was 29.5% at 10 years for women with initial stage I or II disease. (11)

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. (12-19) Risk-reducing options include intensive surveillance, chemoprophylaxis, 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. (13) Prophylactic oophorectomy significantly reduces the risk of ovarian cancer to less than 10% (16, 17) and reduces the risk of breast cancer by approximately 50%. (17) In women who have already had breast cancer, prophylactic oophorectomy reduces the risk of cancer relapse. (15) Studies indicate that genotyping results significantly influence treatment choices. (14, 18, 19)

The prevalence of BRCA mutations is approximately 0.1–0.2% in the general population. Prevalence may be much higher for particular ethnic groups with characterized founder mutations (e.g., 2.5% [1 in 40] 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 (20) estimated that hereditary breast cancer accounts for 36–85% of patients diagnosed before 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). (20-23) In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 mutations is in the 40s. (24) In the Ashkenazi Jewish population, Frank et al. (21) 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. (25) 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. (9, 26, 27)

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. (23) Several other studies document the significant influence of family history. (6, 9, 25-27)

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 (28). In 200 randomly selected patients with triple-negative breast cancer from a tertiary care center, (29) 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. (30) 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. (31)

Unaffected individuals with a family history suggestive of hereditary breast and/or ovarian cancer 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 familial mutation. (21, 32) In addition, specific missense mutations and noncoding intervening sequence mutations may be interpreted as deleterious on the basis of accumulated data or from specific functional or biochemical studies. However, some BRCA 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 disease-associated mutation in an as yet undiscovered gene.

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. (33) Couch et al. (34) 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. (35) tested 187 Ashkenazi 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. (36) 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, (37) 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. (38) 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. (39) 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. (40) Malone and colleagues reported on racial and ethnic differences in the prevalence of BRCA1 and BRCA2 in American women. (41) 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. (34)

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). (42) 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). (43) 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. (44) 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.

There has been interest in further risk-stratifying patients with known BRCA mutations in order to further assist in clinical decision making. Numerous recent publications have identified a large number of candidate modifier genes, (45-51) and there have also been non-genetic modifying factors examined. Antoniou et al. (45) examined the risk of breast cancer associated with 9 genetic polymorphisms, the majority of which had previously shown an increase cancer risk among BRCA carriers. Seven of the 9 polymorphisms were confirmed to increase breast cancer risk. The magnitude of increased risk varied by whether the patient was a BRCA1 versus a BRCA2 carrier, and the polymorphisms appeared to interact multiplicatively to increase risk.

Kleibl et al. (49) reported that the AIB1 genotype in general did not influence breast cancer risk in BRCA carriers but that the specific genotype AIB1 consisting of 28/28 glutamine repeats conferred a decreased risk of breast cancer (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.41-0.99, p=0.045). Zhou et al. (52) reported an increased risk of cancer in BRCA carriers who also had the RAD51 135G>C polymorphism (odds ratio [OR]: 1.34, 95% CI: 1.01-1.78, p=0.04). Metcalfe et al. (53) reported that family history provided additional predictive information in BRCA carriers. For each first-degree relative with breast cancer, there was a 1.7-fold increase in risk of cancer for BRCA carriers.

The use of genetic testing for BRCA mutations has limited or no clinical utility in minors. This is because there is no change in management for minors as a result of knowledge of the presence or absence of a deleterious mutation. In addition, there are potential harms related to stigmatization and discrimination.

Testing for Large BRCA Rearrangements

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 U.S. families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic tests for BRCA1 and BRCA2. (54) 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. (55) 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.

