Breast Cancer Risk After Bilateral Prophylactic Oophorectomy in BRCA1 Mutation Carriers

Timothy R. Rebbeck .upenn 0 1 Albert M. Levin 0 1 Andrea Eisen 0 1 Carrie Snyder 0 1 Patrice Watson 0 1 Lisa Cannon-Albright 0 1 Claudine Isaacs 0 1 Olofunmilayo Olopade 0 1 Judy E. Garber 0 1 Andrew K. Godwin 0 1 Mary B. Daly 0 1 Steven A. Narod 0 1 Susan L. Neuhausen 0 1 Henry T. Lynch 0 1 Barbara L. Weber 0 1 0 Oxford University Press 1 Journal of the National Cancer Institute , Vol. 91, No. 17, September 1, 1999 - Background: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. Methods: We studied a cohort of women with diseaseassociated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. Results: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.330.84). This risk reduction was even greater in women who were followed 510 (HR = 0.28; 95% CI = 0.080.94) or at least 10 (HR = 0.33; 95% CI = 0.120.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. Conclusions: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations. [J Natl Cancer Inst 1999;91:14759] Women who carry germline BRCA1 mutations have a greatly increased risk of breast and ovarian cancers when compared with the general population. The clinical management of women with BRCA1 mutations may include bilateral prophylactic oophorectomy (i.e., the surgical removal of both ovaries). The rationale for this surgery is that removing ovarian epithelium reduces ovarian cancer risk. In premenopausal women, an additional benefit from this surgery is a decrease in ovarian hormone exposure, which could in turn reduce breast cancer risk. However, limited data are available to guide specific recommendations regarding the use of this surgery to reduce cancer risk in women with a germline BRCA1 mutation (1). Some evidence suggests that ovarian cancer risk may be reduced in high-risk women who have undergone this surgery (2,3). Other reports (47) have shown a decreased breast cancer risk among oophorectomized women, and oophorectomy has been used to treat breast cancer. To evaluate whether bilateral prophylactic oophorectomy alters the risk of developing breast cancer in women who have BRCA1 mutations, we compared the incidence of breast cancer in BRCA1 mutation carriers who had and had not undergone this surgery. METHODS Study Participants All women with germline, disease-causing BRCA1 mutations who reported having undergone an oophorectomy were identified as potential study subjects from the registry databases of five participating institutions: Creighton University (Omaha, NE), the Dana-Farber Cancer Institute (Boston, MA), the Fox Chase Cancer Center (Philadelphia, PA), the University of Pennsylvania (Philadelphia), and the University of Utah (Salt Lake City). While these represent geographically distinct groups, all of these centers ascertained study participants through similar clinical and research programs involving genetic screening for women at increased risk of breast and/or ovarian cancers. The population of inference, therefore, reflects a relatively homogeneous set of high-risk women. Women were included in the study sample if they had undergone bilateral oophorectomy prior to or at the time of enrollment in these registries or if they reported having had this procedure during periodic follow-up by the collaborating institutions. Women were excluded from the study sample if they had only unilateral oophorectomies, if they had undergone mastectomy prior to their oophorectomy, or if they had a personal history of breast or ovarian cancer at or before the time of their oophorectomy. Surgical subjects were, therefore, included only if their surgery was not performed to treat ovarian or related peritoneal cancers. After a set of eligible surgical subjects was identified, a matched set of control subjects was selected from women in the registries at each of the five collaborating centers. Potential control subjects were eligible if they had inherited a confirmed disease-causing BRCA1 mutation, were alive and had both ovaries (i.e., no history of oophorectomy), had no history of breast or ovarian cancer, and had no history of prophylactic mastectomy at or before the time of the surgical subjects surgery. Control subjects were matched to surgical subjects on year of birth (5 years) and on the collaborative institution from which they were ascertained. Women who had inherited germline BRCA2 mutation were excluded as control subjects. All eligible control subjects that could be matched to a surgical subject were selected for analysis. While at least one matched control subject was selected for each surgical subject, we selected more than one matched control subject per surgical subject whenever possible. Criteria for entry into registries, data collection, and follow-up were undertaken at each collaborating center without regard to surgical status. By use of these criteria, we identified 43 surgical subjects and 79 control subjects. Of these subjects, 44 were ascertained at Creighton University, 26 at the Dana-Farber Cancer Institute, 18 at the Fox Chase Cancer Center, 16 at the University of Pennsylvania, and 18 at the University of Utah. Fifty (41%) study subjects were unrelated to one another. The remainder consisted of individuals who were related to at least one other person in the sample. Related subjects consisted of two (n 4 24 individuals in 12 families, 20%), three (n 4 9 individuals in three families, 7%), or four or more (n 4 39 individuals in five families, 32%) women from the same family. All BRCA1 mutations were disease causing. Mutation testing was undertak (...truncated)