Breast Cancer Risk Following Bilateral Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: An International Case-Control Study
http://www.100md.com
《临床肿瘤学》
the Toronto-Sunnybrook Regional Cancer Center, Toronto, ON, Canada
Pomeranian Medical University, Szczecin, Poland
Daniel den Hoed Cancer Center and Erasmus University Medical Center, Rotterdam, Netherlands
Department of Cancer Genetics, Norwegian Radium Hospital, Oslo, Norway
Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE
Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY
Departments of Medicine and Genetics, University of Pennsylvania, Philadelphia, PA
Division of Epidemiology, Department of Medicine, University of California, Irvine, CA
Epidemiology Research Unit, CHUM H?tel-Dieu, University of Montreal, and the Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, QC, Canada
Institute of Genetics, Rambam Medical Center, Haifa, and the Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, and the CHS National Cancer Control Center, Carmel Medical Center, Haifa, Israel
Private Trust for Breast Health, Division of Senology, University of Vienna, Austria
Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC
BC Cancer Agency, Vancouver, BC, and the London Regional Cancer Program, London, ON, and the Centre for Research in Women's Health, University of Toronto, ON, Canada
ABSTRACT
PURPOSE: The purpose of this study was to estimate the extent of protection offered against breast cancer by prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations and to determine to what extent risk reduction varies with age at oophorectomy, age at diagnosis, and time elapsed since surgery.
PATIENTS AND METHODS: We analyzed 1,439 patients with breast cancer and 1,866 matched controls derived from a registry of BRCA1 and BRCA2 carriers. We estimated odds ratios (ORs) of breast cancer for having had a bilateral oophorectomy, using conditional logistic regression, matched for parity and for oral contraceptive use.
RESULTS: A previous history of oophorectomy was associated with a significant reduction in breast cancer risk of 56% for BRCA1 carriers (OR = 0.44; 95% CI, 0.29 to 0.66) and of 46% for BRCA2 carriers (OR = 0.57; 95% CI, 0.28 to 1.15). The risk reduction was greater if the oophorectomy was performed before age 40 (OR = 0.36; 95% CI, 0.20 to 0.64 for BRCA1 carriers) than after age 40 (OR = 0.53; 95% CI, 0.30 to 0.91). The protective effect was evident for 15 years post-oophorectomy (OR = 0.39; 95% CI, 0.26 to 0.57).
CONCLUSION: Oophorectomy is an effective means of reducing the risk of breast cancer in carriers of BRCA1 mutations. The data suggest oophorectomy is protective in BRCA2 carriers as well, but needs to be confirmed in other studies.
INTRODUCTION
Women with a germline mutation in BRCA1 or BRCA2 face increased risks of breast and ovarian cancers. For BRCA1 mutation carriers, the estimated lifetime risk of breast cancer ranges from 40% to 85%,1-4 and the estimated lifetime risk of ovarian cancer ranges from 20% to 65%.1-4 For BRCA2 mutation carriers, the breast cancer risk is similar, but the lifetime risk of ovarian cancer is approximately 20%.1-4 Strategies for risk reduction include preventive surgery and chemoprevention. Increased surveillance is recommended. Bilateral prophylactic oophorectomy is commonly recommended to BRCA1 and BRCA2 mutation carriers to reduce the risk of ovarian cancer and breast cancer. Approximately 60% of women with BRCA1 or BRCA2 mutations in Canada now undergo prophylactic oophorectomy within 1 year of having been demonstrated to carry a BRCA mutation (Metcalf et al,7 The use of tamoxifen and other preventive measures among healthy women who carry a BRCA1 or BRCA2 mutation, manuscript submitted for publication). Case-control studies in the general population have shown that bilateral oophorectomy in premenopausal women is associated with a significant reduction in breast cancer risk.5,6 Several studies have also shown that oophorectomy is effective in reducing the risk of primary and contralateral breast cancer in BRCA1 and BRCA2 carriers.7-10 However, previous studies have been small and there was not sufficient data to estimate the magnitude of risk reduction by age of oophorectomy or by BRCA1/BRCA2 mutation status, or to measure the duration of the protective effect.
