Genetic Testing for Hereditary Breast and/or Ovarian Cancer ......Genetic Testing for Hereditary Breast and/or Ovarian Cancer 4 2. Two affected first or second degree relatives with

Genetic Testing for Hereditary Breast and/or Ovarian Cancer

Policy Number: Original Effective Date: MM.02.008 07/01/2008 Line(s) of Business: Current Effective Date: HMO; PPO; QUEST 11/01/2011 Section: Medicine Place(s) of Service: Office; Outpatient

I. Description

Several genetic syndromes with an autosomal dominant pattern of inheritance that feature breast cancer have been identified. Of these, hereditary breast and ovarian cancer (HBOC) and some cases of hereditary site-specific breast cancer have in common causative mutations in BRCA genes. Families suspected of having HBOC syndrome are characterized by an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, 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.

Genetic Testing for Hereditary Breast and/or Ovarian Cancer 2

II. Criteria/Guidelines

A. Genetic testing for BRCA1 and BRCA2 mutations in cancer-affected individuals is covered (subject to Limitations/Exclusions and Administrative Guidelines) under any of the following circumstances:

1. Women who are affected with breast cancer, ovarian cancer, cancer of the fallopian tube, or primary peritoneal cancer, and are from families with a high risk of BRCA1 or BRCA2 mutation as defined in the Policy Guidelines; OR;

2. Women who do not have a known family history of breast, ovarian, fallopian tube, or primary peritoneal cancer, but are affected with early onset* breast or ovarian cancer, or with breast or ovarian cancer and multiple primary cancers, or with bilateral breast or ovarian or fallopian tube cancers, (*early onset is defined as <45 years old or premenopausal) OR;

3. Women affected with both breast cancer and either ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, OR;

4. Men affected with breast cancer at any age, OR; 5. Those affected with breast, ovarian, fallopian tube, or primary peritoneal cancer and who

are from an ethnic background, e.g., Ashkenazi Jewish descent, associated with deleterious founder mutations.

B. Genetic testing for BRCA1 and BRCA2 mutations of unaffected adults is covered (subject to Limitations/Exclusions and Administrative Guidelines) under any of the following circumstances: 1. Unaffected individuals (male or female) from families with a known BRCA1 or BRCA2

mutation, OR; 2. 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.

3. 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, ovarian, fallopian tube, or primary peritoneal cancer at any age.

C. Testing for genomic rearrangements of the BRCA1 and BRCA2 genes (or BART testing) is covered (subject to Limitations/Exclusions and Administrative Guidelines) in patients who meet criteria for BRCA testing, whose testing for point mutations is negative.

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. For non-Ashkenazi Jewish women, high-risk includes the following (1):*


A. Three or more first or second degree relatives with breast cancer regardless of age at diagnosis; or

B. Two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 years or younger; or

C. Combination of both breast and ovarian or fallopian tube or primary peritoneal cancer among more than one first- and second degree relatives; or

D. First degree relative with bilateral breast cancer; or

E. 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

F. A first or second degree relative with both breast and ovarian or fallopian tube or primary peritoneal cancer at any age; or

G. A history of breast cancer in a male relative.

*Patient may count as one affected family member.

First-degree relatives=parents, full siblings, offspring. Second-degree relatives=grandparents, grandchildren, aunts, uncles, nephews, nieces, half-siblings. Third-degree relatives= great-grandparents, great-aunts, great-uncles, first cousins.

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. When the testing for founder mutations is negative, comprehensive mutation analysis should then be performed. Genetic Risk Assessments:

A. Genetic risk assessment is covered (subject to Limitations and Administrative Guidelines) in

cancer-affected individuals with:

1. Early onset breast cancer (<45 years old or premenopausal). 2. A first or second degree relative with a BRCA-related cancer (breast, ovarian, fallopian tube

or primary peritoneal cancer). 3. A first or second degree relative with a BRCA mutation.

B. Genetic risk assessment is covered (subject to Limitations and Administrative Guidelines) in unaffected individuals with:

1. A first degree relative with early onset breast cancer (<45 years old or premenopausal).


2. Two affected first or second degree relatives with a BRCA-related cancer (breast, ovarian, fallopian tube or primary peritoneal cancer).