Based on these published studies, a substantial minority of clinically significant BRCA mutations will be large genomic rearrangements that are not detected by sequence analysis. These mutations will be missed if BART testing (BRACAnalysis® Rearrangement Test) is not performed. Commercial laboratories began to offer expanded testing in August 2006 (56); BRCA testing done before this starting time did not include analysis for genomic rearrangement. Subsequent to that, based on information available from the laboratory, this additional testing is conducted on a subset of patients, and additional information on breast cancer risk may be requested in some cases. Clinical guidelines, such as NCCN, consider BART testing as part of comprehensive BRCA testing and do not require additional criteria other than a negative sequence result. Therefore, testing for genomic rearrangements of BRCA1 and BRCA2 with BART may be considered medically necessary as part of comprehensive BRCA analysis, when testing for standard mutations on sequence analysis is negative.

CHEK2and Other 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 U.S., this mutation is much less common than BRCA mutations and BRCA rearrangements. For example, in the study by Walsh et al. (54) 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 et al. concluded that for familial breast cancer, the cumulative risk at age 70 years for CHEK2*1100delC mutation was 37% (95% CI: 26% to 56%). (57) 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. (58) 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 U.S. 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 CHEK2 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.

Since the meta-analysis by Weischer, there have been additional studies looking at the risk of breast cancer associated with the CHEK2 mutation. Myszka et al. (59) examined 284 breast cancer patients, 113 ovarian cancer patients, and 287 healthy women from a cohort of Polish individuals. The CHEK2 mutation rate was not higher among patients with breast or ovarian cancer compared to healthy women.

Zhang et al. (60) 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. (61) 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.

A recent publication described the high rate of occult fallopian tube cancers in at-risk women having prophylactic bilateral salpingo-oophorectomy. (62) 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.

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, with the statement considering CHEK2 testing as investigational, and with adding fallopian tube and primary peritoneal cancer as additional BRCA-associated malignancies to assess when obtaining the family history.

Summary

The presence of a BRCA1 or BRCA2 mutation confers a high lifetime risk for breast and ovarian cancer among affected women. These mutations may be gene sequence variations or large rearrangements/deletions. Knowledge of mutation status in individuals at risk of a BRCA mutation may impact healthcare decisions to reduce risk. Risk-reducing options include intensive surveillance, chemoprophylaxis, prophylactic mastectomy, or prophylactic oophorectomy. Criteria for testing high-risk women have been developed by National Comprehensive Cancer Network (NCCN), the U.S. Preventive Services Task Force (USPSTF) and other review bodies. Definitions of high-risk vary somewhat, and there is not widespread agreement on the optimal criteria that should be used for defining high-risk. When testing high-risk women, health outcomes are improved, therefore, testing high-risk women for BRCA1 and BRCA2 mutations may be considered medically necessary.

Mutations other than BRCA1 and BRCA2 have been reported to be associated with an increased risk of breast cancer. While a number of these, for example the CHEK2 mutation, have been confirmed to be associated with increased risk, clinical utility of testing for these non-BRCA mutations has not been demonstrated. Therefore, genetic testing for mutations other than BRCA1 and BRCA2 to determine risk of breast and/or ovarian cancer is considered investigational.

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer were updated in 2012. (2) 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.

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
    • Diagnosed at age <50 years with at least one close blood relative with breast cancer at age <50 years and/or at least one close blood relative with epithelial ovarian/fallopian tube/primary peritoneal cancer at any age
    • Two breast primaries when the first breast cancer diagnosis occurred prior to age 50 years
    • Diagnosed age <60 years with a triple negative breast cancer
    • Diagnosed age <50 years with a limited family history
    • Diagnosed at any age, with >2 close blood relatives with breast and/or epithelial ovarian/fallopian tube/primary peritoneal cancer at any age
    • Diagnosed at any age, with >2 close blood relatives with pancreatic cancer at any age
    • 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 breast and/or ovarian cancer at any age with >2 close blood relatives with pancreatic cancer at any age
  • Personal history of pancreatic cancer at any age with >2 close blood relatives with breast and/or ovarian cancer at any age and/or pancreatic cancer at any age
  • Family history only:
    • 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 close blood relatives with breast cancer (at least one with breast cancer <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. The guidelines do not address measurement of the CHEK2 mutations.