PATIENTS AND METHODS
Study Subjects
Women with a BRCA1 or BRCA2 mutation were identified through a registry of mutation carriers at the Centre for Research in Women's Health at the University of Toronto. Data were collected from women with known pathogenic BRCA1 and BRCA2 mutations at 48 different centers in seven countries in North America, Europe, and Israel. All patients provided informed written consent for genetic testing. The study has been approved by the ethics committees/human subjects review boards of all participating centers. In most cases, testing was offered initially to women who were affected either by breast cancer or ovarian cancer. When a mutation in either BRCA1 or BRCA2 was found in a proband or in her relative, testing was offered to other at-risk women in her family. Mutation detection was performed using a range of techniques, but all nucleotide alterations were confirmed by direct sequencing of DNA. A woman was eligible for the study when the molecular analysis established that she was a mutation carrier.
There were 5,659 mutation carriers in the database. Of these, 851 patients with ovarian cancer and 92 women with bilateral prophylactic mastectomy were excluded. An additional 147 patients were excluded because information was missing on key variables (ie, parity, oophorectomy, etc.). This left 4,569 subjects eligible for the study. There were 2,283 women with a mutation and breast cancer who were eligible to be patient cases. There were 2,286 women without breast cancer who were eligible to be patient controls. Patient cases and patient controls were matched by year of birth (within 1 year), country of residence, and BRCA1 or BRCA2 mutation status. The matched patient control was at risk for breast cancer at least until the age of diagnosis of the matched patient case. In total, 1,439 matched sets were identified. There was an average of 1.3 patient controls per patient case (range, one to nine). Thirteen patients had a mutation in both genes. These patients were excluded from subset analyses.
Study Protocol
At each center, patients completed a questionnaire regarding their personal history of cancer and potential cancer risk factors. These included questions about oophorectomy, mastectomy, reproductive and menopausal history, smoking, oral contraceptive use, and hormone replacement use. At some centers, the questionnaires were completed by telephone interview. Patients were asked if they had ever had an oophorectomy, if one or two ovaries were removed, and at what age the oophorectomy was performed. Only bilateral oophorectomies were considered as exposures. Oophorectomies could have been done for cancer prophylaxis or for other reasons. Only oophorectomies that took place before the diagnosis of breast cancer (ie, in different calendar years) in the patients were considered as exposures. Similarly, only oophorectomies that took place before the age of diagnosis of breast cancer in the matched patient case were considered to be exposures for the patient controls.
Study Design and Statistical Analysis
The frequency of oophorectomy was compared in BRCA1 and BRCA2 mutation carriers with and without a history of breast cancer using a matched case-control analysis with variable number of controls. The odds ratios (ORs) and P values for breast cancer associated with oophorectomy were calculated using conditional logistic regression, implemented in SAS (SAS Institute Inc, Cary, NC).
RESULTS
In total, 1,439 matched sets were identified (1,060 in BRCA1 and 379 in BRCA2). The characteristics of the patient cases and patient controls are shown in Table 1. Approximately three quarters of the subjects were BRCA1 mutation carriers. Patient cases and patient controls were similar for age, parity, and oral contraceptive use. The mean age of breast cancer diagnosis in patient cases was 38.9 years for BRCA1 carriers and was 40.9 years for BRCA2 carriers.
Fifty-one of the patient cases (3.5%) had an oophorectomy before breast cancer, versus 115 of the patient controls (6.2%). These proportions were similar for subgroups with BRCA1 and BRCA2 mutations. Oophorectomy was associated with a 57% reduction in breast cancer risk in BRCA1 carriers (unadjusted OR = 0.43; P = .00006) and a 46% risk reduction in BRCA2 carriers (OR = 0.57; P = .11). The observed reduction persisted after adjustment for oral contraceptive use and parity (Table 2).