3. A first or second degree relative with a BRCA mutation. III. Limitations/Exclusions

A. An affected family member should be tested first whenever possible. Should a BRCA mutation be found in an affected family member(s), the DNA from the unaffected family member can be tested specifically using a tailored study for the same mutation of the affected family member without having to sequence the entire gene.

B. Genetic testing for unaffected individuals (of both the general population and of potentially high-risk ethnic populations) without a family history suggesting increased risk of BRCA mutation is not covered as payment determination criteria are not met.

C. Genetic testing in minors for BRCA1 and BRCA2 mutations is not covered as payment determination criteria are not met.

D. Genetic testing for BRCA1 and BRCA2 mutations is not covered for assessment of risk of other cancers including but not limited to pancreatic, prostate and colon cancer as payment determination criteria are not met.

E. Benefits are provided only for HMSA members; benefits are not provided for family members without current HMSA coverage.

F. 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 not covered as payment determination criteria are not met.

G. Testing for CHEK2 genetic abnormalities (mutations, deletions, etc.) is not covered in affected and unaffected patients with breast cancer irrespective of family history as payment determination criteria are not met.

H. Laboratories that conduct genetic testing must be CLIA certified.

I. Repeat BRCA1 or BRCA2 mutation testing is not covered as payment determination criteria are not met.

J. Testing for one or more single nucleotide polymorphisms (SNPs) to predict an individual's risk of breast cancer is not covered as payment determination criteria are not met.

IV. Administrative Guidelines

A. Precertification is required for genetic risk assessments and BRCA and BART genetic testing:

1. Unaffected* individuals

a. Genetic risk assessment is considered by HMSA as part of the precertification process to approve genetic testing in unaffected individuals as stated in Criteria/Guidelines - Genetic Risk Assessment.

2. Affected** individuals


a. Genetic risk assessment is not required for affected individuals prior to BRCA genetic testing; however, genetic testing is subject to precertification.

B. Documentation must specify how the results of genetic testing will impact the clinical management of the patient in terms of improving health outcomes.

C. Services must be conducted in a face-to-face consultation and/or telemedicine consult visit (in accordance with HMSA's current telemedicine payment policy) and a subsequent consultation letter or report must be submitted to the treating physician.

D. Services must be conducted by a properly certified/licensed and credentialed genetic specialist (i.e., board-certified medical geneticist (MD), board-certified clinical geneticist (PhD), board-certified genetic counselor (MS and/or CGC), or licensed advanced practice registered nurse in genetics (APRN)).

E. One risk assessment visit after genetic testing is covered for patients who qualified for predictive genetic testing as outlined above.

F. To precertify please complete HMSA's Precertification Request and fax or mail the form as indicated. The information received should include the member's family history and a brief summary as to why the genetic test is needed.

G. If precertification is not obtained, the member will not be held responsible for payment of denied services unless an Agreement of Financial Responsibility is completed and signed.

*Unaffected – No personal history of cancer

**Affected – Personal history of cancer

H. Applicable codes

ICD-9 codes Description

158.8 Malignant neoplasm of specified parts of peritoneum

174.0–174.9 Malignant neoplasm of female breast

175.0 – 175.9 Malignant neoplasm of male breast

183.0 Malignant neoplasm of ovary

183.2 Malignant neoplasm of fallopian tube

233.0 Carcinoma in situ of breast

233.31 Carcinoma in situ, vagina

233.32 Carcinoma in situ, vulva

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

V16.41 Family history of malignant neoplasm of ovary

http://www.hmsa.com/portal/provider/FM.Pre-certification_Request_-_General.pdf

http://www.hmsa.com/portal/provider/FM.Agreement_of_Financial_Responsibility.pdf


V16.8 Family history of malignant neoplasm of breast, male

CPT Codes Description

83890 Molecular diagnostics; molecular isolation or extraction; each nucleic acid type (i.e., DNA or RNA)

83891 isolation or extraction of highly purified nucleic acid, each acid type (i.e. DNA or RNA)

83892 enzymatic digestion; each enzyme treatment

83893 dot/slot blot production, each nucleic acid preparation

83894 separation by gel electrophoresis (e.g., agarose, polyacrylamide), each nucleic acid preparation

