CAM 20402

Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (BRCA1/BRCA2)

Category:Laboratory   Last Reviewed:May 2018
Department(s):Medical Affairs   Next Review:April 2019
Original Date:July 1997    

Description:
Hereditary breast and ovarian cancer (HBOC) syndrome describes the familial cancer syndromes related to mutations in the BRCA genes (BRCA1 located on chromosome 17q21, BRCA2 located on chromosome 13q12-13). Families with HBOC syndrome have an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer at any age, cancer of the fallopian tube, primary peritoneal cancer, as well as other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma and laryngeal cancer.

For individuals who have cancer or a personal or family cancer history and meeting criteria suggesting a risk of HBOC syndrome who receive genetic testing for a BRCA1 or BRAC2 mutation, the evidence includes a TEC Assessment and studies of mutation prevalence and cancer risk. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, quality of life and treatment-related morbidity. The accuracy of mutation testing has been shown to be high. Studies of lifetime risk of cancer for carriers of a BRCA mutation have shown a risk as high as 85%. Knowledge of BRCA mutation status in individuals at risk of a BRCA mutation may impact health care decisions to reduce risk, including intensive surveillance, chemoprevention and/or prophylactic intervention. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background 
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 (breast cancer susceptibility) 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 and 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 evidence review, we refer collectively to both as hereditary breast and/or ovarian cancer.

Germline mutations in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in most HBOC families, especially if ovarian cancer or male breast cancer are features. However, in site-specific cancer, BRCA mutations are responsible only for a proportion of affected families. BRCA gene mutations are inherited in an autosomal dominant fashion through 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 at increased cancer risk. Family members without existing cancer who are found to have BRCA mutations can consider preventive interventions for reducing risk and mortality.

Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Per the www.genetests.org website, there are currently 6 CLIA-certified U.S. laboratories that offer sequence analysis of the entire coding and 4 that offer deletion/duplication/copy number analysis. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Myriad Genetic Laboratories (Salt Lake City, UT) offers (1) Comprehensive BRACAnalysis® that includes complete sequencing of BRCA1/BRCA2 and gap polymerase chain reaction for 5 common rearrangements (deletions/duplications) in BRCA1; (2) BRACAnalysis® Large Rearrangement Test (BART), which may be ordered as a reflex for patients who test negative for Comprehensive BRACAnalysis® to detect uncommon large rearrangements in BRCA1 and BRCA2; and (3) Integrated BRACAnalysis®, which includes BART as part of BRCA1/BRCA2 analysis.

Quest Diagnostics (Madison, NJ) offers BRCAvantage that includes sequencing of BRCA1/BRCA2 and a multiplex ligation-dependent probe amplification assay to detect both common and uncommon gene rearrangements.

LabCorp (Burlington, NC) offers the BRCAssureSM suite of tests that includes: targeted BRCA1/BRCA2 analysis for known BRCA1 or BRCA2 mutations; a founder mutation panel for Ashkenazi Jewish patients (3 mutations); comprehensive BRCA1/BRCA2 analysis (full gene sequencing plus analysis of common and uncommon large rearrangements); and deletion/duplication analysis of uncommon large rearrangements only (without sequencing) for use when comprehensive analysis is negative.

Related Policies:
20493 Genetic Cancer Susceptibility Panels Using Next Generation Sequencing
 

Policy: 

  1. BRCA 1 and 2 testing should be offered for individuals meeting any of the criteria described in 2 through 4 below if the individual
    • Has received genetic counseling AND
    • Is at least 18 years of age.
  2. BRCA 1 and 2 testing in an individual from afamily with a known deleterious BRCA 1 or BRCA 2 gene mutation is considered MEDICALLY NECESSARY and is limited to the known familial mutation. If the specific familial mutation is unknown, testing for large genomic rearrangements of BRCA1 and BRCA2 is considered MEDICALLY NECESSARY:
  3. BRCA 1 and 2 testing is considered MEDICALLY NECESSARY when an individual with cancer meets any of the following criteria:  
    • Has a history of ovarian carcinoma, fallopian tube cancer, or primary peritoneal cancer 
    • Has a history of male breast cancer 
    • Has a personal history of high-grade prostate cancer with Gleason score ≥7 at any age with ≥1 first-, second-, or third-degree relative on same side of the family with ovarian carcinoma at any age or breast cancer ≤ 50 years of age or two relatives with breast, pancreatic, or prostate cancer with Gleason score ≥7 or metastatic at any age 
    • Has a personal history of high-grade prostate cancer with Gleason score ≥7 at any age and is of Ashkenazi Jewish ancestry* (See Note 1) 
    • Has a personal history of metastatic prostate cancer with radiographic evidence of or biopsy-proven disease
    • Has a personal history of pancreatic cancer 
    • Was diagnosed with breast cancer at age ≤ 45 years of age).
    • Was diagnosed with breast cancer and one of the following: 
      • Two or more breast cancer primaries including bilateral disease or clearly separate ipsilateral primary tumors 
      • one first-, second-, or third-degree relative with breast cancer ≤50 years of age 
      • one first-, second-, or third-degree relative with pancreatic cancer 
      • one first-, second-, or third-degree relative with ovarian cancer 
      • one first-, second-, or third-degree relative with male breast cancer 
      • one first-, second-, or third-degree relative with prostate cancer with Gleason score > 7 or metastatic
      • two first-, second-, or third-degree relatives with breast cancer at any age 
      • Limited or unknown family history 
    • Diagnosed with breast cancer at age < 60 years and triple negative breast cancer (estrogen receptor/ ER negative, progesterone receptor/ PR negative and human epidermal growth factor/HER-2 negative) 
    • An individual with ethnicity associated with high mutation frequency (as in Ashkenazi Jewish persons) no additional family history may be required* (See Note 1)
    • Has a BRCA 1 or 2 mutation detected by tumor profiling in the absence of germline mutation testing 
    • Testing for mutations in the BRCA1 and BRCA2 genes is limited to once per lifetime unless a patient with ovarian cancer is undergoing treatment with a PARP (PolyADP-ribose polymerase) inhibitor or a patient has HER2-negative recurrent or metastatic breast cancer eligible for single agent therapy with a PARP inhibitor (eg. Olaparib), testing for additional clinically relevant mutations is warranted.  
  4. Testing for individuals without cancer (note the significant limitation interpreting test results in persons unaffected by cancer) is considered MEDICALLY NECESSARY ONLY if family members affected by breast, ovarian, pancreatic, metastatic prostate cancer, fallopian tube, or primary peritoneal cancers are not available for testing AND: 
    • Individual has a first- or second-degree relative meeting any of the criteria in #3; OR 
    • Individual has a third-degree relative with breast cancer and/ or ovarian carcinoma and who has > 2 first-, second-, or third-degree relatives in the same lineage with breast cancer (one must be < 50 years at diagnosis) and/or ovarian carcinoma; OR 
    • Women who have family members with breast, ovarian, tubal, or peritoneal cancer with positive screening results from a tool designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). 
  5. Testing for BRCA 1 and BRCA 2 is considered NOT MEDICALLY NECESSARY for the following:     
    1. Genetic testing in minors < 18 years of age
    2. General population screening
    3. In all other situations not specified above
  6. Testing family members for a variant of unknown significance is considered INVESTIGATIONAL.   