The effect of age at oophorectomy on subsequent breast cancer risk was examined (Table 3). For BRCA1 carriers, the OR was 0.36 for oophorectomies performed at age 40 or younger and was 0.50 for oophorectomies performed from age 40 to 50. There was a small risk reduction associated with oophorectomies performed after age 50 (OR = 0.66) but there were few subjects in this category, and the result was not statistically significant. Among BRCA2 carriers there was no clear trend associated with age of oophorectomy, but this was a much smaller group and none of the subgroup estimates were statistically significant.
To determine if oophorectomy conferred protection against both early- and late-onset hereditary breast cancer, we examined the association between age at breast cancer diagnosis and prior oophorectomy (Table 4). When carriers of both BRCA1 and BRCA2 mutations were considered together, prior oophorectomy was associated with a greater reduction in the risk of breast cancer diagnosed at age 40 or younger (OR = 0.33; P = .006) or between ages 41 and 50 (OR = 0.43; P = .001) than for cases diagnosed above age 50 (OR = 0.64; P = .14).
Among patient cases, the average time interval between the ovarian surgery and the diagnosis of breast cancer was 7.2 years for BRCA1 mutation carriers (range, 1 to 29 years) and was 10.5 years for BRCA2 mutation carriers (range, 2 to 29 years). The protective effect of oophorectomy was evident for 15 years after surgery (Table 5). In carriers of BRCA1 mutations, the OR for breast cancer within 15 years of oophorectomy was 0.38 (95% CI, 0.25 to 0.59) and more than 15 years after oophorectomy was 1.27 (95% CI, 0.38 to 4.17). In carriers of BRCA2 mutations, the OR for breast cancer within 15 years of oophorectomy was 0.43 (95% CI, 0.19 to 0.99) and more than 15 years of oophorectomy was 1.47 (95% CI, 0.32 to 6.64). When both groups were considered together, there was a highly significant reduction in breast cancer risk within 15 years of oophorectomy (OR 0.39; P = .000003), but no evidence of risk reduction thereafter (OR 1.32; 95% CI, 0.52 to 3.36). The degree of protection by time since surgery is presented in Table 5.
DISCUSSION
In this study of women with inherited BRCA1 and BRCA2 mutations, bilateral oophorectomy is associated with a highly significant reduction in the risk of subsequent breast cancer. The oophorectomy provided substantial risk reduction for 15 years after the operation. Further studies will be necessary to establish if protection persists longer than this. These results confirm findings that have been reported previously in much smaller studies of women with hereditary susceptibility to breast cancer and ovarian cancer.8-10 The results of these studies support the hypothesis that estrogen deprivation reduces the risk of both sporadic breast cancer and hereditary breast cancer. This result was somewhat unexpected, given that the majority of BRCA1-associated breast tumors are estrogen-receptor negative,11 but there are several other hormonally-related modifiers of breast cancer risk that have been identified in BRCA1 carriers.12 For example, the risk of breast cancer has been reported to be modestly increased by the use of oral contraceptives,13 and the risk of contralateral breast cancer is greatly reduced by tamoxifen.7,14
In our study, the reduction in breast cancer risk appeared to be greatest for BRCA1 mutation carriers who underwent oophorectomy before age 40, although a protective effect was also observed for BRCA1 carriers who were older than this at the time of surgery. A lesser magnitude in risk reduction was seen for BRCA2 carriers. It is likely that the smaller overall effect in BRCA2 carriers is because of their later age of diagnosis, and consequently, on average, a greater period of time had elapsed between oophorectomy and breast cancer for BRCA2 carriers than for BRCA1 carriers (10.5 years for BRCA2 carriers versus 7.2 years for BRCA1 carriers). Thirty-one percent of the BRCA2 carriers, who had an oophorectomy, underwent this procedure 15 years or more before breast cancer, compared with 21% of BRCA1 carriers. However, in the 15-year period following oophorectomy, the level of risk reduction was similar for both mutation subgroups, although the sample size of BRCA2 carriers was much smaller, and the result was of borderline significance. It is possible that the difference observed in risk of breast cancer following oophorectomy in BRCA1 versus BRCA2 carriers might reflect biologic differences in tumorigenesis. The functions of the BRCA1 and BRCA2 proteins are closely linked, however, the pathologic characteristics of BRCA1- and BRCA2-associated breast cancers are distinct and the profile of risk factors are different for the two subgroups.12,15,16 In general, exogenous hormones appear to have a less profound effect on BRCA2 carriers than on BRCA1 carriers. Similar differences are seen with breastfeeding17 and parity (Cullinane et al, The effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers, manuscript in preparation).