83896 nucleic acid probe, each

83897 nucleic acid transfer (e.g., Southern, Northern) each nucleic acid preparation

83898 amplification, target, each nucleic acid sequence

83900 amplification, target, multiplex, first two nucleic acid sequences

83901 amplification ,target, each nucleic acid sequence beyond 2

83902 Molecular diagnostics; reverse transcription

83903 Molecular diagnostics; mutation scanning, by physical properties (eg, single strand conformational polymorphisms [SSCP], heteroduplex, denaturing gradient gel electrophoresis [DGGE], RNA'ase A), single segment, each

83904 Molecular diagnostics; mutation identification by sequencing, single segment, each segment

83905 Molecular diagnostics; mutation identification by allele specific transcription, single segment, each segment

83906 single segment, each segment

83912 interpretation and report

96040 Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family

HCPCS Codes Description

S0265 Genetic counseling, under physician supervision, each 15 minutes

I. These codes are no longer effective for services rendered after 04/01/2012

HCPCS Codes Description

S3818 Complete gene sequence analysis; BRCA 1 gene


S3819 Complete gene sequence analysis; BRCA 2 gene

S3820 Complete BRCA 1 and BRCA 2 gene sequence analysis for susceptibility to breast and ovarian cancer

S3822 Single mutation analysis (in individual with a known BRCA1 or BRCA 2 mutation in family) for 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

J. ICD-10 codes are provided for your information. These will not become effective until

10/1/2014.

ICD-10 Codes Description

C45.1 Mesothelioma of peritoneum

C48.1 Malignant neoplasm of specified parts of peritoneum

C48.8 Malignant neoplasm of overlapping sites of retroperitoneum and peritoneum

C5Ø.Ø11 Malignant neoplasm of nipple and areola, right female breast

C5Ø.Ø12 Malignant neoplasm of nipple and areola, left female breast

C5Ø.111 Malignant neoplasm of central portion of right female breast

C5Ø.112 Malignant neoplasm of central portion of left female breast

C50.211 Malignant neoplasm of upper-inner quadrant of right female breast

C50.212 Malignant neoplasm of upper-inner quadrant of left female breast

C50.311 Malignant neoplasm of lower-inner quadrant of right female breast

C50.312 Malignant neoplasm of lower-inner quadrant of left female breast

C50.411 Malignant neoplasm of upper-outer quadrant of right female breast

C50.412 Malignant neoplasm of upper-outer quadrant of left female breast

C50.511 Malignant neoplasm of lower-outer quadrant of right female breast

C50.512 Malignant neoplasm of lower-outer quadrant of left female breast

C5Ø.611 Malignant neoplasm of axillary tail of right female breast

C5Ø.612 Malignant neoplasm of axillary tail of left female breast

C5Ø.811 Malignant neoplasm of overlapping sites of right female breast

C5Ø.812 Malignant neoplasm of overlapping sites of left female breast

C50.021 Malignant neoplasm of nipple and areola right male breast

C50.022 Malignant neoplasm of nipple and areola left male breast

C50.121 Malignant neoplasm of central portion of right male breast


C50.122 Malignant neoplasm of central portion of left male breast

C50.221 Malignant neoplasm of upper- inner quadrant of right male breast portion of right male breast

C50.222 Malignant neoplasm of upper- inner quadrant of right male breast portion of left male breast

C50.321 Malignant neoplasm of lower- inner quadrant of right male breast portion of right male breast

C50.322 Malignant neoplasm of lower- inner quadrant of right male breast portion of left male breast

