Correspondence
Oophorectomy in Carriers of BRCA Mutations
N Engl J Med 2002; 347:1037-1040September 26, 2002
- Article
To the Editor:
Kauff et al. (May 23 issue)1 present data suggesting that salpingo-oophorectomy provides protection against breast or gynecologic cancer in women with a BRCA1 or BRCA2 mutation. Although the follow-up period was relatively short and overall survival data are not yet available, the authors should be applauded for undertaking the only known prospective study of its kind. Since there are other options for reducing the risk of breast cancer,2,3 we believe that the benefit of salpingo-oophorectomy should be evaluated separately in women with breast cancer and in those with gynecologic cancer. In a separate analysis shown in Table 3 of the article by Kauff et al., the 95 percent confidence intervals for the hazard ratios for breast and gynecologic cancer both include 1 and hence fail to show statistical significance.
In Table 2 of the article, a Kaplan–Meier estimate shows a significant benefit in reducing the risk of gynecologic cancer but not of breast cancer. This analysis is limited by a potential bias introduced as a result of the fact that the authors excluded from the analysis the three cases of ovarian cancer found at surgery but included any potential early-stage cancers in the surveillance group. Figure 1 of the article shows that 5 of the 12 cancers in the surveillance group were detected during the first eight months, whereas no cancers were detected in the surgery group. This observation is consistent with a bias due to the delayed detection of tumors in the surveillance group.
3 ReferencesSen H. Zhuang, M.D., Ph.D.
Gregory D. Leonard, M.D.
Sandra M. Swain, M.D.
National Cancer Institute, Bethesda, MD 20892
swains@mail.nih. gov 1
Kauff ND ,Satagopan JM ,Robson ME , et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609-1615
Full Text | Web of Science | Medline2
Meijers-Heijboer H ,van Geel B ,van Putten WLJ , et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159-164
Full Text | Web of Science | Medline3
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. Lancet 2000;356:1876-1881
CrossRef | Web of Science | Medline
To the Editor:
Rebbeck et al. (May 23 issue)1 and Kauff et al. demonstrate that prophylactic oophorectomy in women with a BRCA1 or BRCA2 mutation significantly decreases the risk of ovarian and breast cancer. Clarification of these data is important for clinical practice. Although the two studies showed that the risks of both cancers are significantly reduced after prophylactic oophorectomy, the data reported by Rebbeck et al. showed that the residual risk of ovarian cancer is very low (4 percent), whereas the residual risk of breast cancer remains high (47 percent). The residual risk of breast cancer among women with BRCA mutations certainly remains high enough to warrant additional management strategies (e.g., surveillance, chemoprophylaxis, and in some cases, prophylactic mastectomy). Also, most of the benefit of oophorectomy in terms of the reduction in the risk of breast cancer was found in premenopausal carriers of BRCA mutations who did not have a history of breast cancer. Rebbeck et al. did not report the effects of prophylactic oophorectomy according to menopausal status, but among women who were 50 years of age or older, the hazard ratio for breast cancer was 0.52. However, the 95 percent confidence interval was quite wide and included 1.0. In addition, for women with unilateral breast cancer diagnosed before the age of 50 years, prophylactic oophorectomy may substantially reduce the risk of cancer in the contralateral breast.2 Thus, postmenopausal women should not be advised that prophylactic oophorectomy is effective in reducing their risk of breast cancer. Our approach to counseling high-risk women is to explain that prophylactic oophorectomy is mainly a means of reducing the risk of ovarian cancer, with the added potential benefit, for some women, of reducing the risk of breast cancer.
2 ReferencesBeth N. Peshkin, M.S.
Tiffani A. DeMarco, M.S.
Marc D. Schwartz, Ph.D.
Georgetown University, Washington, DC 20007
peshkinb@georgetown.edu 1
Rebbeck TR ,Lynch HT ,Neuhausen SL , et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616-1622
Full Text | Web of Science | Medline2
Narod SA ,Brunet JS ,Ghadirian P , et al. Tamoxifen and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet 2000;356:1876-1881
CrossRef | Web of Science | Medline
To the Editor:
Kauff et al. and Rebbeck et al. report that prophylactic oophorectomy reduced the risks of BRCA1- or BRCA2- related gynecologic cancer and hereditary breast cancer. As Haber notes in the accompanying editorial,1 a mean age for the entire data set of 50.8 years at the time of the diagnosis of ovarian cancer supported the recommendation of delaying risk-reducing oophorectomy until the completion of childbearing, but such a delay may be problematic in the case of hereditary breast cancer. Notably, in the study by Kauff et al., hereditary breast cancer had developed in 70 percent of the women with a BRCA mutation when prophylactic surgical menopause was deferred until 47.5 years of age.