Note 1: Testing of Ashkenazi Jewish individuals without a known familial mutation should be initially limited to the three known founder mutations (185delAG and 518insC in BRCA1; 617delT in BRCA2). If testing is negative for founder mutations, comprehensive genetic testing may be CONSIDERED. Comprehensive genetic testing can also be CONSIDERED if ancestry also include non-Ashkenazi Jewish relatives or if other BRCA-related criteria are met. In addition, before August 2006, testing for large deletions and rearrangements was not performed, thus some patients with familial breast cancer who had negative BRCA testing before this time may consider repeat testing for the rearrangements.  

Note 2: Close blood relatives include 1st-degree relatives (e.g., parents, siblings, and children), 2nd-degree relatives (e.g., grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings), and 3rd-degree relatives (great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins), all of whom are on the same side of the family.

Policy Guidelines:
The Policy Statements above are based on current guidelines from NCCN1 (see Practice Guidelines and Position Statements section).

Current USPSTF guidelines recommend screening women with any family history of breast, ovarian, tubal or peritoneal cancer. Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing.2,3 (Grade B Recommendation), please see CAM 089.

Recommended screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in BRCA1 or BRCA2 are: 

  • Ontario Family History Assessment Tool (FHAT)
  • Manchester Scoring System 
  • Referral Screening Tool (RST) 
  • Pedigree Assessment Tool (PAT) 
  • Family History Screen (FHS-7)  

A Recommended Testing Strategy
Patients who meet criteria for genetic testing as outlined in the Policy Statements above should be tested for mutations in BRCA1 and BRCA2

  • In patients with a known familial BRCA mutation, targeted testing for the specific mutation is recommended. 
  • In patients with unknown familial BRCA mutation: 
    • Non-Ashkenazi Jewish descent 
      • To identify clinically significant mutations, NCCN advises testing a relative who has breast or ovarian cancer, especially with early-onset disease, bilateral disease, multiple primaries or ovarian cancer, because that individual has the highest likelihood for a positive test result. 
      • If no living family member with breast or ovarian cancer exists, NCCN suggests testing first- or second-degree family members affected with cancer thought to be related to deleterious BRCA1/BRCA2 mutations (e.g., prostate cancer, pancreatic cancer, melanoma). 
      • If no familial mutation can be identified, two possible testing strategies are: 
        • Full sequencing followed by testing for common large genomic rearrangements (deletions/duplications) only if sequencing detects no mutation (negative result). 
          • More than 90 percent of BRCA mutations will be detected by full sequencing.4  
        • Alternatively, simultaneous full sequencing and testing for common large genomic rearrangements (also known as comprehensive BRCA testing; see Comprehensive Mutation Analysis, below) may be performed as is recommended by NCCN. 
          • Comprehensive testing can detect 92.5 percent of BRCA1/BRCA2 mutations.4  
      • If comprehensive BRCA testing is negative, testing for uncommon large genomic rearrangements (e.g., BART) may be done. 
        • Testing for uncommon large rearrangements should not be done unless both sequencing and testing for common large rearrangements have been performed and are negative. 
          • Among patients with negative comprehensive testing, BART identified a deleterious mutation (positive result) in less than 1 percent.4 
    • Ashkenazi Jewish descent
      • In patients of known Ashkenazi Jewish descent, NCCN recommends testing for the 3 known founder mutations (185delAG and 5182insC in BRCA1; 6174delT in BRCA2) first. 
      • If testing is negative for founder mutations, comprehensive genetic testing may be considered (see Comprehensive Mutation Analysis, below). 

Comprehensive Mutation Analysis
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, before August 2006, testing for large deletions and rearrangements was not performed; thus, some patients with familial breast cancer who had negative BRCA testing before this time may consider repeat testing for the rearrangements (see Policy Statements section for criteria). 

High-Risk Ethnic Groups
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 section). When testing for founder mutations is negative, comprehensive mutation analysis should then be performed.

Testing Unaffected Individuals
In unaffected family members of potential BRCA mutation families, most test results will be negative and uninformative. Therefore, 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), DNA from an unaffected family member can be tested specifically for the same mutation of the affected family member without having to sequence the entire gene. Interpreting 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 (uninformative negative) or mutations of uncertain significance because the possibility of a causative BRCA mutation is not ruled out. 

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 considered sufficient justification for BRCA testing. 

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.

Rationale
This evidence review was originally developed in July 1997 following a 1997 TEC Assessment1 and has been updated on a regular basis with literature searches of the MEDLINE database for articles that contain information on professional guidelines for BRCA testing, testing of unaffected family members and testing of high-risk ethnic populations. The most recent update covers the period through Oct. 7, 2016 (see Appendix Table 1 for genetic testing categories). 