C50.421 Malignant neoplasm of upper-outer quadrant of right male breast

C50.422 Malignant neoplasm of upper-outer quadrant of left male breast

C50.521 Malignant neoplasm of lower-outer quadrant of right male breast

C50.522 Malignant neoplasm of lower-outer quadrant of left male breast

C50.621 Malignant neoplasm of axillary tail of right male breast

C50.622 Malignant neoplasm of axillary tail of left male breast

C50821 Malignant neoplasm of overlapping sites of right male breast

C50.822 Malignant neoplasm of overlapping sites of left male breast

C50921 Malignant neoplasm of unspecified site of right male breast

C56.0 Malignant neoplasm of right ovary

C56.1 Malignant neoplasm of left ovary

C57.01 Malignant neoplasm of right fallopian tube

C57.02 Malignant neoplasm of left fallopian tube

D05.01 Lobular carcinoma in situ of right breast

D05.02 Lobular carcinoma in situ of left breast

D05.11 Intraductal carcinoma in situ of right breast

D05.12 Intraductal carcinoma in situ of left breast

D05.81 Other specified type of carcinoma in situ of right breast

D05.82 Other specified type of carcinoma in situ of left breast

D07.30 Carcinoma in situ of other and unspecified female genital organs

D07.39 Carcinoma in situ of other female genital organs

Z13.71- Encounter for nonprocreative screening for genetic disease carrier status

Z13.79 Encounter for other screening for genetic and chromosomal anomalies

Z80.3 Family history of malignant neoplasm of breast


Z80.41 Family history of malignant neoplasm of ovary

Z85.3 Personal history of malignant neoplasm of breast

Z85.43 Personal history of malignant neoplasm of ovary

V. Scientific Background

This policy was developed following a TEC Assessment (2) 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 American Society of Clinical Oncology (ASCO) recommended in 2003 (3) 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) (4) 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 o the patient was diagnosed at 45 years of age or less, or o a family member has been identified with a detectable mutation, or o 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 o there are multiple primary or bilateral breast cancers in the patient or one family

member, or o there is breast cancer in a male patient, or in a male relative, or o 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.”

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 initially 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. (12-20) Risk-reducing options include intensive surveillance, prophylactic mastectomy, or prophylactic oophorectomy. Prophylactic mastectomy reduces the risk of breast cancer in high-risk women (based on family history) by 90% or more, but is invasive and disfiguring. (12) Prophylactic oophorectomy significantly reduces the risk of ovarian cancer to less than 10% (14, 16) and reduces the risk of breast cancer by approximately 50%. (14) In women who have already had breast cancer, prophylactic oophorectomy reduces the risk of cancer relapse. (17) Studies indicate that genotyping results significantly influence treatment choices. (18-20)

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 (21) estimated that hereditary breast cancer accounts for 36%–85% of patients diagnosed under age 30. In several studies, BRCA mutations are independently predicted by early age at onset, being present in 6–10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (ages 35–50 years). (21-24) In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 mutations is in the 40s (25). In the Ashkenazi Jewish population, Frank et al. (23) 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. (26) 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. (8, 27, 28)

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. (7, 8, 26-28) 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. (24, 29) 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.

2006–2008 Update This policy was updated with a literature review using MEDLINE in January 2008. While the ASCO and ACMG guidelines noted above have not been updated, new guidelines for breast and ovarian cancer susceptibility have been published by the U.S. Preventive Services Task Force (USPSTF; 1, 30) and the National Comprehensive Cancer Network (NCCN; 31). Table 3 in the USPSTF review (30) includes a summary of criteria from various groups on genetic testing in this situation. These guidelines help to better define families where there is a “high risk of a mutation” and also provide information about testing both for men with breast cancer and for women with ovarian cancer. A clinical approach to these patients was recently published by Robson and Offit. (32) Phillips reported that while uptake of prophylactic surgery and screening was associated with knowing one’s mutation status, in their cohort of 70 unaffected female mutation carriers who had chosen to receive results, the minority utilized risk-reducing surgery (11% had bilateral mastectomy and 29% bilateral oophorectomy) or chemoprevention. (33) 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. (34) Malone and colleagues reported on racial and ethnic differences in the prevalence of BRCA1 and BRCA2 in American women. (35) 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. (36)

Using information from the USPSTF, a family at high risk of having a mutation is determined by having any of the following characteristics: 3 or more first- or second-degree relatives with breast cancer regardless of age at diagnosis; or 2 first-degree relatives with breast cancer, one of whom was diagnosed at age 50 years or younger; or combination of both breast and ovarian cancer among first- and second-degree relatives; or first-degree relative with bilateral breast cancer; or a combination of 2 or more first- or second-degree relatives with ovarian cancer regardless of age at diagnosis; or a first- or second-degree relative with both breast and ovarian cancer at any age; or a history of breast cancer in a male relative. (1) These criteria have been added to the Policy Guidelines section. In addition, based on information in the NCCN guidelines and in recognition of changes in management (including mammography) that can occur in males with, or at high risk for, breast cancer, testing males affected by breast cancer was added to the policy statement.