Prophylactic oophorectomy is associated with a low risk of operative complications,9,18 but can commonly result in the abrupt onset of menopausal symptoms. The long-term complications of early surgical menopause include an increased risk of heart disease19 and of osteoporosis20 together with a decline in libido and psychological well-being.21 Hormone replacement therapy until age 50 is often recommended to prevent these complications. However, hormone replacement therapy has not been found to reduce the risk of cardiovascular disease following natural menopause,22,23 and it is not yet known to what extent, if at all, hormone replacement diminishes the protective effect of oophorectomy on breast cancer risk (this study is currently underway).
In summary, we found a significant degree of protection against breast cancer offered by surgical oophorectomy in BRCA1 carriers, and a similar, but nonsignificant reduction in BRCA2 carriers. The protective effect may be limited to the period of 15 years following the surgery. The strongest effects were observed for early oophorectomies (before 40 years of age) and for early-onset breast cancers (diagnosed before 40 years of age) in BRCA1 carriers. On the basis of the typically early age of onset of hereditary breast cancers, we recommend that preventive oophorectomy be considered for women with BRCA1 or BRCA2 mutations aged 35 and older. This surgery is expected to prevent the majority of ovarian cancers in this high risk group as well.
Appendix
Other members of the study group who contributed patients were Fergus J. Couch, Judy E. Garber, Mary Daly, Barry Rosen, Olufunmilayo Olopade, Beth Karlan, Nadine Tung, Howard M. Saal, Jeffrey Weitzel, Charis Eng, Carrie Snyder, Michael Osborne, Jane McLennan, Ellen Warner, Wendy McKinnon, Marie Wood, David Fishman, Donna Gilchrist, Albert Chudley, Ed Lemire, Kevin Hughes, Dianne Provencher, Sofia Merajver, Noah Kauff, Mark Robson, and Wendy Meschino.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank the Canadian Breast Cancer Research Initiative for their support for this research study. SLN was supported by NIH CA74415 and Noah Kauff was supported by DAMD 17-03-1-0375.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676-689, 1998
Warner E, Goodwin P, Foulkes W, et al: Prevalence of BRCA mutations in an unselected population of Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91:1241-1247, 1999
Antoniou A, Pharoah PDP, Narod SA, et al: Average risks of breast and ovarian cancer associated with mutations in BRCA1 or BRCA2 detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003
Risch HA, McLaughlin JR, Cole DE, et al: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68:700-710, 2001
Trichopoulos D, MacMahon B, Cole P: Menopause and breast cancer risk. J Natl Cancer Inst 48:605-613, 1972
Kelsey JL, Gammon MD, John EM: Reproductive factors and breast cancer. Epidemiol Rev 15:36-47, 1993
Metcalfe K, Lynch HT, Ghadirian P, et al: Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328-2335, 2004
Rebbeck TR, Levin AM, Eisen A, et al: Reduction in breast cancer risk after bilateral prophylactic bilateral oophorectomy in BRCA1 carriers. J Natl Cancer Inst 91:1475-1479, 1999
Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002
Rebbeck TR, Lynch HT, Neuhausen SL, et al: Reduction in cancer risk after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. N Engl J Med 346:1616-1622, 2002
Loman N, Johannsson O, Bendahl PO, et al: Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 mutations or unknown susceptibility genes. Cancer 83:310-319, 1998
Narod SA: Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2:113-123, 2002
Narod SA, Dubé MP, Klijn J, et al: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Can Inst 94(23):1773-1779, 2002