TESTING FOR BRCA1 AND BRCA2 MUTATIONS IN HIGH-RISK WOMEN
Nelson et al. (2013) conducted a systematic review that included meta-analytic estimates of the prevalence and penetrance of BRCA mutations, in order to update the U.S. Preventive Services Task Force (USPSTF) recommendation for risk assessment, genetic counseling and genetic testing for BRCA-related cancer.2 Based on a literature search through Dec. 31, 2012, reviewers selected 70 articles to address 5 key questions. BRCA prevalence and penetrance were estimated to assess the clinical validity of mutation testing. In high-risk women with positive test results, cumulative risks for developing breast cancer by age 70 were 46% for BRCA1 and 50% for BRCA2 when a single family member was tested and 70% for BRCA1 and 71% for BRCA2 when multiple family members were tested; cumulative risks for developing ovarian cancer by age 70 were 41% for BRCA1 and 17% for BRCA2 when a single family member was tested; and 46% for BRCA1 and 23% for BRCA2 when multiple family members were tested. For Ashkenazi Jewish women with positive test results, cumulative risks for developing breast or ovarian cancer by age 75 were 34% and 21%, respectively.  

Gabai-Kapara et al. (2014) studied breast and ovarian cancer risks among 211 Ashkenazi Jewish female BRCA1 or BRCA2 founder mutation carriers identified through an unaffected male carrier relative.3 All study participants underwent BRCA1/BRCA2 genotyping for 3 founder mutations (BRCA1 185delAG, BRCA1 5382insC, BRCA2 6174delT) that account for 11% of breast cancer and 40% of ovarian cancer in this population. Approximately half of identified carriers were from low-risk families who would not have satisfied testing criteria. Cumulative risks for developing breast or ovarian cancer were similar to those observed in female BRCA1 or BRCA2 mutation carriers from high-risk families who satisfy testing criteria. (For example, cumulative risks for developing breast or ovarian cancer by age 60 and 80 were 60% and 83%, respectively, for BRCA1 mutation carriers, and 33% and 76%, respectively, for BRCA2 mutation carriers; for breast cancer only, cumulative risks were 41% and 60%, respectively, for BRCA1 mutation carriers, and 26% and 40%, respectively, for BRCA2 mutation carriers; for ovarian cancer only, cumulative risks were 27% and 53%, respectively, for BRCA1 mutation carriers, and 7% and 62%, respectively, for BRCA2 mutation carriers. Among BRCA2 mutation carriers, higher than expected cumulative risk of ovarian cancer and lower than expected cumulative risk of breast cancer were attributed to reduced prevalence of nongenetic risk factors for breast cancer [e.g., late age at first pregnancy] in the study sample and therefore reduced competing risk.) Duration of follow-up was not specified. Based on these findings, several authors of this study advocated universal screening of women for BRCA1 and BRCA2 mutation status.4 However, despite their assertion that study results were "widely applicable," this is unlikely to be true; as the authors themselves stated, "The Ashkenazi Jewish population is unusual." Others have urged caution in communicating risks associated with radical surgery (prophylactic mastectomy, oophorectomy) in BRCA1 and BRCA2 mutation carriers identified through population screening.5  

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.6 Studies of founder mutations in ethnic populations (e.g., Ashkenazi Jewish, Polish, Icelandic populations) unselected for family history indicated lower penetrance estimates, in the range of 40% to 60% for BRCA1 and 25% to 40% for BRCA2.7-10 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 (185delAG, 5382insC, 6174delT).11 Importantly, the risk of cancer in mutation carriers from families with little history of cancer (≈50% of all carriers) did not differ significantly. 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 prospective study (2004), the 10-year risk was 29.5% for women with initial stage I or II disease.12 In a 2013 prospective study (EMBRACE), the cumulative risk of contralateral breast cancer by age 70 years was 83% in BRCA1 mutation carriers and 62% for BRCA2 mutation carriers.13 These investigators also reported cumulative risks of breast cancer by age 70 years in women without previous cancer of 60% in BRCA1 carriers and 55% in BRCA2 carriers. Similarly, the cumulative risks of ovarian cancer by age 70 years in women without previous ovarian cancer were 59% for BRCA1 carriers and 17% for BRCA2 carriers. Although there is a significantly increased risk of cancer in BRCA carriers, the association between BRCA and cancer mortality is not clear. Observational studies have suggested that BRCA mutations, in particular BRCA2, might be associated with longer overall survival (OS) and progression-free survival in patients with ovarian cancer,14,15 at least in the short term.16 The observed improvement in survival might be due to higher chemotherapy response.15 BRCA mutations are generally associated with poorer OS in patients with breast cancer.17  

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 health care decisions to reduce risk.18-25 Risk-reducing options include intensive surveillance, chemoprevention, 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.19 Prophylactic oophorectomy significantly reduces the risk of ovarian cancer to less than 10%22,23 and reduces the risk of breast cancer by approximately 50%.23 In women who have already had breast cancer, prophylactic oophorectomy reduces the risk of cancer relapse.21 Systematic reviews of observational studies comparing prophylactic surgeries to observation in women with BRCA1 and BRCA2 mutations demonstrate that prophylactic bilateral oophorectomy in women with and without breast cancer and contralateral prophylactic mastectomy in women with breast cancer are associated with significantly lower all-cause mortality while bilateral prophylactic mastectomy was not associated with all-cause mortality.26-28 Studies have indicated that genotyping results significantly influence treatment choices.20,24,25  

Prevalence of BRCA Mutations  
Nelson et al. included meta-analytic estimates of BRCA prevalence in their 2013 systematic review for USPSTF.2 In unselected women, BRCA mutation prevalence estimates were 0.2% to 0.3%; in women with breast cancer, 1.8% for BRCA1 and 1.3% for BRCA2; in women with breast cancer onset at age 40 years or younger, 6%; in women from high-risk families, 13.6% for BRCA1, 7.9% for BRCA2 and 19.8% for BRCA1 or BRCA2; in unselected Ashkenazi Jewish women, 2.1%; and in Ashkenazi Jewish women from high-risk families, 10.2%.  

The prevalence of BRCA mutations is approximately 0.1% to 0.2% in the general population. Prevalence may be much higher for particular ethnic groups with characterized founder mutations (e.g., 2.5% [1/40] 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. Malone et al. (2006) reported on racial and ethnic differences in the prevalence of BRCA1 and BRCA2 in American women.29 Among their subjects, 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.  