In applying this policy, an accurate family history is a key component in deciding which patients will be tested. In interpreting this history, it is important to evaluate the maternal and paternal lineage separately. Finally, one of the policy statements indicates that this testing is investigational in minors. This is considered investigational 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.

2009-2010 Update 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 US families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic tests for BRCA1 and BRCA2. (37) 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. (38) In the 136 non-Ashkenazi Jewish probands, 36 (26%) had BRCA point mutations and 8 (6%) had genomic rearrangements, 7 in BRCA1 and 1 in BRCA2. No genomic rearrangements were identified in the 115 Ashkenazi Jewish probands, but 47 of the 115 (40%) had point mutations. In this population genomic rearrangements constituted 18% of all identified BRCA mutations. The authors also indicated that the estimated prevalence of a mutation was not predictive of the presence of a genomic rearrangement. Thus, based on these published studies, testing for genomic rearrangements of BRCA1 and BRCA2 may be considered medically necessary when testing for standard mutations is negative in familial breast cancer when (1) there are 3 or more family members in one lineage affected with breast or ovarian or fallopian tube or primary peritoneal cancer or (2) in individuals with a risk of a BRCA mutation of at least 10%. (The threshold of 3 or more family members [instead of 4 or more] was selected because of concerns raised by the impact of having a small number of offspring.) Commercial laboratories began this expanded testing in August 2006. (39) Thus, BRCA testing done before this starting time did not have analysis for genomic rearrangement. Subsequent to that, based on information available from the laboratory, this additional testing is conducted on the subset of patients whose likelihood of a BRCA mutation is 30% or greater. When the likelihood of a BRCA mutation is between 10% and 30%, the test for genomic rearrangement must be ordered separately.


CHEK2 Mutations A number of publications have also described the association of CHEK2 (cell cycle checkpoint kinase 2) mutations with hereditary breast cancer. The prevalence of this finding varies greatly by geographic regions, being most common in northern and eastern Europe. It has been detected in 4% of early breast cancer patients in the Netherlands, in 2.3% of such patients in Germany, but has been noted to be rare in these patients in Spain or Australia. In the US, this mutation is much less common than BRCA mutations and BRCA rearrangements. For example, in the study by Walsh (37) cited above, 14 (4.7%) of the 300 patients with a positive family history of breast cancer (4 affected relatives) who were negative by standard BRCA testing, were positive for CHECK2 mutations. The low frequency makes evaluation of risk and treatment implications less precise. In general, the risk of breast cancer associated with this mutation is less that that associated with either BRCA1 or BRCA2. A meta-analysis by Weischer concluded that for familial breast cancer, the cumulative risk at age 70 years for CHEK2*1100delC mutation was 37% (confidence interval 26% to 56%). (40) 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. (41) In particular, they raise questions about the breast cancer risk estimates presented in the Weischer study; a number of the questions relate to the variable methods of ascertainment used in the studies in this meta-analysis. They also note that other mutations, such as CHEK2*S428F, are observed in other populations. The varying frequency is mentioned, with the mutation noted in 0.5 – 1.0% of the population in northern and eastern Europe compared with 0.2 – 0.3% in the US. Finally, they raise concerns about the implications of the low penetrance of this mutation. They concluded that on the basis of data available at this time, there is not compelling evidence to justify routine clinical testing for CHECK2 to guide the management of families affected with breast cancer. Thus, based on a number of concerns, testing for CHEK2 mutations is considered investigational because the impact on net health outcome is uncertain.

A recent publication described the high rate of occult fallopian tube cancers in at-risk women having prophylactic bilateral salpingo-oophorectomy. (42) 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 (43) 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 two conditions are added to the policy statements and policy guidelines.