The U.S. Preventive Services Task Force (USPSTF) published guidelines for genetic testing of BRCA1/BRCA2 in 2005. (1) Their recommendations were as follows:

  • The 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 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)

The American Society of Clinical Oncology (ASCO) recommended in 2003 (63) 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) (64) 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, or
    • 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 mutation(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.”

References:

  1. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. US Preventive Services Task Force. Available online at: www.ahrq.gov/clinic/uspstf05/brcagen/brcagenrs.htm. Last accessed September 29, 2011.
  2. Genetic/Familial High-Risk Assessment: Breast and Ovarian (V.1.2012). 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 October, 2012.
  3. ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol 2009; 113(4):957-66.
  4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). BRCA1 and BRCA2 testing to determine the risk of breast and ovarian cancer. TEC Assessments 1997; volume 12, tab 4.
  5. Begg CB. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 2002; 94(16):1221-6.
  6. Moslehi R, Chu W, Karlan B et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 2000; 66(4):1259-72.
  7. Satagopan JM, Offit K, Foulkes W et al. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2001; 10(5):467-73.
  8. Thorlacius S, Struewing JP, Hartge P et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 1998; 352(9137):1337-9.
  9. Warner E, Foulkes W, Goodwin P et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 1999; 91(14):1241-7.
  10. 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.
  11. 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.
  12. Grann VR, Whang W, Jacobson JS et al. Benefits and costs of screening Ashkenazi Jewish women for BRCA1 and BRCA2. J Clin Oncol 1999; 17(2):494-500.
  13. 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.
  14. Menkiszak J, Rzepka-Gorska I, Gorski B et al. Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in Poland. Eur J Gynaecol Oncol 2004; 25(1):93-5.
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  16. 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.
  17. Rebbeck TR, Lynch HT, Neuhausen SL et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346(21):1616-22.
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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):922-9.
  24. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998; 62(3):676-89.
  25. Gershoni-Baruch R, Patael Y, Dagan et al. Association of the I1307K APC mutation with hereditary and sporadic breast/ovarian cancer: more questions than answers. Br J Cancer 2000; 83(2):153-5.
  26. Hartge P, Struewing 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.
  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. de Ruijter TC, Veeck J, de Hoon JP et al. Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol 2011; 137(2):183-92.
  29. Kandel MJ, Stadler Z, Masciari S et al. Prevalence of BRCA1 mutations in triple negative breast cancer (BC). J Clin Oncol 2006; 24(18S):508.
  30. 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.
  31. 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.
  32. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004; 4(9):665-76.
  33. Hruban RH, Canto MI, Goggins M et al. Update on familial pancreatic cancer. Adv Surg 2010; 44:293-311.
  34. Couch FJ, Johnson MR, Rabe KG et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2007; 16(2):342-6.
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  36. 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.
  37. 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.
  38. Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med 2007; 357(2):154-62.
  39. 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(3):198-206.
  40. 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(2):115-23.
  41. 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(16):8297-308.
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  53. Metcalfe K, Lubinski J, Lynch HT et al. Family history of cancer and cancer risks in women with BRCA1 or BRCA2 mutations. J Natl Cancer Inst 2010; 102(24):1874-8.
  54. 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.
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Codes

Number

Description

CPT 

81211, 81212, 81213, 81214, 81215, 81216, 81217

BRCA1 and BRCA2 testing, code range (new codes effective 1/1/12)

 

83890–83906 

Code range, Molecular diagnostics; DNA isolation, amplification or analysis (New or revised 1999 CPT codes) 

 

83912 

Molecular diagnostics; interpretation and report 

 

Modifier -0A 

BRCA1 (hereditary breast/ovarian cancer) (new 1/1/05) 

 

Modifier -0B 

BRCA2 (hereditary breast cancer) (new 1/1/05) 

ICD-9 Procedure 

99.99 

Other miscellaneous procedures (no specific code currently available for genetic testing) 

ICD-9 Diagnosis 

174.0–174.9 

Malignant neoplasm of female breast 

 