Clinical Features Suggestive of BRCA Mutation  
Young age of onset of breast cancer, even in the absence of family history, is a risk factor for BRCA1 mutations. Winchester estimated that hereditary breast cancers account for 36% to 85% of patients diagnosed before age 30.30 In several studies, BRCA mutations are independently predicted by early age at onset, being present in 6% to 10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (age range, 35-50 years).30-33 In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 mutations is in the 40s.34 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.31 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.35 Additional studies have indicated that early age of breast cancer diagnosis is a significant predictor of BRCA mutations in the absence of family history in this population.10,36,37 

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% to 31% will have a BRCA mutation depending on the extent and nature of the family history.33 Several other studies have documented the significant influence of family history.7,10,35-37

In patients with "triple-negative" breast cancer (i.e., negative for expression of estrogen and progesterone receptors and for overexpression of human epidermal growth factor receptor 2 receptors), there is an increased prevalence 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.38 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.39 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.40 A total of 6 BRCA mutations (5 BRCA1, 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, 3 in BRCA2).41

Testing Results
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.31,42 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).

BRCA Mutation Rates Associated With Pancreatic Cancer
Unaffected individuals also may 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- to 10-fold over the general population.43 Couch et al. reported on screening for BRCA2 mutations 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 (3%) BRCA mutations in 151 probands; in the second cohort, there were another 5 (17%) BRCA2 mutations in 29 probands.44 The combined BRCA2 mutation rate for these 2 cohorts was 6% (10/180). Ferrone et al. tested 187 Ashkenazi Jewish patients with pancreatic cancer for BRCA mutations and found that 5.5% (8/187) had a BRCA mutation.45

BRCA Mutation Rates Associated With Ovarian Cancer
Women with a personal history of ovarian cancer have an increased rate of BRCA mutations. In a 2010 systematic review of 23 studies, Trainer et al. estimated the rate of BRCA mutations among women with ovarian cancer to be 3% to 15%.46 In this review, 3 U.S. studies tested for both BRCA1 and BRCA2; incidences of BRCA mutations were 11.3%, 15.3% and 9.5%. In a 2011 population-based study of 1,342 unselected patients with invasive ovarian cancer in Canada, 176 women had BRCA mutations, for a rate of 13.3%.47 Mutation prevalence was higher for women in their 40s (24%) and for women with serous ovarian cancer (18%). Ethnicity was another risk factor for BRCA, with higher rates seen in women of Italian (43.5%), Jewish (30%) and Indo-Pakistani (29.4%) origin. In the 2013 systematic review for USPSTF by Nelson et al., meta-analytic estimates of BRCA prevalence among women with ovarian cancer were 4.4% for BRCA1 and 5.6% for BRCA2.2

BRCA Mutation Rates Associated With Fallopian Tube Cancer
A 2009 study described the high rate of occult fallopian tube cancers in at-risk women having prophylactic bilateral salpingo-oophorectomy.48 In this prospective series of 45 women, 4 (9%) had fallopian tube malignancies. Reviewers noted that these findings supported 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, 2017 National Comprehensive Cancer Network guidelines for assessing high risk in breast and ovarian cancer include both fallopian tube and primary peritoneal cancer as other malignancies that should be documented when assessing family history for BRCA1 and BRCA2 genotyping decisions.49

A long-term study (median follow-up, 7 years; range, 3-14 years) followed 32 BRCA mutation carriers with occult malignancy (4 ovarian, 23 fallopian tube, 5 ovarian and fallopian tube) diagnosed of prophylactic salpingo-oophorectomy.50 Among 15 women with invasive carcinoma (median age, 50 years), 7 (47%) experienced recurrence at a median of 33 months, and OS was 73%. Among 17 women with noninvasive neoplasia (median age, 53 years), 4 (24%) received chemotherapy, none of whom experienced recurrence. One (6%) patient who did not receive chemotherapy experienced recurrence at 43 months. OS was 100%. The authors concluded that, in BRCA mutation carriers, unsuspected invasive carcinoma has a relatively high rate of recurrence, but noninvasive neoplasms rarely recur and may not require adjuvant chemotherapy.

Clinical Outcomes in BRCA Mutation Carriers  
A clinical approach to BRCA mutation carriers was published in 2007 by Robson and Offit.51 Phillips et al. (2006) reported that although 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, a minority had risk-reducing surgery (11% had bilateral mastectomy; 29% bilateral oophorectomy) or chemoprevention.52

In their 2014 systematic review for USPSTF, Nelson et al. assessed efficacy of risk-reducing surgery in BRCA-positive women.53 For high-risk women and mutation carriers, bilateral mastectomy reduced breast cancer incidence by 85% to 100% and breast cancer mortality by 81% and 100%, respectively; salpingo-oophorectomy reduced breast cancer incidence by 37% to 100%, ovarian cancer incidence by 69% to 100% and all-cause mortality by 55% to 100%, respectively. Some women experienced reduced anxiety. Although comparison groups varied across studies, results were consistent. Adverse events included physical complications of surgery, postsurgical symptoms and changes in body image. Limitations of the analysis included the small number of studies (N=7) and small sample sizes. As the authors observed, whether BRCA mutation testing reduces cause-specific or all-cause mortality and improves quality of life is currently unknown. Harms associated with false-negative results or variants of uncertain significance also are unknown.

Rennert et al. (2007) reported that breast cancer-specific rates of death among Israeli women were similar for carriers of a BRCA founder mutation and noncarriers.54

Lesnock et al. (2013) compared OS in 393 women with BRCA1-mutated and BRCA1-nonmutated epithelial ovarian cancer who were treated with intraperitoneal or intravenous-only chemotherapy.55 All patients had "optimally resected" (<1 cm residual disease) stage III disease. BRCA1 mutation status was determined by blinded review of immunohistochemistry assays of archived tumor samples. Treatment regimens were intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel (IP therapy) or intravenous paclitaxel and cisplatin (IV therapy). In 204 women with nonmutated BRCA1, median OS did not differ statistically between treatment groups (58 months for IP therapy vs. 50 months for IV therapy; p=0.82). In 189 women with mutated BRCA1, median OS was significantly longer in the IP therapy group (84 months vs. 47 months, respectively; p<0.001).

