Articles that were published since a 1997 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment were reviewed for information regarding professional guidelines for BRCA (breast cancer genes) testing, testing of unaffected family members, and testing of high-risk ethnic populations. In addition, web sites for relevant professional organizations were consulted for posted guidelines.
The American Society of Clinical Oncology (ASCO) recommends that cancer predisposition testing be offered when (1) the person has a strong family history of cancer or very early age of onset of disease, (2) the test can be adequately interpreted, and (3) the results will influence the medical management of the patient or family member.
In 1999, the American College of Medical Genetics (ACMG) published guidelines for BRCA testing under the auspices of a grant from the New York State Department of Health to the ACMG Foundation. The guidelines suggest that increased risk for a mutation in a known cancer susceptibility gene is evident if:
- There are three or more affected first or second degree relatives on the same side of the family, regardless of age at diagnosis, or
- There are fewer than three affected relatives, but
- the patient was diagnosed at 45 years of age or less, or
- a family member has been identified with a detectable mutation, or
- there are one or more cases of ovarian cancer at any age, and one or more members on the same side of the family with breast cancer at any age, or
- there are multiple primary or bilateral breast cancers in the patient or one family member, or
- there is breast cancer in a male patient, or in a male relative, or
- the patient is at increased risk for specific mutation(s) due to ethnic background (for instance: Ashkenazi Jewish descent) and has one or more relatives with breast cancer or ovarian cancer at any age.
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 or ovarian cancer histories, early penetrance estimates may have been biased upward. Studies of founder mutations in ethnic populations (e.g., Ashkenazi Jewish, Polish, and Icelandic populations) unselected for family history indicated lower penetrance estimates, in the range of 40–60% for BRCA1 (breast cancer 1) and 25–40% for BRCA2 (breast cancer 2). 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 three BRCA founder mutations. Importantly, the risk of cancer in mutation carriers from families with little history of cancer (approximately 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.
Thus, the risk of cancer in a BRCA mutation carrier is significant, and knowledge of mutation status in individuals at potentially increased risk of a BRCA mutation may impact healthcare decisions to reduce risk. Risk-reducing options include intensive surveillance, prophylactic mastectomy, or prophylactic oophorectomy. Prophylactic mastectomy reduces the risk of breast cancer in high-risk women (based on family history) by 90% or more, but is invasive and disfiguring. Prophylactic oophorectomy significantly reduces the risk of ovarian cancer to less than 10% and reduces the risk of breast cancer by approximately 50%. In women who have already had breast cancer, prophylactic oophorectomy reduces the risk of cancer relapse. Studies indicate that genotyping results significantly influence treatment choices.
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 or ovarian cancer is an important risk factor for BRCA mutation. Age and, in some cases, ethnic background can also be independent risk factors.
Young age of onset of breast cancer, even in the absence of family history, has been demonstrated to be a risk factor for BRCA1 mutations. Winchester estimated that hereditary breast cancer accounts for 36%–85% of patients diagnosed under age 30. In several studies, BRCA mutations are independently predicted by early age at onset, being present in 6–10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (ages 35–50 years). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 mutations is in the 40s. In the Ashkenazi Jewish population, Frank et al. reported BRCA mutations in 13% of 248 cases with no known family history and diagnosed before 50 years of age. In a similar study, 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA mutations. Additional studies indicate that early age of breast cancer diagnosis is a significant predictor of BRCA mutations in the absence of family history in this population.
As in the general population, family history of breast or ovarian cancer, particularly of early age onset, is a significant risk factor for a BRCA mutation in ethnic populations characterized by founder mutations. For example, in unaffected individuals of Ashkenazi Jewish descent, 12–31% will have a BRCA mutation depending on the extent and nature of the family history. Several other studies document the significant influence of family history.
Unaffected individuals with a family history suggestive of HBOC 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. 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.
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 or ovarian cancer susceptibility have been published by the U.S. Preventive Services Task Force (USPSTF) and the National Comprehensive Cancer Network (NCCN). The USPSTF review includes summary of criteria from various groups on genetic testing in this situation. These guidelines help to better define families where there is a “high risk of a mutation” and also provide information about testing both for men with breast cancer and for women with ovarian cancer.