175.0–175.9 

Malignant neoplasm of male breast 

 

183.0 

Malignant neoplasm of ovary 

 

198.6 

Secondary malignant neoplasm of ovary 

 

198.81 

Secondary malignant neoplasm of breast 

 

233.0 

Carcinoma in situ of breast 

 

233.3 

Carcinoma in situ of other and unspecified female genital organs (includes ovary) 

 

V10.3 

Personal history of malignant neoplasm of breast 

 

V10.43 

Personal history of malignant neoplasm of ovary 

 

V16.3 

Family history of malignant neoplasm of breast 

 

V16.4 

Family history of malignant neoplasm of ovary 

 

V16.8 

Family history of malignant neoplasm of breast, male 

 

175.0 – 175.9 

Malignant neoplasm of male breast 

HCPCS 

S3818 

Complete gene sequence analysis; BRCA 1 gene 

 

S3819 

Complete gene sequence analysis; BRCA 2 gene 

 

S3820 

Complete BRCA1 and BRCA2 gene sequence analysis for susceptibility to breast and ovarian cancer 

  S3822 Single mutation analysis (in individual with a known BRCA1 or BRCA2 mutation in the family) or susceptibility to breast and ovarian cancer

 

S3823

Three mutation BRCA 1 and BRCA 2 analysis for susceptibility to breast and ovarian cancer in Ashkenazi individuals 

ICD-10-CM (effective 10/1/14) C50.011 – C50.929  Malignant neoplasm of nipple and breast, code range  
   C56.0 – C56.9 Malignant neoplasm of ovary; code range  
   C79.60 – C79.62 Secondary malignant neoplasm of ovary, code range  
   C79.81 Secondary malignant neoplasm of breast  
   D05.01 – D05.99 Carcinoma in situ of breast; code range  
   D07.30 – D07.39 Carcinoma in situ of other and unspecified female genital organs; code range  
   Z13.71-Z13.79 Encounter for screening for genetic and chromosomal anomalies code range
   Z85.3 Personal history of malignant neoplasm of breast, female or male
   Z85.43 Personal history of malignant neoplasm of ovary  
   Z80.3 Family history of malignant neoplasm of breast  
  Z80.41 Family history of malignant neoplasm of ovary  
ICD-10-PCS (effective 10/1/14)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. 

Type of Service 

Medicine 

Place of Service 

Outpatient 
Physician’s Office
 


Index

BRCA1
BRCA2
CHEK2
Genetic Testing for Inherited BRCA1 or BRCA2 Mutations


Policy History

Date Action Reason
07/31/97 Add to Pathology/Lab section New policy
11/15/98 Coding update 1999 CPT coding release
10/08/02 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
12/17/03 Replace policy New 2004 HCPCS codes added; no other review
11/09/04 Replace policy New references added; policy updated. No change in policy statements
09/27/05 Replace policy Updated policy with literature review; no new references added. No change in policy statements. Assigned policy to “no further review”
02/14/08 Replace policy  Policy returned to active review status and updated with literature review in January 2008. Policy title changed to omit “Inherited BRCA1 or BRCA2 Mutations”. Policy statements and policy guidelines revised. Reference numbers 1, 30 to 36 added.
02/11/10 Replace policy Policy updated with literature search, references 37-43 added, clinical input reviewed. Two policy statements were added: one to indicate testing for genomic rearrangements may be considered medically necessary in specific situations and a second that testing for CHEK2 mutations is investigational. Fallopian tube cancer and primary peritoneal cancer added to policy statements and policy guidelines as additional cancers to be assessed in determining family history to assess risk.
11/10/11 Replace policy Policy updated with literature review; references 32-40 and 46-48 added. Policy statement on CHEK2 testing amended to read: “Testing for mutations other than BRCA1 and BRCA2, such as the CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of the family history.”
12/13/12 Replace policy-correction only Rationale section on large BRCA rearrangements updated to reflect change in policy statement made in November 2012.