BRCA Mutation Rates Associated With Prostate Cancer
A number of studies have indicated that BRCA mutations are associated with increased risk of prostate cancer in men. In a 2010 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 to 6.66).56 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 more than a 3-fold increased risk of prostate cancer (OR=3.41; 95% CI, 1.64 to 7.06).57 When analyzed by type of BRCA mutation, BRCA2 was associated with an almost 5-fold increased risk (OR=4.82; 95% CI, 1.87 to 12.25), and BRCA1 mutations were not associated with an increased risk (OR=2.20; 95% CI, 0.72 to 6.70). A 2013 retrospective analysis compared prostate cancer outcomes in 79 BRCA mutation carriers (18 BRCA1, 61 BRCA2) and 2019 noncarriers.58 Men with BRCA mutations more often had Gleason scores of 8 or higher (p<0.001), nodal involvement (p<0.001) and metastases at diagnosis (p=0.005) than noncarriers. Median OS was 8.1 years in carriers and 12.9 years in noncarriers (hazard ratio [HR] ,1.9; 95% CI, 1.1 to 3.3; p=0.012). In subgroup analyses, BRCA2 mutations were independently associated with reduced OS (HR=1.9; 95% CI, 1.1 to 3.1; p=0.004), but BRCA1 mutations were not, possibly due to small sample size and limited follow-up.

Other studies have looked at the results of prostate cancer screening in men with BRCA mutations. The IMPACT study (2011) evaluated the results of screening in 205 men 40 to 69 years of age who were BRCA mutation carriers and 95 control patients.59 At the baseline screen, biopsies were performed in 7.0% of men with a prostate-specific antigen level 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.

Candidate Modifier Genes
There has been interest in risk-stratifying patients with known BRCA mutations to further assist in clinical decision making. Numerous recent publications have identified a large number of candidate modifier genes,60-66 and nongenetic modifying factors also have been examined. Antoniou et al. examined the risk of breast cancer associated with 9 genetic polymorphisms, most which had previously shown an increase cancer risk among BRCA carriers.60 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. reported that the AIB1 (amplified in breast 1) genotype in general did not influence breast cancer risk in BRCA carriers but that the specific AIB1 genotype consisting of 28 glutamine repeats in both alleles (28/28) conferred a decreased risk of breast cancer (HR=0.64; 95% CI, 0.41 to 0.99; p=0.045).64 In 2013, Bianco et al. conducted a meta-analysis to examine the effect of AIB1 polyglutamine repeats on breast cancer risk in BRCA mutation carriers.67 Seven case-control and cohort studies of 28 of 28, 29 of 29 and 26 or fewer repeats in 1 or both alleles were included. No statistically significant association with breast cancer risk was observed for polyglutamine repeats of any length in BRCA, BRCA1 or BRCA2 mutation carriers. Statistical heterogeneity was significant in the analyses of 28 of 28 repeats in BRCA1 and BRCA2 mutation carriers.

Zhou et al. reported an increased risk of cancer in BRCA carriers who also had the RAD51 135G>C polymorphism (OR=1.34; 95% CI, 1.01 to 1.78; p=0.04).68 Metcalfe et al. reported that family history provided additional predictive information in BRCA carriers.69 For each first-degree relative with breast cancer before age 50 years, the risk of ovarian cancer increased 1.6-fold (HR=1.61; 95% CI, 1.21 to 2.14) in BRCA1 mutation carriers, and the risk of breast cancer increased 1.7-fold in BRCA2 mutation carriers (HR=1.67; 95% CI, 1.04 to 2.07).

BRCA Testing in Minors
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.

In its updated (2014) statement on risk assessment for inherited gynecologic cancer, the Society of Gynecologic Oncologists (SGO) acknowledged that the risk of developing breast or ovarian cancer in a woman younger than age 21 is very low, "even in families with inherited cancer susceptibility as a result of hereditary breast and ovarian cancer (HBOC) syndrome."70 Because detection of an HBOC-associated mutation "would change the management of very few women in this age group," and because testing has potential negative consequences, SGO did "not recommend genetic testing of women younger than age 21 for HBOC in the absence of a family history of extremely early-onset cancer."

Testing for Large BRCA Rearrangements  
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 et al. 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 BRCA2.71 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 2008 study evaluated 251 patients with an estimated BRCA mutation prevalence using the Myriad II model of at least 10%.72 In 136 non-Ashkenazi Jewish probands, 36 (26%) had BRCA point mutations and 8 (6%) had genomic rearrangements (7 in BRCA1, 1 in BRCA2). Genomic rearrangements comprised 18% of all identified BRCA mutations. No genomic rearrangements were identified in the 115 Ashkenazi Jewish probands, but 47 (40%) had point mutations. The authors indicated that the estimated prevalence of a mutation did not predict the presence of a genomic rearrangement.

SUMMARY OF EVIDENCE
For individuals who have cancer or a personal or family cancer history and meeting criteria suggesting a risk of hereditary breast and ovarian cancer (HBOC) syndrome who receive genetic testing for a BRCA1 or BRAC2 mutation, the evidence includes a TEC Assessment and studies of mutation prevalence and cancer risk. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, quality of life and treatment-related morbidity. The accuracy of mutation testing has been shown to be high. Studies of lifetime risk of cancer for carriers of a BRCA mutation have shown a risk as high as 85%. Knowledge of BRCA mutation status in individuals at risk of a BRCA mutation may impact health care decisions to reduce risk, including intensive surveillance, chemoprevention and/or prophylactic intervention. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

CLINICAL INPUT FROM PHYSICIAN SPECIALTY SOCIETIES AND ACADEMIC MEDICAL CENTERS
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.

In response to requests, input was received through 3 physician specialty societies (5 reviewers) and 3 academic medical centers (5 reviewers) while this policy was under review in 2010. Those providing input were in general agreement with the Policy statements considering testing for genomic rearrangements of BRCA1 and BRCA2 as medically necessary and with adding fallopian tube and primary peritoneal cancer as BRCA-associated malignancies to assess when obtaining the family history.  

PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
Current National Comprehensive Cancer Network (NCCN) guidelines on genetic and familial high-risk assessment of breast and ovarian cancers (v.1.2017) include criteria for identifying individuals who should be referred for further risk assessment, and separate criteria for genetic testing.49 Patients who satisfy any of the testing criteria listed in Table 1 should undergo "further personalized risk assessment, genetic counseling and often genetic testing and management." For these criteria, both invasive and in situ breast cancers were included. Maternal and paternal sides of the family should be considered independently for familial patterns of cancer. Testing of unaffected individuals should be considered "only when an appropriate affected family member is unavailable for testing."

