Lay Summary: I discuss the guidelines for BRCA testing.
There are two approaches to determining necessity for BRCA testing, one that focuses on specific family history and another that focuses on global risk. The USPSTF recommends against routine referral for genetic counseling or routine breast cancer susceptibility genes (BRCA) testing for women whose family history is not associated with an increased risk for deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA).
The USPSTF found fair evidence that women without certain specific family history patterns, termed here “increased risk family history” have a low risk for developing breast or ovarian cancer associated with BRCA1 or 2 mutations. Thus, any benefit to routine screening of these women for BRCA1 or 2 mutations, or routine referral for genetic counseling, would be small or zero. The USPSTF found fair evidence regarding important adverse ethical, legal, and social consequences that could result from routine referral and testing of these women. Interventions such as prophylactic surgery, chemoprevention, or intensive screening have known harms. The USPSTF estimated that the magnitude of these potential harms is small or greater. The USPSTF concluded that the potential harms of routine referral for genetic counseling or BRCA testing in these women outweigh the benefits.
The USPSTF found fair evidence that women with certain specific family history patterns (“increased risk family history”) have an increased risk for developing breast or ovarian cancer associated with BRCA1 or 2 mutations. The USPSTF determined that these women would benefit from genetic counseling that allows informed decision-making about testing and further prophylactic treatment. This counseling should be done by suitably trained health care providers. There is insufficient evidence to determine the benefits of chemoprevention or intensive screening in improving health outcomes in these women if they test positive for deleterious BRCA1 or 2 mutations. However, there is fair evidence that prophylactic surgery for these women significantly decreases breast and ovarian cancer incidence. Thus, the potential benefits of referral and discussion of testing and prophylactic treatment for these women may be substantial.
The USPSTF concluded that the benefits of referring women with an increased risk family history to suitably trained healthcare providers outweigh the harms.
This recommendation applies to women who have not been diagnosed with either breast or ovarian cancer. It does not apply to women with a family history of breast or ovarian cancer that includes a relative with a known deleterious mutation in BRCA1 or BRCA2 genes; these women should be referred for genetic counseling. This recommendation does not apply to men.
While there currently are no standardized referral criteria, women with an increased risk family history (see below) should be considered for genetic counseling to further evaluate their potential risks.
Certain specific family history patterns are associated with an increased risk for deleterious mutations in BRCA1 or 2 genes. Both maternal and paternal family histories are important. For non-Ashkenazi Jewish women, these patterns include:
Two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 or younger
A combination of 3 or more first- or second-degree relatives with breast cancer, regardless of age of diagnosis
A combination of both breast and ovarian cancer among first- and second- degree relatives
A first-degree relative with bilateral breast cancer
A combination of 2 or more first- or second-degree relatives with ovarian cancer, regardless of age of diagnosis
A first- or second-degree relative with both breast and ovarian cancer, at any age
A history of breast cancer in a male relative
For women of Ashkenazi Jewish heritage, an increased risk family history includes any first-degree relative (or 2 second-degree relatives on the same side of the family) with breast or ovarian cancer.
About 2% of adult women in the general population have an increased risk family history as defined above. Women without one of these family history patterns have a low probability of having a deleterious mutation in BRCA1 or BRCA2 genes.
Computational tools are available to predict the risk for clinically important BRCA mutations (i.e., BRCA mutations associated with the presence of breast and/or ovarian cancer), but these tools have not been verified in the general population. There is no empirical evidence concerning what level of risk for a BRCA mutation merits referral for genetic counseling.
Not all women with a potentially deleterious BRCA mutation will develop breast or ovarian cancer. The probability of developing breast or ovarian cancer by the age of 70 in a woman who has a clinically important BRCA mutation is estimated to be 35% to 84% for breast cancer and 10% to 50% for ovarian cancer.
Appropriate genetic counseling helps women make informed decisions and can improve their knowledge and perception of absolute risk for breast and ovarian cancer and often reduce anxiety. Genetic counseling includes elements of counseling, risk assessment, pedigree analysis, and, in some cases, recommendations for testing for BRCA mutations in affected family members and/or the presenting patient. It is best delivered by a suitably trained healthcare provider.
Ordering a BRCA test typically is done by a physician. When done in concert with genetic counseling, the test assures the linkage of testing with appropriate management decisions. Genetic testing may lead to potential adverse ethical, legal, and social consequences, such as insurance and employment discrimination; these issues should be discussed in the context of genetic counseling and evaluation for testing.
Among women with BRCA1 or 2 mutations, prophylactic mastectomy or oophorectomy decreases the incidence of breast and ovarian cancer; there is inadequate evidence for mortality benefits. Chemoprevention with selective estrogen receptor modulators (SERMs) may decrease breast cancer incidence of estrogen receptor-positive cancers; however, it is also associated with adverse effects such pulmonary embolism, deep vein thrombosis, and endometrial cancer. Most breast cancers associated with BRCA1 mutations are estrogen-receptor negative and thus not prevented by tamoxifen. Intensive screening with mammography has poor sensitivity, and there is no evidence of benefit of intensive screening for women with BRCA1 or BRCA2 gene mutations; magnetic resonance imaging (MRI) may detect more cancers, but the effect on mortality is not clear.
Women with an increased risk family history are at risk not only for deleterious BRCA1 or BRCA2 mutations, but potentially for other unknown mutations as well. Women with an increased risk family history who test negative for BRCA1 and BRCA2 mutations may also benefit from surgical prophylaxis.
NCCN also advises BRCA testing for women below age 60 with a personal history of triple negative breast cancer.
The American Society of Clinical Oncology (ASCO) has recently established a policy statement on guidelines for genetic testing for cancer predisposition genes (ASCO, J Clin Oncol, 2003 Jun 15;21(12):2397-2406). ASCO recommends genetic testing be offered when:
- an individual or the family history shows features of a cancer predisposition syndrome such as a cancer of early onset or the presence of specific and rare tumors
- the test is known to be technically sound
- the test results will help to clarify a diagnosis or provide management guidelines for the patient or family member.
In addition, there are guidelines by NICE, ACHG, PDQ, NCCN and other authoritative bodies.They generally require risk > 20% of brest cancer in general as measured by standard instruments to indicate BRCA testing. Using instruments, such as BRCPro, measures the overall risk of breast cancer, and if it is greater than 20%, BRCA testing is recommended. BRCAPRO is a specifically BRCA risk analysis. Gail scoring is specifically not recommended by NCCN.
In general courts have rules that the state of being a BRCA carrier is considered an illness. The Nebraska Supreme Court, for example, found that illness includes an abnormal state resulting from a genetic deviation from the norm, and so contract language dealing with illness applied to patients with a family history of cancer.
Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005 Sep 6;143(5):355-61
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