By Ellen Blaine, M.P.H.

dm01.jpg (11348 bytes)The power and paradox of predictive medicine is that it can be used as an aid in the management of diseases that have not developed in an individual. As new genetic tests identify high risk for disease, methods can be selected to treat patients who are healthy but believed to be predisposed to a disease based on the presence of deleterious genetic mutations. In a proportion of cases, however, the disease being managed through prophylaxis is one the individual would never have had.

Disease prevention methods focused on healthy lifestyle changes and watchful health screenings may hold benefit regardless of the predictive power of a genetic test, but pharmaceutical or surgical interventions raise a higher level of concern. Some herald the potential of preventive medicine or predisposition profiling as a shift in the medical paradigm from diagnosis and treatment to prediction and prevention. Others reiterate the caution that careful examination of the penetrance of a mutation, i.e., the probability that it will lead to disease, must precede any clinical recommendations.

In 1994, scientists discovered that women who carry mutations in the breast cancer associated genes BRCA1 and BRCA2 have a higher risk than non-carriers of developing breast and ovarian cancer. Both BRCA1 and BRCA2 are tumor suppression genes encoding proteins that participate in the repair of damage to the DNA. Alterations in these genes may stop them from performing their role in suppressing tumor growth, though it is uncertain why this inactivation heightens susceptibility to breast and ovarian cancers specifically. The lifetime risk of breast cancer for women with BRCA mutations ranges from 50 to 85 percent compared with 12 percent among the general population of women. Alterations in the BRCA genes may account for up to 10 percent of all breast cancer cases, but about 75 percent of familial cases occur in carriers of the mutations. The risk for ovarian cancer is 20 to 40 percent for women with BRCA1 mutations and 10 to 20 percent with BRCA2 mutations, compared with 1.5 percent of women in the general population. The age at which familial breast and ovarian cases occur tends to be younger than that for sporadic cases, but the risk is lifelong and may include development of bilateral breast cancer or both breast and ovarian cancer.

For women with a medical or family history that places them at high risk for a genetic predisposition to cancer, genetic counseling that includes information on testing for BRCA1 and BRCA2 mutations has become a recommended part of care. A negative test tells a woman that her risk for breast and ovarian cancer is not elevated based on these genetic alterations. The follow-up to a positive test, however, is far less clear.

Prophylactic mastectomy is an option considered by some women at defined high breast cancer risk. This would include women in families with apparent inherited breast cancer high risk and those who through genetic testing are found to carry BRCA mutations. Prospective studies on known carriers of breast-cancer associated gene mutations are needed to more accurately assess the true protective effect of prophylactic mastectomy. Data from recent retrospective studies, however, indicate that prophylactic removal of both breasts reduces the risk of a subsequent breast cancer by 90 percent or more in women known to be carriers of mutations in the BRCA1 and BRCA2 susceptibility genes.

The use of prophylactic mastectomy remains controversial for many reasons. Its protective effect is not complete, and breast cancer can still develop after complete removal of both breasts and nipples. Further, a proportion of BRCA mutation carriers will never develop breast cancer absent any intervention. The possibility that cancer risk based on positive BRCA mutations has been overestimated is a topic of ongoing investigation that includes more in-depth analysis of other genetic and environmental contributors to disease, along with study of risk modifiers that can alter predisposition. If breast cancer does develop and is discovered early through surveillance, it may be treatable. If the appropriate level of treatment for such cancer would most often involve breast-conserving surgery, then prophylactic mastectomy as a prevention is more extreme than the cure. Finally, the decision to remove the breasts involves a balancing of anticipated improvement in life expectancy against a change in body image and function that can only be measured on a personal level by an individual woman. Under any circumstances, prophylactic mastectomy is not considered an urgent procedure and time, care and counseling are recommended in reaching a decision.

The risk of ovarian cancer in carriers of BRCA mutations is lower than the risk of breast cancer, but the high mortality rate for ovarian cancer is a cause for increased concern. In the absence of reliable early detection methods, approximately two-thirds of women with ovarian cancer have advanced disease at the time of diagnosis. When ovarian cancer is diagnosed in the later stages, the five-year survival rate is below 30 percent. Such delayed diagnosis and lethality, according to Daniel Haber, M.D., Ph.D., has “prompted many oncologists to recommend bilateral prophylactic oophorectomy after childbearing is complete. This reduces risk for both breast and ovarian cancers.” Nonetheless, cases of breast cancer after bilateral mastectomy and peritoneal ovarian cancer after bilateral oophorectomy are well documented.

Chemopreventive agents have also been shown to reduce risk for breast cancer, and targeted chemoprevention that is as effective as prophylactic bilateral mastectomy has been called a hope for the future. The state of current research shows that tamoxifen has a protective effect among carriers of BRCA2 mutations, and less frequently among carriers of BRCA1 mutations because tumors that develop among these women tend to be estrogen receptor negative. Tamoxifen given to women with BRCA1 and BRCA2 mutations following surgery for breast cancer has been shown to reduce risk in the contralateral breast by half. An 84 percent risk reduction was found in women who both underwent oophorectomy and received tamoxifen. While tamoxifen has been found to be effective in reducing breast cancer incidence among high-risk women, it is also associated with increased endometrial cancer risk, particularly among long-term users. Hysterectomy and oophorectomy would remove the risk of endometrial cancer caused by tamoxifen, but such treatments represent another great burden for prophylaxis.

More vigilant surveillance for breast cancer has also been suggested as a risk management strategy for BRCA mutation carriers. It is recommended that mammography for carriers begin at age 25, along with clinical breast examination and self-examination, and breast MRI as an investigational screening tool. The efficacy of this strategy is not yet clearly demonstrated. And given that mammography is already recommended for women in the United States from age 40 forward, information on genetic susceptibility may not add much to surveillance planning after this age. For ovarian cancer, current surveillance methods remain limited regardless of BRCA status.

Imperfect surveillance tools and difficult surgical choices complicate clinical recommendations based on BRCA testing. On the one hand, this underscores the need for better screening and detection methods for breast and ovarian cancer; on the other, it inhibits the clinical utility of the genetic test. Prophylactic mastectomy affords the greatest protection against breast cancer and has been well accepted in study groups of high-risk women, but the overwhelming majority of women who would opt for removal of both breasts would have survived without the mastectomies. Further, the disfiguring nature of the surgery makes it a highly personal choice. Ovarian cancer is more difficult to detect in early, treatable stages and oophorectomy affords protection against both breast and ovarian cancer. Companion articles appearing in the May 23, 2002 issue of the New England Journal of Medicine support the current practice of recommending prophylactic bilateral oophorectomy after the completion of childbearing for a woman carrying a mutant BRCA gene.

Prospective studies clarifying the effectiveness of surgical intervention, development of better chemopreventive agents and improved diagnostic screening to monitor for disease are all needed. These will further establish the medical benefit of identifying a BRCA carrier, and enhance the value of the testing as a tool for guiding treatment.