Table 1. NCCN BRCA1 and BRCA2 Testing Criteria for HBOC Compared to SGO Criteria for Genetic Assessment (Counseling With or Without Testing)  

NCCN49 SGO70

1. Individual from a family with a known BRCA1/BRCA2 mutation

2.Personal history of breast cancer and ≥1 of the following:

 
  a.Diagnosed age ≤45 years
  b.2 primary breast cancers when 1st breast cancer diagnosis occurred age ≤50 years f
  c.Diagnosed age ≤ 50 years AND:  
    i. One or more 1st-, 2nd- or 3rd-degree relativea with breast cancer at any age, or  
    ii. Unknown or limited family historyb    √
  d.Diagnosed age ≤ 60 years with a triple negative (ER, PR, HER2) breast cancer   √
  e. Diagnosed any age AND one or more 1st-, 2nd- or 3rd-degree relativeswith breast cancer diagnosed ≤50 years  √
  f. Diagnosed any age AND two or more 1st-, 2nd- or 3rd-degree relativesa with breast cancer at any age   √
  g. Diagnosed any age AND one or more 1st-, 2nd- or 3rd-degree relativea with epithelial ovarian/fallopian tube/primary peritoneal CA 
  h. Diagnosed any age AND two or more 1st-, 2nd- or 3rd-degree relativesa with pancreatic cancer or prostate cancerc at any age   
  i. 1st-, 2nd- or 3rd-degree male relative with breast cancer     
  j. For individuals of ethnicity associated with increased mutation frequency (e.g., Ashkenazi Jewish), no additional family history may  be requiredd  √

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

 √

4. Personal history of male breast cancer 

 

5. Personal history of pancreatic cancer or prostate cancerc at any age AND two or more 1st-, 2nd- or 3rd-degree relativesa with any of the following at any age. For pancreatic cancer, if Ashkenazi Jewish ancestry, only 1 additional affected relative is needed: 

g 
   a. Breast cancer   √
   b. Ovarian/fallopian tube/primary peritoneal cancer  √
   c. Pancreatic or prostate cancerc  √

6. Family history onlye 

 
  a. 1st- or 2nd-degree blood relative meeting any of the above criteria 

 

  b. 3rd-degree blood relative with breast cancer and/or ovarian/fallopian tube/primary peritoneal cancer AND ≥ 2 1st -, 2nd- or 3rd-degree relatives with breast cancer (≥ 1 at age ≤ 50 years) and/or ovarian/fallopian tube/primary peritoneal cancer 

h 

HBOC: hereditary  breast and/or ovarian cancer; NCCN: National Comprehensive Cancer Network; SGO: Society of Gynecologic Oncology
aBlood relatives on the same side of the family (maternal or paternal). 

  • 1st-degree relatives are parents, siblings and children.
  • 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren and half-siblings.
  • 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren and first cousins. 

bFor example, fewer than 2 first- or second-degree female relatives having lived beyond age 45 in either lineage. 
cGleason score ≥ 7. 
dTesting for Ashkenazi Jewish or other founder mutation(s) should be performed first. 
eSignificant limitations of interpreting test results for an unaffected individual should be discussed. 
fSGO does not include age restriction. 
gSGO does not include qualifier for Ashkenazi-Jewish patients. 
hFor unaffected women, this SGO criterion states, “A first or several close relatives who meet one of the above criteria.” SGO additionally recommends genetic assessment for unaffected women who have a male relative with breast cancer.  

American Society of Clinical Oncology
The American Society of Clinical Oncology recommended in 2003 that cancer predisposition testing be offered when (1) there is a personal or family history suggesting genetic cancer susceptibility, (2) the test can be adequately interpreted and (3) results will influence medical management of the patient or family member at hereditary risk of cancer.73 A 2010 update of this policy statement recommended that "genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials."74  

Society of Gynecologic Oncology
In 2014, Society of Gynecologic Oncology (SGO) updated its 2007 evidence-based consensus statement on risk assessment for inherited gynecologic cancer.70 The statement included criteria for recommending genetic assessment (counseling with or without testing) to patients who may be genetically predisposed to breast or ovarian cancer. Overall, SGO and NCCN recommendations align. Differences are: exclusion of women with breast cancer onset at age 50 years or younger who have 1 or more first-, second- or third-degree relatives with breast cancer at any age; women with breast cancer or history of breast cancer who have a first-, second- or third-degree male relative with breast cancer; and men with a personal history of breast cancer. SGO additionally recommended genetic assessment for unaffected women who have a male relative with breast cancer. SGO had indicated that some patients who do not satisfy criteria may still benefit from genetic assessment (e.g., few female relatives), hysterectomy or oophorectomy at a young age in multiple family members, or adoption in the lineage.

U.S. PREVENTIVE SERVICES TASK FORCE
Current U.S. Preventive Services Task Force (USPSTF) recommendations for genetic testing of BRCA1 and BRCA2 mutations in women are listed next.75

"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 breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing. (B recommendation)

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 the BRCA1 or BRCA2 gene. (D recommendation)"

Recommended screening tools include the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool and Family History Screen—7.

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 2. 

Table 2. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing
NCT00685256 Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children 400 Dec 2016
NCT00287898 Telephone-Based Genetic Counseling or Standard Genetic Counseling in Women at Risk of Carrying the BRCA1 or BRCA2 Mutation 600 Dec 2016
NCT02133703 Decision Making Interventions for Women Receiving Uninformative BRCA1/2 Test Results or Positive BRCA1/2 Test Results 600 Jul 2017
NCT02225015 Cancer Prevention in Women With a BRCA Mutation: A Follow-up Genetic Counselling Intervention 300 Jun 2019
Unpublished
NCT01851109 Prevention of Ovarian Cancer in Women Participating in Mammography 458 Dec 2015 (completed)

NCT: national clinical trial. 

