Updated May 2013
Genetic testing for breast cancer risk has limited value in the clinical setting and should only be performed in the context of well-designed clinical trials and research studies. Genetic testing must not be used as a screening tool because it is an unreliable indicator of true risk of developing breast cancer. We do not know how to prevent breast cancer and there are few and limited options available to women who wish to reduce their risk of developing breast cancer. Women considering genetic testing must receive counseling by a certified genetic counselor who provides accurate and unbiased information about the potential benefits and limitations of genetic testing.
Genetic Mutations Associated with Breast Cancer
By studying families with multiple cases of breast cancer, scientists have discovered several genetic mutations associated with a higher risk of developing breast cancer. Mutations in two genes known as BRCA1 and BRCA2 (“BReast CAncer genes 1 and 2,” also referred to as breast cancer susceptibility genes) are strongly associated with breast cancer risk.
When functioning properly, BRCA1 and BRCA2 are thought to help suppress the growth of cancerous cells. People who have certain alterations, or mutations, in these genes have an increased risk of developing breast cancer and several other types of cancer. Mutations in the BRCA1 and BRCA2 genes can be inherited and passed on to offspring by both fathers and mothers. These mutations are very rare in the general population but may contribute to the development of several cases of breast and/or ovarian cancer within one family. However, not all individuals with such mutations develop cancer. Despite the association between mutations in these genes and breast cancer, only 5-10% of all breast cancer patients have BRCA1 or BRCA2 mutations.1 Scientists believe there may be other unknown genes that are strongly associated with breast cancer risk. However, the majority of breast cancer cases are “sporadic” cancers, meaning that the individual has no known inherited predisposition to breast cancer.
Susceptibility Genes and Risk of Cancer
Some women have a family history of breast cancer and do not have mutations in either of the breast cancer susceptibility genes BRCA1 and BRCA2. Other women do not have a family history of breast cancer, but do have a mutation in one of these genes. Both of these groups of women are presumed to have a higher risk of breast cancer than the general population, but the exact amount of risk increase is unknown.2
Several studies of Ashkenazi Jewish women with breast cancer have shown that women with a BRCA1 or BRCA2 mutation have between a 55% and 85% risk of developing breast cancer during their lifetime. A large, more recent study of Ashkenazi Jewish women has shown that breast cancer risk in BRCA1 or BRCA2 mutation carriers increases with age. Women with a mutation in a BRCA gene were found to have a 20% risk of breast cancer by age 40, 55% by age 60, and 82% by age 80 in this study.3
It has been estimated that a woman who has a BRCA1 or BRCA2 mutation and a previous diagnosis of breast cancer may have a 24-65% risk of developing cancer in her other (contralateral) breast.4 Some data suggests that BRCA1 and BRCA2 mutations may also be associated with prostate, pancreatic, and colon cancer risk, but to a smaller degree than breast and ovarian cancer risk
What Information Can Genetic Testing Provide?
Laboratory tests have been developed that can detect the most common mutations in the BRCA1 and BRCA2 genes. These genetic tests cannot predict precisely who will develop breast cancer; they can only attempt to identify those individuals that carry BRCA1 or BRCA2 mutations. The tests do not and cannot protect women who carry mutations from developing the disease, nor can they cure existing disease. Furthermore, current genetic testing technology often cannot deliver conclusive results about one’s predisposition to disease. For example, a recent research study found that the standard genetic test used to identify BRCA mutations in the U.S. was unable to identify 12% of people who carried a potentially dangerous mutation in one of the BRCA genes that could lead to breast cancer.7 In addition, the sensitivity of currently used selection criteria for testing of the BRCA1 mutation is in the range of 25% to 30%, meaning that about three-quarters of women who meet the criteria for testing do not actually possess this mutation.8
If a woman tests negative for BRCA1 and BRCA2 mutations, the finding does not mean that she is protected from getting breast cancer. The large majority of women who develop breast cancer do not have BRCA1 or BRCA2 mutations. Even if BRCA1 and BRCA2 are thoroughly checked for mutations, it is still possible that a mutation could be present in another breast cancer susceptibility gene, such as CHEK2 or TP53. Thus, a woman with a strong family history who tests negative for BRCA1 and BRCA2 mutations may still have an elevated risk of breast cancer.