VI. Important Reminder

The purpose of this Medical Policy is to provide a guide to coverage. This Medical Policy is not intended to dictate to providers how to practice medicine. Nothing in this Medical Policy is


intended to discourage or prohibit providing other medical advice or treatment deemed appropriate by the treating physician.

Benefit determinations are subject to applicable member contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. This Medical Policy has been developed through consideration of the medical necessity criteria under Hawaii’s Patients’ Bill of Rights and Responsibilities Act (Hawaii Revised Statutes §432E-1.4), generally accepted standards of medical practice and review of medical literature and government approval status. HMSA has determined that services not covered under this Medical Policy will not be medically necessary under Hawaii law in most cases. If a treating physician disagrees with HMSA’s determination as to medical necessity in a given case, the physician may request that HMSA reconsider the application of the medical necessity criteria to the case at issue in light of any supporting documentation.

VII. References

1. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Available online at www.ahrq.gov/clinic/uspstf05/brcagen/brcagenrs.htm. Last accessed February 2008.

2. BCBSA TEC Assessments 1997; Tab 4. 3. American Society of Clinical Oncology. Policy Statement Update: Genetic Testing for Cancer

Susceptibility (posted online April 11, 2003). J Clin Oncol 2003; 21(12):1-10. 4. The American College of Medical Genetics, Policy Statement: Genetic Susceptibility to Breast

and Ovarian Cancer: Assessment, Counseling and Testing Guidelines, 1999, available at http://www.acmg.net.

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. 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.

7. 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.

8. 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.

9. 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.

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. 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.


13. 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.

14. 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.

15. Scheuer L, Kauff N, Robson M et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002; 20(5):1260-8.

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. 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 2002; 101(6):555-9.

18. 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.

19. Weitzel JN, McCaffrey SM, Nedelcu R et al. Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg 2003; 138(12):1323-8.

20. Scheuer L, Kauff N, Robson M et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002; 20(5):1260-8.

21. Winchester DP. Breast cancer in young women. Surg Clin North Am 1996; 76(2):279-87. 22. 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 1996; 334(3):137-42. 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. 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 2002; 20(6):1480-90.

25. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998; 62(3): 676-89.

26. Gershoni-Baruch R, Dagan E, Fried G et al. Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 2000; 36(8):983-6.

27. Hodgson SV, Heap E, Cameron J et al. Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 1999; 36(5):369-73.

28. Hartge P, 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.

29. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004; 4(9):665-76. 30. Nelson HD, Huffman, LH, Fu R et al. Genetic risk assessment and BRCA mutation testing for

breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2005; 143:362-79. (Also available at www.ahrq.gov/clinic/uspstf05/brcagen/brcagenrev.pdf

31. National Comprehensive Cancer Network. Practice Guidelines in Oncology. Hereditary Breast and/or Ovarian Cancer. V.1.2007. Available online at http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf . Last accessed February 2008.


32. Robson M, Offit K. Management of an inherited predisposition to breast cancer. N Engl J Med 2007; 357:154-62.

33. Phillips KA, Jenkins MA, Lindeman GJ et al. Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Clin Genet 2006; 70:198-206.

34. Rennert G, Bisland-Naggan S, Barnett-Griness O et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 2007; 357:115-23.

35. Malone KE, Daling JR, Doody DR et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population–based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 2006; 66:8297-308.

36. Couch FJ, Johnson MR, Rabe KG et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2007; 16:342-6.

37. 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.

38. Palma MD, Domchjeck SM, Stopfer J et al. The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 2008; 68(17):7006-14.

39. Myriad Website. http://www.myriadresourceguide.com/pdfs/Myriad-Resource-Guide-BART-Criteria.pdf and http://www.myriadtests.com/provider/brca-mutation-prevalence.htm Accessed Sept 2, 2009.

40. Weischer M, Bojesen SE, Ellervik C et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 2008; 26(4):542-8.

41. Offit K, Garger JE. Time to Check CHEK2 in Families with breast cancer? J Clin Oncol 2008; 26(4):519-20.

42. 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 2009; 19(5):826-9.

43. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian (V.1.2011). Available at http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf . Accessed April 25, 2011.

44. BlueCross BlueShield Association. Genetic Testing for Hereditary Breast and/or Ovarian Cancer. 2.04.02. 02/10.

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