References:

  1. 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. 
  2. Nelson HD, Fu R, Goddard K, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Evidence Synthesis No. 101 (AHRQ Publication No. 12-05164-EF-1). Rockville, MD Agency for Healthcare Research and Quality; 2013.
  3. Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. Sep 30 2014;111(39):14205-14210. PMID 25192939
  4. King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA. Sep 17 2014;312(11):1091-1092. PMID 25198398
  5. Rhiem K, Schmutzler R. Impact of prophylactic mastectomy in BRCA1/2 mutation carriers. Breast Care (Basel). Dec 2014;9(6):385-389. PMID 25759620
  6. Begg CB. On the use of familial aggregation in population-based case probands for calculating penetrance. Journal of the National Cancer Institute. Aug 21 2002;94(16):1221-1226. PMID 12189225
  7. Moslehi R, Chu W, Karlan B, et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. American journal of human genetics. Apr 2000;66(4):1259-1272. PMID 10739756
  8. 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. May 2001;10(5):467-473. PMID 11352856
  9. Thorlacius S, Struewing JP, Hartge P, et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. Oct 24 1998;352(9137):1337-1339. PMID 9802270
  10. 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. Jul 21 1999;91(14):1241-1247. PMID 10413426
  11. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. Oct 24 2003;302(5645):643-646. PMID 14576434
  12. Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. Jun 15 2004;22(12):2328-2335. PMID 15197194
  13. Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. Jun 5 2013;105(11):812-822. PMID 23628597
  14. Xu K, Yang S, Zhao Y. Prognostic significance of BRCA mutations in ovarian cancer: an updated systematic review with meta-analysis. Oncotarget. Sep 28 2016. PMID 27690218
  15. Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. Oct 12 2011;306(14):1557-1565. PMID 21990299
  16. Candido-dos-Reis FJ, Song H, Goode EL, et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer. Clin Cancer Res. Feb 1 2015;21(3):652-657. PMID 25398451
  17. Zhu Y, Wu J, Zhang C, et al. BRCA mutations and survival in breast cancer: an updated systematic review and meta-analysis. Oncotarget. Sep 21 2016. PMID 27659521
  18. Grann VR, Whang W, Jacobson JS, et al. Benefits and costs of screening Ashkenazi Jewish women for BRCA1 and BRCA2. J Clin Oncol. Feb 1999;17(2):494-500. PMID 10080590
  19. 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. Jan 14 1999;340(2):77-84. PMID 9887158
  20. 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):93-95. PMID 15053071
  21. Moller P, Borg A, Evans DG, et al. Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy. Int J Cancer. Oct 20 2002;101(6):555-559. PMID 12237897
  22. Olopade OI, Artioli G. Efficacy of risk-reducing salpingo-oophorectomy in women with BRCA-1 and BRCA-2 mutations. Breast J. Jan-Feb 2004;10 Suppl 1:S5-9. PMID 14984481
  23. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. May 23 2002;346(21):1616-1622. PMID 12023993
  24. 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. Mar 1 2002;20(5):1260-1268. PMID 11870168
  25. Weitzel JN, McCaffrey SM, Nedelcu R, et al. Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg. Dec 2003;138(12):1323-1328; discussion 1329. PMID 14662532
  26. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: a meta-analysis and systematic review. Clin Cancer Res. Aug 1 2016;22(15):3971-3981. PMID 26979395
  27. Ludwig KK, Neuner J, Butler A, et al. Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review. Am J Surg. Jul 18 2016. PMID 27649974
  28. Marchetti C, De Felice F, Palaia I, et al. Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health. 2014;14:150. PMID 25494812 
  29. 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. Aug 15 2006;66(16):8297-8308. PMID 16912212
  30. Winchester DP. Breast cancer in young women. Surg Clin North Am. Apr 1996;76(2):279-287. PMID 8610264
  31. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. Mar 15 2002;20(6):1480-1490. PMID 11896095
  32. Langston AA, Malone KE, Thompson JD, et al. BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med. Jan 18 1996;334(3):137-142. PMID 8531967
  33. 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. Mar 25 1998;279(12):922-929. PMID 9544766
  34. 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. Mar 1998;62(3):676-689. PMID 9497246
  35. 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. Jul 2000;83(2):153-155. PMID 10901363
  36. Hartge P, Struewing JP, Wacholder S, et al. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet. Apr 1999;64(4):963-970. PMID 10090881
  37. 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. May 1999;36(5):369-373. PMID 10353781
  38. de Ruijter TC, Veeck J, de Hoon JP, et al. Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol. Feb 2011;137(2):183-192. PMID 21069385
  39. Kandel MJ, Stadler D, Masciari S, et al. Prevalence of BRCA1 mutations in triple negative breast cancer (BC) [abstract 508]. J Clin Oncol. 2006;24(18S):508. PMID
  40. 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. PMID 19298662
  41. 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. Mar 1 2011;17(5):1082-1089. PMID 21233401
  42. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. Sep 2004;4(9):665-676. PMID 15343273
  43. Hruban RH, Canto MI, Goggins M, et al. Update on familial pancreatic cancer. Adv Surg. 2010;44:293-311. PMID 20919528
  44. Couch FJ, Johnson MR, Rabe KG, et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev. Feb 2007;16(2):342-346. PMID 17301269
  45. Ferrone CR, Levine DA, Tang LH, et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol. Jan 20 2009;27(3):433-438. PMID 19064968
  46. 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. Jul 2010;20(5):704-716. PMID 20973257
  47. 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. May 1 2011;121(2):353-357. PMID 21324516
  48. Hirst JE, Gard GB, McIllroy K, et al. High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingo-oophorectomy. Int J Gynecol Cancer. Jul 2009;19(5):826-829. PMID 19574767
  49. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. May 1991;41(5):617-618. PMID 2027473
  50. Powell CB, Swisher EM, Cass I, et al. Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia identified at risk reducing salpingo-oophorectomy. Gynecol Oncol. May 2013;129(2):364-371. PMID 23391663
  51. Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. Jul 12 2007;357(2):154-162. PMID 17625127
  52. 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. Sep 2006;70(3):198-206. PMID 16922722
  53. Nelson HD, Pappas M, Zakher B, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: a systematic review to update the U.S. Preventive Services Task Force recommendation. Ann Intern Med. Feb 18 2014;160(4):255-266. PMID 24366442
  54. 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. Jul 12 2007;357(2):115-123. PMID 17625123 
  55. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. Apr 2 2013;108(6):1231-1237. PMID 23462720
  56. Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. Apr 1 2010;16(7):2115-2121. PMID 20215531
  57. Kirchhoff T, Kauff ND, Mitra N, et al. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res. May 1 2004;10(9):2918-2921. PMID 15131025
  58. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. May 10 2013;31(14):1748-1757. PMID 23569316
  59. 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. Jan 2011;107(1):28-39. PMID 20840664
  60. Antoniou AC, Beesley J, McGuffog L, et al. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res. Dec 1 2010;70(23):9742-9754. PMID 21118973
  61. Casadei S, Norquist BM, Walsh T, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. Mar 15 2011;71(6):2222-2229. PMID 21285249
  62. Cox DG, Simard J, Sinnett D, et al. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers. Hum Mol Genet. Sep 16 2011. PMID 21890493
  63. Engel C, Versmold B, Wappenschmidt B, et al. Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. Nov 2010;19(11):2859-2868. PMID 20978178
  64. 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. Feb 2011;137(2):331-338. PMID 20422428
  65. 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. Apr 12 2011;104(8):1356-1361. PMID 21427728
  66. 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. Jan 19 2011;103(2):105-116. PMID 21169536
  67. Bianco A, Quaresima B, Pileggi C, et al. Polymorphic repeat length in the AIB1 gene and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a meta-analysis of observational studies. PLoS One. 2013;8(3):e57781. PMID 23483928
  68. Zhou GW, Hu J, Peng XD, et al. RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. Jan 2011;125(2):529-535. PMID 20623332
  69. 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. Dec 15 2010;102(24):1874-1878. PMID 21098759
  70. Lancaster JM, Powell CB, Chen LM, et al. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. Jan 2015;136(1):3-7. PMID 25238946
  71. 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. Mar 22 2006;295(12):1379-1388. PMID 16551709
  72. Palma MD, Domchek 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. Sep 1 2008;68(17):7006-7014. PMID 18703817
  73. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. Jun 15 2003;21(12):2397-2406. PMID 12692171
  74. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. Feb 10 2010;28(5):893-901. PMID 20065170
  75. 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. Feb 18 2014;160(4):271-281. PMID 24366376
  76. Louis D, More K, Oberoi S, et al. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. Jul 2014;99(4):F325-331. PMID 24514437 