Why Get Genetic Testing?
Genetic testing may be useful to women if the test results help them make medical decisions that benefit them in some way. A woman may want to undergo genetic testing because she may find relief from knowing the results, particularly if the results are negative. A 2007 study found that among women with a personal or family history of breast cancer, there was a comparable increase in anxiety in both mutation carriers and women who elected not to receive genetic testing, while women with a negative (uninformative) result did not have elevated anxiety levels.9 Six months following testing, however, the distress felt by mutation carriers had dissipated.9
There are very limited options available to women to reduce their risk of breast cancer, and none of them are fully protective against the disease. Currently, if a woman tests positive for a BRCA1 or BRCA2 mutation, health professionals may offer her the following health management options alone or in combination:
It should be noted that a study of close to 2000 carriers of BRCA1 or BRCA2 mutations in Europe found that those exposed to diagnostic radiation before the age of 30 had a significantly increased risk of developing breast cancer. The increased risk of breast cancer appeared at considerably lower doses of radiation than those at which increases have been found in non-BRCA mutation carriers.10
Prophylactic surgery has been shown to reduce the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.11 There is some evidence that tamoxifen, raloxifene, and aromatase inhibitors may reduce risk among women considered to be at high risk.12-14 Unfortunately, there is no long-term data on healthy women who have taken chemoprevention drugs for risk reduction.
Few studies have looked at the effectiveness of these drugs specifically for women with a BRCA1 or BRCA2 mutation. In one study, tamoxifen reduced breast cancer risk by 62% in women with BRCA2 mutations but showed no associated risk reduction for women with BRCA1 mutations.15 More research is needed to evaluate the benefits of tamoxifen for women with BRCA mutations.
Women must be informed that none of these health management options have been proven in scientific studies to reduce the risk of dying from breast cancer. Furthermore, these medical interventions have risks and side effects that should be thoroughly discussed with a health care provider.
Until 2008, it was possible that the results of genetic testing could be used as a basis for discrimination in employment and health insurance. However, that year, the Genetic Information Nondiscrimination Act (GINA) became Federal law prohibiting genetic discrimination in relation to health insurance and employment. GINA prohibits employers from making adverse employment decisions based on a person’s genes and forbids insurance companies from discriminating through reduced coverage or pricing. Unfortunately, the law does not cover life insurance, disability insurance, and long-term care insurance.16
The Health Insurance Portability and Accountability Act (HIPAA) of 1996 also addresses the issue of discrimination on the basis of genetic information. This law prohibits group health plans from using genetic information, and other health-status factors, as a basis for denying or limiting eligibility for coverage or for charging an individual more for coverage. However, this law only pertains to discrimination in health insurance in the context of group plans under limited circumstances.17
Beginning in January 2014, the Affordable Care Act will implement strong reforms that prohibit insurance companies from refusing to sell coverage or renew policies because of an individual’s pre-existing conditions. Also, in the individual and small group market, it eliminates the ability of insurance companies to charge higher rates due to gender or health status.18 Since October 2012, the Act has guaranteed insurance coverage for genetic counseling and BRCA testing, if appropriate, as a preventive service without cost-sharing.19
Genetic Testing in the Context of Clinical Trials and Research Studies
Currently, the main benefit of genetic testing is that it may identify a subset of women from whom we can learn more about inherited breast cancer risk within the context of well-designed research protocols. Genetic testing research studies should be available to those for whom testing is appropriate, and the results of such studies be published and made available to the wider community. All those who participate in peer-reviewed research protocols must be guaranteed continuing follow-up and provided information regarding further refinements of these tests and therapies associated with the genes. Research study participants also must be guaranteed that their genetic testing results will be kept confidential.