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 356:1876-1881, 2000
Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4:665-676, 2004
Scully R, Livingston DM: In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 408:429-432, 2000
Jernstr?m H, Lubinski L, Lynch HT, et al: Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96:1094-1098, 2004
Elit L, Rosen B, Goel V, et al: Prophylactic oophorectomy in Ontario. Fam Cancer 1:143-148, 2001
Colditz GA, Willett WC, Stampfer MJ, et al: Menopause and the risk of coronary heart disease in women. N Engl J Med 316:1105-1110, 1987
Aitken JM, Hart DM, Anderson JB, et al: Osteoporosis after oophorectomy for non-malignant disease in premenopausal women. Br Med J 2:325-328, 1973
Elit L, Esplen MJ, Butler K, et al: Quality of life and psychosexual adjustment after prophylactic oophorectomy for a family history of ovarian cancer. Fam Cancer 1(3-4):149-156, 2001
Writing Group for the Women's Health Initiative Investigators Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA 288:321-333, 2002
The Women's Health Initiative Steering Committee: Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial. JAMA 291:1701-1712, 2004(Andrea Eisen, Jan Lubinsk)
Pomeranian Medical University, Szczecin, Poland
Daniel den Hoed Cancer Center and Erasmus University Medical Center, Rotterdam, Netherlands
Department of Cancer Genetics, Norwegian Radium Hospital, Oslo, Norway
Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE
Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY
Departments of Medicine and Genetics, University of Pennsylvania, Philadelphia, PA
Division of Epidemiology, Department of Medicine, University of California, Irvine, CA
Epidemiology Research Unit, CHUM H?tel-Dieu, University of Montreal, and the Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, QC, Canada
Institute of Genetics, Rambam Medical Center, Haifa, and the Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, and the CHS National Cancer Control Center, Carmel Medical Center, Haifa, Israel
Private Trust for Breast Health, Division of Senology, University of Vienna, Austria
Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC
BC Cancer Agency, Vancouver, BC, and the London Regional Cancer Program, London, ON, and the Centre for Research in Women's Health, University of Toronto, ON, Canada
ABSTRACT
PURPOSE: The purpose of this study was to estimate the extent of protection offered against breast cancer by prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations and to determine to what extent risk reduction varies with age at oophorectomy, age at diagnosis, and time elapsed since surgery.
PATIENTS AND METHODS: We analyzed 1,439 patients with breast cancer and 1,866 matched controls derived from a registry of BRCA1 and BRCA2 carriers. We estimated odds ratios (ORs) of breast cancer for having had a bilateral oophorectomy, using conditional logistic regression, matched for parity and for oral contraceptive use.
RESULTS: A previous history of oophorectomy was associated with a significant reduction in breast cancer risk of 56% for BRCA1 carriers (OR = 0.44; 95% CI, 0.29 to 0.66) and of 46% for BRCA2 carriers (OR = 0.57; 95% CI, 0.28 to 1.15). The risk reduction was greater if the oophorectomy was performed before age 40 (OR = 0.36; 95% CI, 0.20 to 0.64 for BRCA1 carriers) than after age 40 (OR = 0.53; 95% CI, 0.30 to 0.91). The protective effect was evident for 15 years post-oophorectomy (OR = 0.39; 95% CI, 0.26 to 0.57).
CONCLUSION: Oophorectomy is an effective means of reducing the risk of breast cancer in carriers of BRCA1 mutations. The data suggest oophorectomy is protective in BRCA2 carriers as well, but needs to be confirmed in other studies.
