Salpingo-Oophorectomy Reduces Cancer Risk for Women with BRCA Mutations
September 1, 2002 5 minutes read
Abstract & Commentary
Synopsis: In a recent issue of the New England Journal of Medicine, 2 important studies addressing the role of prophylactic oophorectomy in individuals with BRCA mutations were published. The first was a nonrandomized, single institution (Memorial Sloan Kettering) prospective evaluation and the second was a multigroup (Prevention and Observation of Surgical End Points Study Group) retrospective analysis. The studies came to nearly identical conclusions; prophylactic oophorectomy reduces the occurrence of ovarian and breast cancer in women with BRCA mutations.
Sources: Kauff ND, et al. N Engl J Med. 2002;346: 1609-1615; Rebbeck TR, et al. N Engl J Med. 2002;346: 1616-1622.
Recently, the New England Journal of Medicine published 2 consecutive reports that provide solid evidence supporting the recommendation for bilateral salpingo-oophorectomy (BSO) for women who carry mutations in either BRCA1 or BRCA2 genes. The first was a prospective study from Memorial Sloan Kettering Cancer Center, in which Kauff and colleagues prospectively compared the risk-reducing effect of BSO with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer. Women (n = 170) with either BRCA1 or BRCA2 chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. At the time of this report the mean follow-up was 24.2 months. Three women from the group that had chosen prophylactic salpingo-oophorectomy were found to have early stage ovarian cancer at time of surgery and, during the follow-up period, one developed a primary peritoneal papillary serous carcinoma. Ovarian cancer developed in 5 of 72 women who elected to intensive surveillance rather than surgery. Several in both groups had previously undergone prophylactic mastectomy. Among women who had not had prophylactic bilateral mastectomy, breast cancer developed in 8 of 62 women in the surveillance group (12.9%) and 3 of 69 (4.3%) women in the oophorectomy group. The time to breast cancer or BRCA-related gynecologic cancer was longer (by Kaplan-Meier analysis and a Cox proportional-hazards model) in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95% confidence interval, 0.08-0.74). Thus, Kauff et al concluded that salpingo-oophorectomy decreases the risk of breast cancer and BRCA-related gynecologic cancer for those who carry the BRCA mutations.
The second report in the same issue was a retrospective analysis of a large group (n = 551) of at-risk women (carriers of BRCA mutations) performed by Rebbeck and colleagues in the Prevention and Observation of Surgical End Points Study Group. Subjects were identified from registries and studied for the occurrence of ovarian or breast cancer. The group included 259 women who had undergone bilateral prophylactic oophorectomy and 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of follow-up for both groups was more than 8 years.
Six women who had undergone prophylactic salpingo-oophorectomy (2.3%) were found to have early stage ovarian cancer at the time of surgery. Subsequently, from this group, 2 women (0.8%) were found to have papillary serous peritoneal carcinoma 3.8 and 8.6 years after prophylactic oophorectomy. In contrast, 58 women (19.9%) received a diagnosis of ovarian cancer after a mean follow-up of 8.8 years. Excluding the 6 patients who were found to have cancer at the time of prophylactic oophorectomy, the procedure significantly reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95% confidence interval, 0.01-0.16).
Of the 99 women who underwent bilateral prophylactic oophorectomy and who were followed for the development of breast malignancy, breast cancer developed in 21 (21.9%) as compared with 60 (42.3%) in the control group (hazard ratio, 0.47; 95% confidence interval, 0.29-0.77). Thus, like the prospective study reported above, this larger, but retrospective analysis came to an identical conclusion: bilateral prophylactic oophorectomy reduces the risk of coelomic epithelial cancer and breast cancer in women with BRCA1 or BRCA2 mutations.
Comment by William B. Ershler, MD
Women who inherit certain mutations within the BRCA1 or BRCA2 genes face a 35-85% lifetime risk of developing breast cancer1,2 and a 16-57% chance of developing ovarian cancer.3 Genetic counseling and medical or surgical interventions are likely to reduce these risks.
The data presented individually and in composite provide compelling support for the value of bilateral salpingo-oophorectomy in the prevention of both ovarian and breast cancer in women with BRCA mutations. The prospective study by Kauff et al was relatively small, nonrandomized, and of shorter duration. Over time, it is likely that there will be significant differences in the overall development of ovarian cancer in the different groups (as witnessed in the retrospective study that followed). The data for the prevention of breast cancer, derived from both of these reports, are quite solid. Prophylactic oophorectomy reduces breast cancer development in BRCA carriers, and curiously, it appears that both BRCA1 and BRCA2 carriers are similarly protected. This is in contrast to what might have been expected, inasmuch as BRCA1 carriers typically develop estrogen receptor negative tumors4 and in at least 1 large primary prevention trial, the use of the anti-estrogen Tamoxifen did not seem to protect BRCA1 carriers.5
A scientific methodologies purist might raise the concern that this is not a randomized or blinded study, but certainly the ethical concerns that would surround such an effort would be overwhelming and likely preclude ever getting useful data. In light of the larger, retrospective analysis from the Prevention and Observation of Surgical End Points Study Group, the findings are not only credible, but also clinically important.
The precise clinical implications from these reports remain to be determined. Of course there is a downside to oophorectomy (increased cardiovascular events, osteoporosis, etc), and yet, for women with such a high likelihood of developing either ovarian or breast cancer, it would seem in general that the benefits outweigh the risks. Issues that need to be taken on an individual basis until clinical trial data are available include the appropriate age for intervening, whether to include a hysterectomy, and whether some form of hormone replacement therapy will be allowable without undermining the beneficial effects of the oophorectomy. Furthermore, the data support the assessment of genetic susceptibility and referral for genetic counseling for all patients suspected to have BRCA mutations. The issues are complex, the variables are many, and discussions on the topic oftentimes raise very sensitive issues. The data from these reports will be useful for genetic counselors, BRCA carriers and their families as they consider the risks and weigh the options available to best prevent the development of either of these life-threatening diseases.
Dr. Ershler of INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.
References
1. Easton DF, et al. Am J Hum Genet. 1995;56:265-271.
2. Antoniou AC, et al. Genet Epidemiol. 2000;18:173-190.
3. Struewing JP, et al. N Engl J Med. 1997;336:1401-1408.
4. Fisher B, et al. J Natl Cancer Inst. 1998;90:1371-1388.
5. King MC, et al. JAMA. 2001;286:2251-2256.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content