A clinical approach to these patients was recently published by Robson and Offit. Phillips reported that while uptake of prophylactic surgery and screening was associated with knowing one’s mutation status, in their cohort of 70 unaffected female mutation carriers who had chosen to receive results, the minority utilized risk-reducing surgery (11% had bilateral mastectomy and 29% bilateral oophorectomy) or chemoprevention. Rennert and colleagues reported that breast cancer-specific rates of death among Israeli women were similar for carriers of a BRCA founder mutation and noncarriers. Malone and colleagues reported on racial and ethnic differences in the prevalence of BRCA1 and BRCA2 in American women. Among their cases, 2.4% and 2.3% carried deleterious mutations in BRCA1 and BRCA2, respectively. BRCA1 mutations were significantly more common in “white” (2.9%) versus “black” (1.4%) cases and in Jewish (10.2%) versus non-Jewish (2.0%) cases; BRCA2 mutations were slightly more frequent in “black” (2.6%) versus “white” (2.1%) cases. Couch et al. studied familial pancreatic cancer and noted that BRCA2 mutations accounted for 6% of moderate and high-risk pancreatic cancer families.
Using information from the USPSTF, a family at high-risk of having a mutation is determined by having any of the following characteristics: three or more first- or second-degree relatives with breast cancer regardless of age at diagnosis; or two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 years or younger; or combination of both breast and ovarian cancer among first- and second-degree relatives; or first-degree relative with bilateral breast cancer; or a combination of two or more first- or second-degree relatives with ovarian cancer regardless of age at diagnosis; or a first- or second-degree relative with both breast and ovarian cancer at any age; or a history of breast cancer in a male relative. In addition, based on information in the NCCN guidelines and in recognition of changes in management (including mammography) that can occur in males with, or at high-risk for, breast cancer, testing males affected by breast cancer was added to the policy statement.
In applying this policy, an accurate family history is a key component in deciding which patients will be tested. In interpreting this history, it is important to evaluate the maternal and paternal lineage separately.
Finally, one of the policy statements indicates that this testing is experimental, investigational and unproven in minors, because there is no change in management for minors as a result of knowledge of the presence or absence of a deleterious mutation. In addition, there are potential harms related to stigmatization and discrimination.
Testing for BRCA1 and BRCA2
The medical policy update was based upon a review of the published 2011 NCCN Guidelines criteria of genetic or familial high-risk assessment of breast and ovarian cancer. According to the Guidelines: “For the majority of families in whom mutation status is unknown, it is best to consider testing an affected family member first, especially a family member with early-onset disease, bilateral disease, or multiple primaries, because that individual has the highest likelihood for a positive test result. Unless the affected individual is a member of an ethnic group for which particular founder gene mutations are known, full sequencing of the genes is usually performed. For individuals with family histories consistent with a pattern of HBOC on both the maternal and paternal sides, the possibility of a second deleterious mutation in the family should be considered, and full sequencing may be indicated. The testing of unaffected family members may be considered when there is no known deleterious mutation in the family and no affected member is available. A negative test result in this case, however, is considered indeterminate and does not provide the same level of information as when there is a known deleterious mutation in the family. In the case of HBOC (i.e., BRCA mutation), if no family member with breast or ovarian cancer is living, consideration can be given to testing first- or second-degree family members affected with cancers thought to be related to the deleterious mutation in question (e.g., prostate or pancreatic cancer).”
NCCN reports that some histopathological features occur in breast cancer mutations, such as in the BRCA1 mutation of ER-, PR-, and HER-2 “triple-negative” breast cancer characterization. The studies reveal, “BRCA 1 mutations in 11% to 28% of patients with triple-negative breast cancer. In addition, it appears that among patients with triple-negative disease, BRCA mutation carriers were diagnosed at a younger age compared with non-carriers.” In fact a study of 284 patients demonstrated the mean age of diagnosis was 40 years in carriers of BRCA1 with triple-negative breast cancer. Interestingly, those patients with early onset of triple-negative disease, diagnosed at 40 years or younger, were shown to have the BRCA1 mutation.