Moreover, the effect of surgical menopause on hereditary breast cancer in women with a BRCA mutation may vary according to the type of mutation,2 and age-specific incidence rates vary dramatically according to the genotype.2,3 Analogous to rates of sporadic breast cancer stratified according to estrogen-receptor status,4,5 rates of BRCA1- related hereditary breast cancer rise initially then flatten after menopause, as do rates of sporadic estrogen-receptor–negative breast cancer, whereas rates of BRCA2-related hereditary breast cancer increase regardless of menopausal status, as do rates of sporadic estrogen-receptor–positive breast cancer.2,3,6 A pattern of age-specific rates that rise and then stabilize after 50 years of age suggests that early endogenous hormonal interactions have a greater effect on carcinogenesis for estrogen-receptor–negative and BRCA1- related breast cancers than for estrogen-receptor–positive and BRCA2-related breast cancers.2,4,5 Therefore, early prophylactic oophorectomy may be very important for the prevention of BRCA1- and BRCA2-related breast cancer, especially BRCA1- related hereditary breast cancer, but this should be tested in studies stratified according to whether women have BRCA1 or BRCA2 mutations. Combining carriers of BRCA1 mutations and carriers of BRCA2 mutations may blur the etiologic differences, typified by two fundamentally different patterns of the age-specific risk of breast cancer.
6 ReferencesWilliam F. Anderson, M.D., M.P.H.
National Cancer Institute, Bethesda, MD 20892-7317
wanderso@mail.nih. gov Otis W. Brawley, M.D.
Winship Cancer Institute of Emory University, Atlanta, GA 30303Shine Chang, Ph.D.
National Cancer Institute, Bethesda, MD 20892-73171
Haber D . Prophylactic oophorectomy to reduce the risk of ovarian and breast cancer in carriers of BRCA mutations. N Engl J Med 2002;346:1660-1662
Full Text | Web of Science | Medline2
Narod SA . Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2002;2:113-123
CrossRef | Web of Science | Medline3
Struewing JP ,Hartge P ,Wacholder S , et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401-1408
Full Text | Web of Science | Medline4
Tarone RE ,Chu KC . The greater impact of menopause on ER- than ER+ breast cancer incidence: a possible explanation (United States). Cancer Causes Control 2002;13:7-14
CrossRef | Web of Science | Medline5
Anderson WF ,Chatterjee N ,Ershler WB ,Brawley OW . Estrogen receptor alpha breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat 2002;76:27-36
CrossRef | Web of Science | Medline6
Easton DF ,Ford D ,Bishop DT . Breast and ovarian cancer incidence in BRCA1- mutation carriers. Am J Hum Genet 1995;56:265-271
Web of Science | Medline
To the Editor:
Kauff et al. excluded three patients found to have early gynecologic cancer at the time of prophylactic salpingo-oophorectomy, whereas the comparison (surveillance) group included five women who had gynecologic cancer after a mean of only 17 months. Some of these five cancers were almost certainly present at the beginning of the follow-up period. The exclusion of patients with preexisting cancers in one study group only, in a study designed to determine the incidence of cancer, biases the results substantially, particularly given the short mean follow-up of two years.
The correct approach is to include the women in whom gynecologic cancers were detected at the time of prophylactic salpingo-oophorectomy. The authors mention in their discussion that with this approach, the hazard ratio for the development of breast or gynecologic cancer would be 0.37 (0.12 to 0.90), which is still statistically significant. However, they fail to point out that the correct analysis would very much weaken their conclusions about, for example, the estimated proportion of women who would be free from gynecologic cancer at five years (given in Table 2 of their article as 98 percent in the oophorectomy group vs. 83 percent in the surveillance group) or free from breast or gynecologic cancer at five years (given as 94 percent, vs. 69 percent).
Gillian A. Whitfield, M.A., M.R.C.P.
Addenbrooke's National Health Service Trust, Cambridge CB2 2QQ, United Kingdom
gillian.whitfield@ukgateway. net Author/Editor Response
The authors reply:
To the Editor: Anderson et al. raise the possibility that estrogen deprivation may have distinct effects on early breast carcinogenesis in carriers of BRCA1 mutations as compared with carriers of BRCA2 mutations. We agree that, for this reason, it is important to perform mutation-specific analyses in future studies. The results of studies that have examined the preventive effects of tamoxifen on BRCA1-associated breast cancer as compared with BRCA2-associated breast cancer have been inconsistent.1,2 However, because of the significantly elevated risk of postmenopausal ovarian cancer in carriers of some BRCA2 mutations,3 there is a rationale apart from breast-cancer prevention for considering risk-reducing salpingo-oophorectomy in such women.
Since the reduction in the risk of breast cancer that is associated with salpingo-oophorectomy presumably results from estrogen deprivation, we agree with Peshkin et al. that the greatest preventive effect with respect to breast cancer is likely to occur in women who are premenopausal at the time of surgery; 66 percent of the women opting for surgery in our series were 50 years of age or younger, and 83 percent were 55 or younger.
Both Zhuang et al. and Whitfield suggest that the optimal statistical analysis of our data would include the three clinically occult gynecologic cancers detected at the time of surgery as events in the surgical group. When this analysis was performed, the reduction in the risk of breast or ovarian cancer remained significant, as Whitfield notes. In our study and that of Rebbeck et al., cancers detected at the time of preventive surgery were not included in the primary comparison of surgery and surveillance, since the incidence of cancer after surgery is the clinical end point of greatest concern to women who are deciding whether to undergo the procedure. Furthermore, in considering the effect on survival of occult cancers identified at the time of planned preventive surgery, it is important to recall the limitations of screening for ovarian cancer. Nine occult gynecologic cancers, all stage I, were found among a total of 360 women undergoing risk-reducing oophorectomy in our series and that of Rebbeck et al.; it remains unclear whether a similar proportion of ovarian cancers detected by screening will be early stage cancers.
