BRCA 1 and 2--A Genetic Link to Familial Breast and Ovarian Cancer

, , , Duke University Medical Center

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Clinical Management Dilemmas

Ideally, the ability to test for mutations in cancer predisposition genes such as BRCA1 and BRCA2 will provide clinicians with the opportunity to more effectively counsel high-risk individuals, monitor for early signs of disease, and treat at an earlier stage. Unfortunately, no proven protocols exist at present for the management of patients carrying these gene mutations.

Several nongenetic approaches to the early detection of cancers of the breast and ovary do exist. Mammography is the principal method of detection of early breast malignancy. Screening mammography has been shown to significantly reduce breast cancer mortality in women over age 50.[59] Given the high lifetime penetrance of germline BRCA1 and BRCA2 mutations, and the early age of onset in many carriers, it may seem prudent to perform regular mammography on carriers from a young age. However, the benefit of such screening must be weighed against the effect of the additional radiation on the wild-type BRCA1 or BRCA2 allele. Furthermore, mammographic results are often difficult to interpret in young women because of the density of breast tissue.[60] The benefit of early screening has not been demonstrated. Radical preventative measures, including prophylactic mastectomy and chemoprevention, still require assessment within research protocols. With respect to ovarian cancer, no ideal screening test exists to reliably detect the disease at an early stage. Regular gynecologic examinations, in association with vaginal ultrasonography and Ca-125 monitoring, may aid early detection of disease, but these have not been proven to decrease morbidity or mortality, and have resulted in unnecessary surgery due to false-positive test results.[61,62] Finally, prophylactic oophorectomy does not completely remove the risk of ovarian cancer development; intra-abdominal carcinomatosis has been reported in a BRCA1 mutation carrier following prophylactic oophorectomy.[48]

In recent years, researchers have identified the genes responsible for a host of other inherited diseases, including cystic fibrosis and Huntington's disease, for which genetic testing and presymptomatic diagnosis are now available. Genetic testing carries inherent dangers that must be fully discussed with patients prior to testing. Patients must be made aware of the potential detrimental consequences of testing, including psychological damage, loss of health or life insurance, loss of employment, lack of access to education, changes in family dynamics, and altered self-image. Large proportions of the at-risk population may decline testing based on these considerations.[63] If patients are to receive optimal care, genetic testing should take place in conjunction with adequate counseling from experts in medical and surgical cancer management, genetics, and psychology. This multidisciplinary approach will contribute to a reduction in disease morbidity and mortality while minimizing detrimental psychological, social, and economic side effects.


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