This issue addresses pharmacogenomics, epigenetics, direct-to-consumer genomic testing, gene therapy, prenatal and newborn screening, and other medical applications of genetics. Commentaries also discuss the social, policy, and ethical issues associated with this technology and the need for health professional education in this area. Original articles describe community perceptions of genomic research and the relation of race and health insurance to long-term risk of mortality among lung cancer patients.
Pros and Cons of Screening for BRCA Mutations
Estimates suggest that about 80% of breast cancers and 90% of ovarian cancers are sporadic ; only 5% to 10% of breast cancers are hereditary. Hereditary mutations of the BRCA1 and BRCA2 genes account for 60% of inherited breast and ovarian cancers . According to data from the National Cancer Institute , the risk of a BRCA2 mutation carrier developing breast cancer by age 70 years is 45%, and her risk of developing ovarian cancer is 11%–17%; BRCA1 mutation carriers have a slightly higher risk of breast cancer (55%–65%) and a higher risk of ovarian cancer (39%).
Until recently, the management of breast cancers resulting from a BRCA mutation did not differ from management of sporadic tumors. However, genetic information is now important in planning surgeries and adjuvant therapies, and genetic testing for BRCA mutations is increasingly being used for risk assessment. This article will examine the pros and cons of such testing and discuss how it can affect patient care.
In multidisciplinary breast centers, genetic counselors play a vital role by identifying and evaluating women who are at high risk for hereditary breast cancer syndromes. The US Preventive Services Task Force guideline on genetic risk assessment and BRCA testing strongly recommends that high-risk individuals be referred for genetic counseling and possible testing . Genetic counseling and testing provide many benefits to the patient and to the health care team . First, counseling and testing help to identify high-risk individuals who do not have cancer; these women will benefit from early screening and consultation. For a woman with a known cancer, counseling and testing may help her decide whether to undergo a bilateral mastectomy at the time of her cancer surgery, or whether to opt for careful surveillance of the remaining breast tissue. Finally, testing can alleviate the anxiety of not knowing one’s carrier status.
The risks of genetic testing include the inability of such testing to detect all mutations, the unclear efficacy of some interventions, and the possibility of psychosocial or financial harm . Genetic counselors can inform patients about Title I of the Genetic Information Nondiscrimination Act of 2008 , which provides protection against discrimination based on genetic information in health insurance underwriting decisions. However, that protection covers only group and individual health insurance; it does not apply to life insurance, disability insurance, or long-term care insurance .
Women who test positive for a BRCA mutation have several options for reducing their risk of developing cancer. These include surveillance, chemoprevention, and surgical risk reduction.
For BRCA mutation carriers, early detection strategies include annual or semiannual clinical breast examination by a physician or allied health professional, annual mammography beginning at age 25 years, and/or annual breast magnetic resonance imaging (MRI) ; if both breast MRI and mammography are being performed, the breast MRI should be performed 6 months after the yearly mammogram. The benefit of a clinical breast examination is under debate, as such exams have not been shown to improve the rate of cancer detection. Nonetheless, patients say that they find the exam reassuring, and it gives the provider an opportunity to discuss the patient’s care .
Mammography has been shown to decrease the breast cancer mortality rate; however, its sensitivity is estimated to be only about 36% in BRCA1 or BRCA2 mutation carriers . In contrast, the sensitivity of MRI screening in women with a familial or genetic predisposition is nearly 80% [7, 8]. The pros of breast cancer surveillance with MRI are that it is noninvasive and it has no long-term side effects. The cons are that it has not been shown to reduce the risk of breast cancer–related death in BRCA mutation carriers, and it carries an increased risk of false-positive results, which can lead to additional imaging or biopsies.
Breast cancer chemoprevention is offered in the form of tamoxifen and raloxifene, with the latter being used for postmenopausal women. The Study of Tamoxifen and Raloxifene (STAR)  showed that these selective estrogen receptor modulators (SERMs) lowered the risk of developing invasive breast cancer by about 50%. However, SERMs do not completely eliminate the risk of developing breast cancer, and data regarding their effectiveness in BRCA mutation carriers are limited.
Bilateral prophylactic mastectomy has been shown to reduce breast cancer risk in women with a family history of breast cancer. The risk reduction in BRCA mutation carriers has been shown to be 90% in women with intact ovaries and 95% in those who have undergone prophylactic oophorectomy . Many women who choose bilateral mastectomy also opt for immediate breast reconstruction with implants or autologous tissue. The advantage of prophylactic mastectomy is that it greatly reduces the risk of developing breast cancer. The disadvantages include the need for extra surgeries with breast reconstruction, possible surgical complications (eg, bleeding and infections), and psychosexual concerns. However, studies have shown that most women are satisfied with their surgical choice and do not experience poor body image after surgery [11, 12].
In addition to prophylactic mastectomy, BRCA mutation carriers may consider prophylactic oophorectomy. Bilateral prophylactic salpingo-oophorectomy is associated with an 85% reduction in the risk of developing gynecologic cancer among BRCA1 mutation carriers .
Breast specialists and genetic counselors play an important role in guiding patients with an increased risk for developing breast cancer through genetic testing and treatment options. There are pros and cons to each risk-reduction strategy, but the more informed a patient is, the better her outcome and overall satisfaction will be.
Potential conflicts of interest. M.H.N. has no relevant conflicts of interest.
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2. National Cancer Institute (NCI). BRCA1 and BRCA2: Cancer Risk and Genetic Testing. NCI Web site. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA. Reviewed August 5, 2013. Accessed November 4, 2013.
3. US Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med. 2005;143(5):355-361.
4. Genetic Information Nondiscrimination Act of 2008. Pub L No. 110-233, 122 Stat 881. http://www.gpo.gov/fdsys/pkg/PLAW-110publ233/pdf/PLAW-110publ233.pdf. Accessed October 7, 2013.
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6. Spiegel TN, Hill KA, Warner E. The attitudes of women with BRCA1 and BRCA2 mutations toward clinical breast examinations and breast self-examinations. J Womens Health (Larchmt). 2009;18(7):1019-1024.
7. Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA. 2004;292(11):1317-1325.
8. Kriege M, Brekelmans CT, Boetes C, et al; Magnetic Resonance Imaging Screening Study Group. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351(5):427-437.
9. Vogel VG, Constantino JP, Wickerman DL, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP). 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):2727-2741.
10. Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055-1062.
11. Frost MH, Slezak JM, Tran NV, et al. Satisfaction after contralateral prophylactic mastectomy: the significance of mastectomy type, reconstructive complications, and body appearance. J Clin Oncol. 2005;23(31):7849-7856.
12. Brandberg Y, Sandelin K, Erikson S, et al. Psychological reactions, quality of life, and body image after bilateral prophylactic mastectomy in women at high risk for breast cancer: a prospective 1-year follow-up study. J Clin Oncol. 2008;26(24):3943-3949.
13. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331-1337.
Marissa Howard-McNatt, MD, FACS director, Breast Care Center, and assistant professor, Department of General Surgery, Wake Forest Baptist Health, Winston-Salem, North Carolina.
Address correspondence to Dr. Marissa Howard-McNatt, Wake Forest Baptist Health, Department of General Surgery, Medical Center Blvd, Winston-Salem, NC 27157 (firstname.lastname@example.org).