We agree with the comments of Zhuang et al. regarding the importance of separately evaluating the effect of salpingo-oophorectomy on the incidence of breast cancer and gynecologic cancer. Rebbeck et al. provide retrospective data indicating that prophylactic oophorectomy was effective in reducing the risk of each of these end points separately. Continued follow-up of our cohort will provide prospective data for a better definition of the magnitude of this effect.
3 ReferencesNoah D. Kauff, M.D.
Mark E. Robson, M.D.
Kenneth Offit, M.D., M.P.H.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
offitk@mskcc.org 1
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. Lancet 2000;356:1876-1881
CrossRef | Web of Science | Medline2
King MC ,Wieand S ,Hale K , et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 2001;286:2251-2256
CrossRef | Web of Science | Medline3
Satagopan J, Boyd J, Kauff N, et al. Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res (in press).
Author/Editor Response
Zhuang et al. state that Kauff and colleagues performed the only known prospective study of bilateral prophylactic oophorectomy in women with BRCA mutations. Although we included women ascertained to have undergone bilateral prophylactic oophorectomy before their ascertainment for participation in the study or genetic testing (i.e., a “retrospective” sample), we also included women for whom ascertainment, testing, or both occurred before bilateral prophylactic oophorectomy was performed. This portion of our sample (55 percent) represents a “prospective” sample. We reported similar hazard ratios for both the total study sample (i.e., prospective and retrospective participants) and the subgroup of prospective participants. For example, the hazard ratio for ovarian cancer was 0.04 in the total sample and 0.02 in the prospective subgroup. This suggests that our primary results were not severely biased by the inclusion of the retrospective participants. More important, our data and those reported by Kauff et al. provide compelling evidence that oophorectomy is strongly associated with a reduction in the risk of cancer. On the basis of the compelling evidence now available that bilateral prophylactic oophorectomy almost eliminates the risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations, we believe this intervention should be the standard of care after childbearing in such women and that additional prospective studies would be unethical.
Anderson et al. suggest that combining women with BRCA1 mutations and women with BRCA2 mutations may be misleading if the patterns of risk (and therefore risk reduction) differ between genes. A limitation of our data is the small number of cancers that developed after bilateral prophylactic oophorectomy and the small number of BRCA2- mutation carriers and, thus, the limited power of the study to evaluate the BRCA2 group separately. We continue to accumulate data and will address this issue as our sample expands.
Peshkin et al. argue that postmenopausal bilateral prophylactic oophorectomy would not be predicted to reduce the risk of breast cancer and that management of breast-cancer risk in women who undergo bilateral prophylactic oophorectomy after menopause may therefore require additional intervention. Similarly, Anderson et al. address the difficulty in determining the optimal timing of oophorectomy, which may have a significant benefit in terms of reducing the risk of ovarian cancer, even if the procedure is delayed until after childbearing, but may have more limited value for reducing the risk of breast cancer. Although both points are valid, we believe that since the reduction in the risk of ovarian cancer that is associated with bilateral prophylactic oophorectomy is almost complete and the age at diagnosis is unpredictable, bilateral prophylactic oophorectomy should be performed once childbearing is finished, regardless of the woman's age at that time. The risk of breast cancer in women who use postoperative estrogen-replacement therapy until the age of 50 years (the approximate time of natural menopause) should be lower than the risk in women who defer surgery until menopause.
Timothy R. Rebbeck, Ph.D.
Barbara L. Weber, M.D.
University of Pennsylvania, Philadelphia, PA 19104
trebbeck@cceb.med. upenn. edu - Citing Articles (4)
Citing Articles
1
Ismail Jatoi, William F. Anderson. (2008) Management of Women Who Have a Genetic Predisposition for Breast Cancer. Surgical Clinics of North America 88:4, 845-861
CrossRef2
Julie D. Lamb, Rochelle L. Garcia, Barbara A. Goff, Pamela J. Paley, Elizabeth M. Swisher. (2006) Predictors of occult neoplasia in women undergoing risk-reducing salpingo-oophorectomy. American Journal of Obstetrics and Gynecology 194:6, 1702-1709
CrossRef3
Robert E. Tarone, Loren Lipworth, V. Leroy Young, Joseph K. McLaughlin. (2004) Breast Reduction Surgery and Breast Cancer Risk: Does Reduction Mammaplasty Have a Role in Primary Prevention Strategies for Women at High Risk of Breast Cancer?. Plastic and Reconstructive Surgery 113:7, 2104-2110
CrossRef4
Elizabeth Swisher. (2003) Prophylactic surgery and other strategies for reducing the risk of familial ovarian cancer. Current Treatment Options in Oncology 4:2, 105-110
CrossRef