INTRODUCTION
Women with a germline mutation in BRCA1 or BRCA2 face increased risks of breast and ovarian cancers. For BRCA1 mutation carriers, the estimated lifetime risk of breast cancer ranges from 40% to 85%,1-4 and the estimated lifetime risk of ovarian cancer ranges from 20% to 65%.1-4 For BRCA2 mutation carriers, the breast cancer risk is similar, but the lifetime risk of ovarian cancer is approximately 20%.1-4 Strategies for risk reduction include preventive surgery and chemoprevention. Increased surveillance is recommended. Bilateral prophylactic oophorectomy is commonly recommended to BRCA1 and BRCA2 mutation carriers to reduce the risk of ovarian cancer and breast cancer. Approximately 60% of women with BRCA1 or BRCA2 mutations in Canada now undergo prophylactic oophorectomy within 1 year of having been demonstrated to carry a BRCA mutation (Metcalf et al,7 The use of tamoxifen and other preventive measures among healthy women who carry a BRCA1 or BRCA2 mutation, manuscript submitted for publication). Case-control studies in the general population have shown that bilateral oophorectomy in premenopausal women is associated with a significant reduction in breast cancer risk.5,6 Several studies have also shown that oophorectomy is effective in reducing the risk of primary and contralateral breast cancer in BRCA1 and BRCA2 carriers.7-10 However, previous studies have been small and there was not sufficient data to estimate the magnitude of risk reduction by age of oophorectomy or by BRCA1/BRCA2 mutation status, or to measure the duration of the protective effect.
PATIENTS AND METHODS
Study Subjects
Women with a BRCA1 or BRCA2 mutation were identified through a registry of mutation carriers at the Centre for Research in Women's Health at the University of Toronto. Data were collected from women with known pathogenic BRCA1 and BRCA2 mutations at 48 different centers in seven countries in North America, Europe, and Israel. All patients provided informed written consent for genetic testing. The study has been approved by the ethics committees/human subjects review boards of all participating centers. In most cases, testing was offered initially to women who were affected either by breast cancer or ovarian cancer. When a mutation in either BRCA1 or BRCA2 was found in a proband or in her relative, testing was offered to other at-risk women in her family. Mutation detection was performed using a range of techniques, but all nucleotide alterations were confirmed by direct sequencing of DNA. A woman was eligible for the study when the molecular analysis established that she was a mutation carrier.
There were 5,659 mutation carriers in the database. Of these, 851 patients with ovarian cancer and 92 women with bilateral prophylactic mastectomy were excluded. An additional 147 patients were excluded because information was missing on key variables (ie, parity, oophorectomy, etc.). This left 4,569 subjects eligible for the study. There were 2,283 women with a mutation and breast cancer who were eligible to be patient cases. There were 2,286 women without breast cancer who were eligible to be patient controls. Patient cases and patient controls were matched by year of birth (within 1 year), country of residence, and BRCA1 or BRCA2 mutation status. The matched patient control was at risk for breast cancer at least until the age of diagnosis of the matched patient case. In total, 1,439 matched sets were identified. There was an average of 1.3 patient controls per patient case (range, one to nine). Thirteen patients had a mutation in both genes. These patients were excluded from subset analyses.
Study Protocol
At each center, patients completed a questionnaire regarding their personal history of cancer and potential cancer risk factors. These included questions about oophorectomy, mastectomy, reproductive and menopausal history, smoking, oral contraceptive use, and hormone replacement use. At some centers, the questionnaires were completed by telephone interview. Patients were asked if they had ever had an oophorectomy, if one or two ovaries were removed, and at what age the oophorectomy was performed. Only bilateral oophorectomies were considered as exposures. Oophorectomies could have been done for cancer prophylaxis or for other reasons. Only oophorectomies that took place before the diagnosis of breast cancer (ie, in different calendar years) in the patients were considered as exposures. Similarly, only oophorectomies that took place before the age of diagnosis of breast cancer in the matched patient case were considered to be exposures for the patient controls.
Study Design and Statistical Analysis
The frequency of oophorectomy was compared in BRCA1 and BRCA2 mutation carriers with and without a history of breast cancer using a matched case-control analysis with variable number of controls. The odds ratios (ORs) and P values for breast cancer associated with oophorectomy were calculated using conditional logistic regression, implemented in SAS (SAS Institute Inc, Cary, NC).
RESULTS
In total, 1,439 matched sets were identified (1,060 in BRCA1 and 379 in BRCA2). The characteristics of the patient cases and patient controls are shown in Table 1. Approximately three quarters of the subjects were BRCA1 mutation carriers. Patient cases and patient controls were similar for age, parity, and oral contraceptive use. The mean age of breast cancer diagnosis in patient cases was 38.9 years for BRCA1 carriers and was 40.9 years for BRCA2 carriers.
