Lessons Learned From Genetic Testing

Abstract

THE STUDY REPORTED BY DOMCHEK AND COLleagues 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 riskreducing 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 allcause 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, atrisk women must first be identified, and, as Domchek et al 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 Oncology or National Comprehensive Cancer Network 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, which has shown usefulness in various ethnic groups. In the study by Domchek et al, 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. 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. Screening with CA 125 blood testing and vaginal ultrasonography is recommended to be performed every 6 months, although ovarian cancer screening has limited value. However, unlike RRSO and RRM, surveillance is not prevention. As the report by Domchek et al 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, 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. Potential shortand long-term effects from the resultant early menopause—such as hot flashes and osteoporosis—can be managed with hormone therapy, at least until the age of natural menopause. 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 mas-