There are reports of other malignancy types in families with a BRCA1 or BRCA2 gene mutation, such as prostate cancer and melanoma, however there are no known studies. BRCA1 or BRCA2 screening for risk assessment of HBOC when there is a family history of prostate cancer or melanoma has not been recommended by the NCCN.
In addition to the NCCN statement above, the NCCN Guidelines recommend BRCA testing for those individuals with a personal history of male breast cancer, a personal history of epithelial ovarian, fallopian tube or primary peritoneal cancer (particularly suspicious when there is an early onset), or when the patient is a member of a family with a known deleterious BRCA1 or BRCA2 mutation (such as coming from a founder population). Generally, individuals of Ashkenazi Jewish descent are considered a founder population; however, full-sequencing may be considered if the individual’s ancestry also includes non-Ashkenazi Jewish relative or HBOC criteria. Examples of other founder populations within an individual’s ancestry include Icelandic, Swedish, Hungarian, and Dutch. The NCCN Guidelines maintain when investigating genetic family histories, the maternal and paternal sides should be considered independently. Close relatives should be considered as first-, second-, and third-degree relatives. Since the NCCN Guidelines are derived from a uniform consensus, the recommendation is categorized as level 2A strength of evidence that indicates BRCA mutation testing is appropriate for a specific subset of individuals who are at high-risk for HBOCs.
Testing for Large BRCA Rearrangements (BRCA Analysis Rearrangement Test [BART])
Over the past few years, a number of studies have shown that a significant percentage of women with a strong family history of breast cancer and negative tests for BRCA mutations have large genomic rearrangements (including deletions or duplications) in one of these genes. For example, in 2006 Walsh and colleagues reported on probands from 300 U.S. families with four or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic tests for BRCA1 and BRCA2. These patients underwent screening with additional multiple DNA-based and RNA-based methods. Of these 300 patients, 17% carried previously undetected mutations, including 35 (12%) with genomic rearrangement of BRCA1 or BRCA2.
A more recent study evaluated 251 patients with an estimated BRCA mutation using the Myriad II model of 10% or greater. In the 136 non-Ashkenazi Jewish probands, 36 (26%) had BRCA point mutations and eight (6%) had genomic rearrangements, seven in BRCA1 and one 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 three 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 three or more family members (instead of four or more) was selected because of concerns raised by the impact of having a small number of offspring.
Commercial laboratories, such as Myriad’s BART technology, began this expanded testing in August 2006; BRCA testing before then did not include analysis for genomic rearrangement. After 2006, additional rearrangement 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.
Testing for 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 U.S., this mutation is much less common than BRCA mutations and BRCA rearrangements. For example, in the study by Walsh cited above, 14 (4.7%) of the 300 patients with a positive family history of breast cancer (four affected relatives), who were negative by standard BRCA testing, were positive for CHEK2 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 than that associated with either BRCA1 or BRCA2.
A meta-analysis by Weischer concluded that for familial breast cancer, the cumulative risk at age 70 years for CHEK2 1100delC mutation was 37% (confidence interval 26% to 56%). This risk is lower than cumulative risk at age 70 of 57% for BRCA1 and 49% for BRCA2. In particular, they raise questions about the breast cancer risk estimates presented in the Weischer study; a number of the questions relate to the variable methods of ascertainment used in the studies in this meta-analysis. They also note that other mutations, such as CHEK2 S428F, are observed in other populations. The varying frequency is mentioned, with the mutation noted in 0.5 – 1.0% of the population in northern and eastern Europe compared with 0.2 – 0.3% in the U.S. Finally, they raise concerns about the implications of the low penetrance of this mutation. They concluded that on the basis of data available at this time, there is not compelling evidence to justify routine clinical testing for CHEK2 to guide the management of families affected with breast cancer. Thus, based on a number of concerns, testing for CHEK2 mutations is considered experimental, investigational and unproven because the impact on net health outcome is uncertain.
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