Coding Section

Codes Number Description
CPT

81162, 81211-81217

BRCA1and BRCA2 testing, code range

 

81211  

Molecular Pathology Procedures. (effective 01/01/2019 this code will be DELETED) 

 

81163 (effective 01/01/2019) 

BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis

 

81164 (effective 01/01/2019) 

BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)

 

81165 (effective 01/01/2019) 

BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis

 

81166 (effective 01/01/2019) 

BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)

 

81167 (effective 01/01/2019) 

BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements) 

 

96040 

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

 

S0265 

Genetic counseling, under physician supervision, each 15 minutes 

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   No Code
ICD-10-CM (effective 10/01/15)

All C25 Codes

Malignant neoplasm of pancreas

 

All C56 Codes

Malignant neoplasm of ovary

 

C78.89 

Secondary malignant neoplasm pancreas 

 

C79.60-C79.62

Secondary malignant neoplasm of ovary

 

C79.81

Secondary malignant neoplasm of breast

 

D01.7

Carcinoma in situ of pancreas 

 

D05.00-D05.92

Carcinoma in situ of breast

 

D07.39

Carcinoma in situ of ovary

 

Z12.39 

Screening for malignant neoplasm of breast 

 

Z12.73

Screening for malignant neoplasm of ovary 

 

Z14.8 

Genetic carrier of other disease 

 

Z15.01 

Genetic susceptibility malignant neoplasm of breast 

 

Z15.02 

Genetic susceptibility malignant neoplasm of ovary 

 

Z80.0 

Family history pancreas cancer 

 

Z80.3

Family history of breast cancer

 

Z80.41

Family history of malignant neoplasm of ovary

 

Z80.42 

Family history of malignant neoplasm of prostate

 

Z40.49 

Family history of malignant neoplasm of other genital organs 

 

Z85.07 

Personal history of malignant neoplasm of pancreas

 

Z85.3

Personal history of malignant neoplasm of breast 

 

Z85.43 

Personal history of malignant neoplasm of ovary 

 

Z85.44 

Personal history of malignant neoplasm of  femal genital organs

 

Z85.46 

Personal history of malignant neoplasm of  prostate

 

Z86.000 

Personal history of in-situ neoplasm of breast 

ICD-10-PCS (effective 10/01/15)

 

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

01/08/2019 

Interim review, updating policy verbiage for clarity, also updating coding. 

12/19/2018

Updating with 2019 codes.  

11/27/2018 

Updated policy with 2019 coding. No other changes made. 

08/15/2018 

Corrected formatting issues. 

06/26/2018 

Updated coding section. Removed codes  81432, 81433, 81479, 81519, 81520, 81521, 83950, 84233, 84234, 88360. 88361, S3854. No other changes made

05/10/2018 

Interim review, expanding medical necessity criteria related to first or second degree relatives who meet the criteria in #2. Adding investigational statement for testing family members for a variant of unknown significance. 

04/30/2018 

Updated Next Review Date. No change to policy intent 

02/14/2018 

Interim review to add clarifying language to medical necessity criteria #4, also removing criteria #6 as it is addressed in a separate policy. No other changes made. 

12/7/2017 

Updating policy with 2018 coding. No other changes. 

07/31/2017 

Correcting formatting error in coverage criteria 3 last bullet points.

05/04/2017 

Corrected a typo in the Rationale section. No other changes.

04/18/2017 

Annual review, extensive revision of policy verbiage for clarity and updated coverage. Updating coding. 

01/05/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

04/26/2016 

Interim review to update verbiage related to testing with a history of pancreatic and prostate cancers. 

02/04/2016 

Updating criteria for patients without cancer or without history of cancer criteria for 1st or 2nd degree relatives to add specificity and clarity of information. 

01/06/2016 

Annual review, no change to policy intent. Updated background, description, regulatory status, rationale, references and coding. 

02/03/2015 

Annual review, CHEK2 eliminated from policy and added coding.

 01/15/2014

Annual review, updated ratonale, reference, guidelines. Added related policy. Update policy verbiage to include " including those with a family history of pancreatic cancer" to the investigational statement to mirror BCA change.


Go Back