Correspondence to: Kathy J. Helzlsouer, M.D., M.H.S., Department of Epidemiology, The Johns Hopkins School of Hygiene and Public Health, 615 N. Wolfe St., Baltimore, MD 21205.
The ability to test for mutations in BRCA1 and BRCA2 genes and to identify women at high risk for breast cancer came before knowing what to do to effectively reduce the associated cancer risks. BRCA1 was cloned in the fall of 1994 (1), and BRCA2 was cloned in December 1995 (2). Genetic testing for mutations in these two genes came quickly after their discovery. Here we are in 1999 with only preliminary data on how effective the management options are for women who carry mutations and are thus at high risk for breast cancer.
What is it like for women who are members of these families with inherited cancer syndromes? Women see close family members develop cancer, suffer through the treatments, and often die prematurely of their disease. A commonly used expression by women in these families to describe their risk is "I feel like a time bomb," Before genetic testing was a reality, women would know that they were at increased risk of cancer, be told that it is suspected that they have a mutation in the family that is predisposing them to breast and/or ovarian cancers, and that they have a 50/50 chance of inheriting the mutation. Women had screening beginning at early ages or thought seriously about removing their breasts (mastectomy) or ovaries (oophorectomy) (or were told to do so by their physicians, family, or friends) and wondered if these options would work and what else they could do to lower their risk. However, there was always the hope that they had escaped the "family curse." Genetic testing is now a reality and for some women erases the uncertainty of whether or not they escaped or inherited this curse. Women who have had an informative genetic test and are told that the mutation was in the family but they did not inherit it can be reassured that they do not have to further consider drastic ways to prevent cancer such as removing their breasts or their ovaries. However, in women who have heard the news that they inherited the mutation, their hope of escaping what was happening in the family disappears. The risks are high and have been confirmed with the genetic test.
Now, what to do? Certainly, continue screening with mammography (at least that was shown to be effective in reducing mortality), but is it effective for young women? Is it effective for women who carry a mutationwould their type of breast cancer be found early enough to be able to cure it? What about ovarian cancer? No trials have shown screening with transvaginal ultrasound and carbohydrate antigen 125 (a diagnostic marker for ovarian cancer) to be effective for the general populations let alone for women who carry a mutation in BRCA1 or BRCA2.
What can be done to prevent cancer, not just to catch it early? Now we know that tamoxifen lowers the risk of breast cancer among women at increased risk (3), but we do not yet know if this will hold true among women with BRCA1 and BRCA2 mutations. What about ovarian cancer? No clinical trials have been done, but observational studies (4) have consistently shown oral contraceptives to be associated with a lower risk of getting ovarian cancer. Will this be true for mutation carriers? Last year the Hereditary Ovarian Cancer Clinical Study Group (5) reported that the same protective effect of oral contraceptives observed among population-based studies of ovarian cancer also was observed among women carrying BRCA1 and BRCA2 mutations. At last we have information that something may lower the risk! Unfortunately, many women with strong family histories of breast cancer avoided oral contraceptives because of the fear of breast cancer.
Then women turn to consider the option of whether or not to undergo surgery before there is a problem. But what surgery? Remove the ovaries? Remove the breasts? Remove both? All of these options have major physical and psychological consequences, and decisions have to be made in the absence of solid data regarding the effectiveness of the surgery for women who carry mutations.
In a report in this issue of the Journal, Rebbeck et al. (6) give women who carry BRCA1 mutations and who have made the difficult decision to remove their ovaries some hope that oophorectomy has also helped lower their risk of breast cancer, even, apparently, if they took hormone replacement therapy (6). The benefit was limited to women who had oophorectomy at younger ages. The results suggest that what we know about hormone exposures and their association with breast cancer in general also applies to the breast cancer that occurs among mutation carriers. The type of study undertaken by Rebbeck et al. is challenging. Since inherited cancer family syndromes are rare, sample sizes are small and observations are not always independent because multiple family members may be included. Data from clinical centers are not uniformly collected in content or format. Follow-up is limited, and survivorship issues must be considered. Only women with BRCA1 mutations were included; too few women in the study centers had BRCA2 mutations. The authors have dealt with these limitations as best as possible, and their results are reassuring. This study, however, is only a first step in determining what are the best management options for women who carry BRCA1 mutations and needs to be interpreted with caution.
The results of this study by Rebbeck et al. do not suggest that oophorectomy should be considered as a means to lower the risk of breast cancer. In fact, women who choose this option do so primarily to lower their risk of ovarian cancer. The results are consistent with the amount of protection seen in observational studies of breast cancer risk (7) and are also consistent with the magnitude of risk reduction associated with tamoxifen use observed in the Breast Cancer Prevention Trial among women with three or more first-degree relatives with breast cancer (3). Taken together, these findings suggest that hormonal interventions should help to lower the risk among women who carry mutations. This needs to be confirmed in prevention trials, such as the ongoing Study of Tamoxifen and Raloxifene, and these trials should include young women who carry mutations in BRCA1 or BRCA2.
What is very interesting in the report by Rebbeck et al. (6) is that the use of hormone replacement therapy apparently did not eliminate the protective effect of oophorectomy. Unfortunately the authors did not present their finding stratified by hormone replacement therapy use. This clearly needs additional study because a major problem with oophorectomy is premature menopause with associated long-term complications of early osteoporosis, heart disease, premature mortality, and menopausal symptoms. Hormone replacement therapy may improve overall health, including lowering the risk of premature death (8,9), but, like oral contraceptives, hormone replacement therapy is often avoided by women with strong family histories of cancer because of the potential risk of breast cancer (10).
Studies of the effectiveness of clinical management for the prevention of cancer in genetically susceptible individuals are desperately needed. These studies should not lose sight of the big picturemaintaining overall health not just preventing breast cancer. Prophylactic oophorectomy or chemically induced menopause is associated with an array of side effects that affect quality of life and mortality. The studies of efficacy of preventive measures need to be done rapidly and should be in concert with the introduction of technologies that identify risk, not lagging behind. Research networks, such as the National Cancer Institute-sponsored Cancer Genetics Network and the proposed Early Detection Research Network, will, hopefully, provide a mechanism to speed the evaluation process of clinical management options for individuals at high risk. In the near future we need to be able to say to women who carry mutations in cancer susceptibility genes, the bad news is that you are at risk, the good news is that we now know what we can do about it.
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