Commentary (Stopfer/Domchek): Evaluation and Management of Women With BRCA1/2 Mutations

OncologyONCOLOGY Vol 19 No 11
Volume 19
Issue 11

More than a decade has passedsince the cancer predispositiongenes BRCA1 andBRCA2 were cloned. Collectively,these genes are responsible for virtuallyall hereditary breast/ovarian cancerfamilies as well as a smaller subsetof hereditary site-specific breast cancerfamilies.[1] Their discovery helped usherin a new age of predictive and preventivemedicine for those at risk ofbreast and ovarian cancer, two of themost common forms of cancer in womenin the United States.[2] Peshkin andIsaacs provide an excellent summaryof cancer susceptibility due to inheritedmutations in BRCA1 and BRCA2,including approaches to assessing personaland family history for the likelihoodof finding these mutations, theirassociated cancer risks, and options forclinical management.

More than a decade has passed since the cancer predisposition genes BRCA1 and BRCA2 were cloned. Collectively, these genes are responsible for virtually all hereditary breast/ovarian cancer families as well as a smaller subset of hereditary site-specific breast cancer families.[1] Their discovery helped usher in a new age of predictive and preventive medicine for those at risk of breast and ovarian cancer, two of the most common forms of cancer in women in the United States.[2] Peshkin and Isaacs provide an excellent summary of cancer susceptibility due to inherited mutations in BRCA1 and BRCA2, including approaches to assessing personal and family history for the likelihood of finding these mutations, their associated cancer risks, and options for clinical management. Variants of Uncertain Significance
The first step in assessing an individual for BRCA1/2 genetic testing is to determine the likelihood of finding a mutation. Peshkin and Isaacs summarize the features of BRCA1/2 associated families, and some of the available models used to determine the likelihood of finding a positive result are reviewed. The expense of BRCA1/2 testing is used to illustrate why identifying an at-risk population with such models is preferable to a broader testing approach. Both limiting expense and properly allocating limited genetic counseling resources are excellent reasons to utilize such predictive models; another is the issue of the "variant of uncertain significance" (VUS). Although sequencing typically returns a clear-cut "positive" result, meaning a deleterious mutation has been identified, or a "negative" result, meaning no significant sequence variant has been found, on occasion an equivocal result is found. Known as a VUS, this result often indicates a missense mutation for which the effect on protein function is unknown. The incidence of finding a VUS varies with ethnicity, with Myriad Genetic Laboratories observing about a 9% rate in those of European ancestry, 16% in those of Asian descent, and 29% in individuals of African descent (personal communication, Myriad Genetics, May 2005). Many investigators are working to develop methods of assessing the functional significance of these variants. In addition, existing databases (Myriad Genetics and the Breast Information Core) can provide data that may suggest that a particular VUS is either a polymorphism or a deleterious mutation. Despite these efforts, many VUS results remain uninterpretable. Using current clinical testing techniques, those who have less than a 10% chance of having a detectable deleterious mutation are less optimal candidates for testing, as the chance of finding an uninterpretable result exceeds the chances of finding useful information. Barriers to Genetic Counseling
Apart from equivocal results, another significant barrier to participation in cancer genetic counseling programs is fear of insurance discrimination. There is scant evidence of health insurance discrimination based specifically on genetic testing information, and many health insurance companies have explicitly stated they will not use genetic information.[3] In addition, a variety of federal and state laws make it unlikely that genetic testing information will affect access to health insurance or appropriate insurance rates for anyone in a group health plan. Although there are clearly individuals excluded from the legal protection of existing legislation, the perception that once genetic risk is discovered a patient will lose her health insurance coverage has not been borne out; however, this fear prevents many individuals from even presenting for genetic counseling.[4] National comprehensive genetic nondiscrimination legislation could provide the assurance many individuals need in order to seek out cancer genetics services for themselves. High-risk women who decline to participate in counseling programs sometimes have a limited awareness of the impact that genetic information could have on an individual's health care.[4] Peshkin and Isaacs lay out the options available to those with increased cancer risks and provide a useful summary table of breast and ovarian cancer screening recommendations and cancer risk-reduction strategies for women with germ-line BRCA1/2 mutations. Unfortunately, despite the effective measures that are available, the misconception that there is nothing one can do other than worry about oneself and one's family continues to be a barrier to participation in genetic counseling. We clearly need to raise awareness in both the medical and lay communities about the mounting evidence supporting the efficacy of these interventions. Peshkin and Isaacs wisely point out that prevention and screening strategies must be individualized, and in many cases, there are several rational options for follow-up. Risk-Reduction Measures
For a woman who already has had breast cancer, the risk of a second breast cancer may lead to enhanced surveillance including annual breast magnetic resonance imaging and consideration of prophylactic mastectomy. In addition, Metcalf et al found that 25% of the deaths in women who carried BRCA1/2 mutations with stage I breast cancer were due to a subsequent ovarian cancer.[5] This substantial risk of ovarian cancer, even after a breast cancer diagnosis, means such a woman should strongly consider bilateral prophylactic oophorectomy with or without hysterectomy postchildbearing. In addition, Metcalf et al and Narod et al have shown that women with BRCA1/2 mutations who have had breast cancer and take tamoxifen can reduce their risk of a contralateral breast cancer by 30% to 50%.[6] Thus, effective strategies to reduce the risk of cancer exist even for women who have already had cancer. Bilateral prophylactic oophorectomy is one of the most significant riskreducing options available to women who carry BRCA1/2 mutations. Those who choose this intervention will lower their risk of ovarian cancer by 96%, and women who have this procedure performed premenopausally will also lower their breast cancer risk by 50% to 70%. However, some women are reluctant to proceed with this intervention due to concerns about the sequelae of early and abrupt menopause. Results of a study by Rebbeck et al[7] suggest that women with BRCA1/2 mutations will reduce their risk of breast cancer through bilateral prophylactic oophorectomy irrespective of their subsequent decision about hormone replacement therapy, at least in the short term. Short-term use of hormone replacement tailored to manage postoperative menopausal symptoms has very different implications for breast cancer risk than long-term hormone exposure in postmenopausal women. Thus, women with BRCA1/2 mutations should not deferbilateral prophylactic oophorectomy- which may be lifesaving- because of concerns about the immediate impact of menopausal symptoms on their quality of life. Conclusions
Identifying a BRCA1/2 mutation means that hereditary risk can be tracked within a family, and expensive and intensive follow-up can be reserved for those who are without question at high risk. Learning about the presence of genetic risk for breast and ovarian cancer can be frightening, but as summarized by Peshkin and Isaacs, there are many effective strategies now available for both prevention and earlier detection.


The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Antoniou AC, Pharoah PD, McMullan G, et al: Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol 21:1-18, 2001.
2. American Cancer Society: Cancer Fact and Figures 2005. Atlanta, American Cancer Society, 2005.
3. Hall MA, Rich SS: Laws restricting health insurers’ use of genetic information: Impact on genetic discrimination. Am J Hum Genet 66:293-307, 2000.
4. Peters N, Domchek SM, Polis A, et al: Knowledge, attitudes, and utilization of BRCA1/2 testing among women with early onset breast cancer. Genet Test 9:48-53, 2005.
5. Metcalfe KA, Lynch HT, Ghadirian P, et al: The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol 96:222-226, 2005.
6. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 356:1876- 1881, 2000.
7. Rebbeck TR, Friebel T, Wagner T, et al: Effect of short term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 23(31):Nov 1, 2005 (in press).

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