Lessons Learned From Genetic Testing

The study reported by Domchek and colleagues¹ in this issue of JAMA demonstrates the benefit of risk-reducing procedures for women with strong genetic predispositions for breast cancer. This multicenter study involved almost 2500 women diagnosed with BRCA gene mutations, almost half of whom chose either risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). None of the women who underwent RRM developed breast cancer. Among women who underwent RRSO, only 1.1% developed ovarian cancer. Importantly, RRSO was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.40), breast cancer–specific mortality (HR, 0.44), and ovarian cancer–specific mortality (HR, 0.21).

Women with BRCA gene mutations are at high risk for lethal cancer, the vast majority of which can be prevented in this population. But for this risk reduction to be possible, and for lives to be saved by preventive treatment, at-risk women must first be identified, and, as Domchek et al¹ show, the earlier prophylactic procedures are performed, the greater the benefit.

For some women, genetic testing may reveal that they do not carry the predisposing genetic mutation that is present in their family. However, other women may learn that they indeed share a family predisposition to cancer. Identifying and counseling women with a family history of breast and ovarian cancer can help them better understand their risks and options—and how to reduce those risks. At a minimum, primary care clinicians should be familiar with the American Society of Clinical Oncology² or National Comprehensive Cancer Network³ guidelines and should be able to refer at-risk patients to a genetic counselor. Another approach is to automate breast cancer risk assessments using known risk models, such as BRCAPRO,⁴ which has shown usefulness in various ethnic groups.⁵

In the study by Domchek et al,¹ only 10% and 38% of women chose RRM and RRSO, respectively. Now that better data are available on the potential outcomes associated with these interventions, women who test positive for BRCA1 or BRCA2 can make more informed choices about whether to consider prophylactic surgery or to opt for intensive surveillance. These options can only be offered if a woman is identified as being at risk and is counseled. The recommended breast screening routine for BRCA carriers (in whom breast cancer risk is 10-fold higher than in the general public) is annual mammography and annual breast magnetic resonance imaging, staggered so that a test is performed every 6 months.³ Increasing the frequency of screening in this manner is especially important for BRCA1 mutation carriers, who are predisposed to high-grade tumors that can arise rapidly.⁶ Screening with CA 125 blood testing and vaginal ultrasonography is recommended to be performed every 6 months,³ although ovarian cancer screening has limited value.

However, unlike RRSO and RRM, surveillance is not prevention. As the report by Domchek et al¹ demonstrates, prophylactic surgery for high-risk women not only reduces the risk of developing cancer, but is also associated with decreased mortality. Moreover, women who present with breast or ovarian cancer still benefit from testing because the presence of a mutation significantly increases the risk of a second primary (breast or ovarian) diagnosis and often influences the choice of treatments. In the study by Domchek et al,¹ RRSO was associated with reduced risk of ovarian cancer among women with and without a prior breast cancer diagnosis, illustrating why a woman may want to know about BRCA gene mutation status even if she chooses to undergo bilateral mastectomy.

Women considering prophylactic interventions should be aware that options have changed and improved. Laparoscopic RRSO is a relatively low-risk procedure that can be performed in an outpatient setting, and a more invasive node sampling procedure is no longer required as part of this procedure.⁷ Potential short- and long-term effects from the resultant early menopause—such as hot flashes and osteoporosis⁸ —can be managed with hormone therapy, at least until the age of natural menopause.⁹ Women who have finished bearing children can have RRSO alone or in combination with RRM. The cosmetic options have significantly improved for women undergoing RRM. Total skin-sparing mastectomy—in which the entire breast and nipple complex is removed but the dermis (including the nipple areola dermis) is left intact—results in a more natural appearance. This technique has now been shown to be safe and reliable and is routinely performed in many major breast centers.¹⁰

The identification of a BRCA mutation is a family affair, commonly affecting relatives across states, countries, and insurance policies. Communication of these results is often best facilitated by involving genetic counselors who are specially trained to help manage the complicated issues that often arise within families surrounding testing. Counselors also can help to reinforce that the men in these families have equal risk of being mutation carriers, and can help ensure that all carriers are aware of their options. One important option for female carriers who are identified prior to completing childbearing is testing fertilized eggs for the presence or absence of a BRCA mutation. During in vitro fertilization, fertilized eggs without the mutation can be chosen for implantation.¹¹

Early identification of BRCA1 or BRCA2 mutation status empowers women to better understand their risk and make choices about screening and prophylaxis that are consistent with their values. In addition, not all results of testing are clear: there are cases in which BRCA testing reveals the presence of variants of uncertain significance. Although such variants are more frequently benign polymorphisms, they can also represent deleterious mutations. In these ambiguous cases, it may be difficult to counsel patients as to their risk, and testing all affected family members can help reclassify these polymorphisms to yield a better risk evaluation.

From the time BRCA1 and BRCA2 were identified and testing for them became an option, not all primary care physicians have been convinced of the benefits of hereditary risk assessment. However, risk-reducing surgery has been proved effective—and this evidence has emerged because of the willingness to adopt testing, identify women at risk, and study interventions in this specific population. Furthermore, as scientific investigation has revealed the mechanism of action of cancer-causing mutations, tailored treatments have been developed and are now being tested. For instance, polyadenosine diphosphate ribose polymerase inhibitors¹² target cells with impaired DNA repair mechanism, such as those in BRCA gene mutation carriers. These agents have shown promise for treatment of BRCA gene mutation–related malignancies,^{12 - 13} but clinical trials are needed to evaluate their use as preventive agents.

Due to the complex and sensitive nature of hereditary risk assessments, clinicians need to educate their patients about the risks and benefits of testing and be able to refer their patients to clinicians who can discuss surveillance and surgical prophylaxis. Genetic counselors can be highly effective in this regard. In addition, some women worry about the implication a positive genetic test might have on health insurance premiums for themselves and their families. Educating them about current federal laws—eg, the Genetic Information Nondiscrimination Act of 2008¹⁴ —that protect them from insurance and employer discrimination based on genetic tests should help assuage these fears.

The discovery of biomarkers that identify high-risk individuals for a specific disease and integration of these biomarkers into clinical practice enables the systematic study of these populations—and development and testing of interventions to reduce their risk. The study by Domchek et al¹ required more than 20 clinical centers collaborating to gather data in a standard fashion from the thousands of women who participated in the research. However, better mechanisms are needed to study and evaluate the introduction of new tests, like BRCA gene mutation testing, and to capture key pieces of deidentified information—such as the uptake of testing, results, clinical decisions, and outcomes—so that clinicians and researchers can continually learn from their experience. Measuring clinical outcomes should be a routine aspect of practice. As physicians begin to adopt computerized data-tracking systems, the goal of such systems should be both to facilitate the rapid introduction of innovations for care and to continually learn about the effects of new and established clinical practices.