A genetic test for breast cancer should only be utilized with full consideration of its limitations and implications. Genetic testing cannot cure or prevent breast cancer, and cannot accurately predict whether a woman will or will not develop breast cancer. Most women who get breast cancer do not have BRCA1 or BRCA2 mutations, and some women with confirmed mutations will never get breast cancer. While the tests may help some women who have a strong family history and who have a BRCA1 or BRCA2 mutation make health management decisions, the available medical options are of limited value and have risks and side effects to be considered.
Genetic testing should be done in the context of well-designed clinical trials and research studies and must include an opportunity to meet with a certified genetic counselor who is unbiased and who has the expertise to explain the risks and limited benefits of testing.
It is irresponsible to market and promote the widespread use of genetic tests for breast cancer risk at this time. Research must first focus on finding safe, reliable ways to reduce cancer risk in women. In the future, if women who have BRCA1 and BRCA2 mutations can be offered viable health management options, genetic testing may become more useful. Currently, these tests have limited value in the clinical setting and are most useful in the context of research studies.
1 Burke W, Daly M, Garber J, Botkin J, Ellis Kahn MJ, et. al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. JAMA 1997;277:997-1003.
2 Whittemore AS, Gong G, Itnyre J. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three US populationbased case-control studies of ovarian cancer. Am J Hum Genet 1997;60:496-504.
3 King, MC, Marks, JH, and Mandell, JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302: 643-646.
4 Schrag D, Kuntz KM, Garber JE, Weeks JC. Life expectancy gains from cancer prevention strategies for women with breast cancer and BRCA1 or BRCA2 mutations. JAMA 2000;283:617-624.
5 Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343(8899):692-5.
6 Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 1999;91(15):1310-6.
7 Walsh T, Casadei S, Coats KH, Swisher E, et al. Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast Cancer. JAMA. 2006 295(12):1379-1387
8 Farshid G, Balleine RL, Cummings M, Waring P: Kathleen Cuningham Consortium for Research into Familial Breast Cancer. Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing. Am J Surg Pathol 2006 Nov. 30 (11): 1357-66.
9 Smith AW, Dougall AL, Posluszny DM, Somers TJ, Rubinstein WS, Baum A. Psychological distress and quality of life associated with genetic testing for breast cancer risk. Psycho-Oncology: Vol. 7, Issue 8. 9 Nov 2007.
10 Pijpe A, Andrieu N, Easton DF, et al. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). BMJ 2012; 345 e5660 (Published 06 September 2012) P 202.296.7477 | F 202.265.6854 | BreastCancerDeadline2020.org © National Breast Cancer Coalition
11 Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van’t Veer L, Garber JE, Evans G, Isaacs C, Daly MB, Matloff E, Olopade OI, Weber BL; Prevention and Observation of Surgical End Points Study Group. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002 346(21):1616-22
12 Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 2005;97(22):1652-62.
13 Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295(23):2727-41.
14 Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. NEJM 2011; 364(25):2381-91
15 King M, Wieand S, and Hale, K. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2. Journal of the American Medical Association 2001; 286(18):2251-2256
16 Genetic Information Nondiscrimination Act (GINA) of 2008. http://www.genome.gov/24519851
17 Genetic Privacy Laws are not enacted in all states and the degree of protections vary among states. To check and see if your state has a genetic privacy law you can go to http://www.nhgri.nih.gov/PolicyEthics/ the website for the National Human Genome Research Institute to find a state by state analysis of genetic law
18 Timeline of the Affordable Care Act. HealthCare.gov http://www.healthcare.gov/law/timeline/full.html
19 U.S. Department of Health and Human Services, The Center for Consumer Information and Insurance Oversight, Affordable Care Act FAQs. http://cciio. cms.gov/resources/factsheets/aca_implementation_faqs12.html