Fifty-one of the patient cases (3.5%) had an oophorectomy before breast cancer, versus 115 of the patient controls (6.2%). These proportions were similar for subgroups with BRCA1 and BRCA2 mutations. Oophorectomy was associated with a 57% reduction in breast cancer risk in BRCA1 carriers (unadjusted OR = 0.43; P = .00006) and a 46% risk reduction in BRCA2 carriers (OR = 0.57; P = .11). The observed reduction persisted after adjustment for oral contraceptive use and parity (Table 2).
The effect of age at oophorectomy on subsequent breast cancer risk was examined (Table 3). For BRCA1 carriers, the OR was 0.36 for oophorectomies performed at age 40 or younger and was 0.50 for oophorectomies performed from age 40 to 50. There was a small risk reduction associated with oophorectomies performed after age 50 (OR = 0.66) but there were few subjects in this category, and the result was not statistically significant. Among BRCA2 carriers there was no clear trend associated with age of oophorectomy, but this was a much smaller group and none of the subgroup estimates were statistically significant.
To determine if oophorectomy conferred protection against both early- and late-onset hereditary breast cancer, we examined the association between age at breast cancer diagnosis and prior oophorectomy (Table 4). When carriers of both BRCA1 and BRCA2 mutations were considered together, prior oophorectomy was associated with a greater reduction in the risk of breast cancer diagnosed at age 40 or younger (OR = 0.33; P = .006) or between ages 41 and 50 (OR = 0.43; P = .001) than for cases diagnosed above age 50 (OR = 0.64; P = .14).
Among patient cases, the average time interval between the ovarian surgery and the diagnosis of breast cancer was 7.2 years for BRCA1 mutation carriers (range, 1 to 29 years) and was 10.5 years for BRCA2 mutation carriers (range, 2 to 29 years). The protective effect of oophorectomy was evident for 15 years after surgery (Table 5). In carriers of BRCA1 mutations, the OR for breast cancer within 15 years of oophorectomy was 0.38 (95% CI, 0.25 to 0.59) and more than 15 years after oophorectomy was 1.27 (95% CI, 0.38 to 4.17). In carriers of BRCA2 mutations, the OR for breast cancer within 15 years of oophorectomy was 0.43 (95% CI, 0.19 to 0.99) and more than 15 years of oophorectomy was 1.47 (95% CI, 0.32 to 6.64). When both groups were considered together, there was a highly significant reduction in breast cancer risk within 15 years of oophorectomy (OR 0.39; P = .000003), but no evidence of risk reduction thereafter (OR 1.32; 95% CI, 0.52 to 3.36). The degree of protection by time since surgery is presented in Table 5.
DISCUSSION
In this study of women with inherited BRCA1 and BRCA2 mutations, bilateral oophorectomy is associated with a highly significant reduction in the risk of subsequent breast cancer. The oophorectomy provided substantial risk reduction for 15 years after the operation. Further studies will be necessary to establish if protection persists longer than this. These results confirm findings that have been reported previously in much smaller studies of women with hereditary susceptibility to breast cancer and ovarian cancer.8-10 The results of these studies support the hypothesis that estrogen deprivation reduces the risk of both sporadic breast cancer and hereditary breast cancer. This result was somewhat unexpected, given that the majority of BRCA1-associated breast tumors are estrogen-receptor negative,11 but there are several other hormonally-related modifiers of breast cancer risk that have been identified in BRCA1 carriers.12 For example, the risk of breast cancer has been reported to be modestly increased by the use of oral contraceptives,13 and the risk of contralateral breast cancer is greatly reduced by tamoxifen.7,14
In our study, the reduction in breast cancer risk appeared to be greatest for BRCA1 mutation carriers who underwent oophorectomy before age 40, although a protective effect was also observed for BRCA1 carriers who were older than this at the time of surgery. A lesser magnitude in risk reduction was seen for BRCA2 carriers. It is likely that the smaller overall effect in BRCA2 carriers is because of their later age of diagnosis, and consequently, on average, a greater period of time had elapsed between oophorectomy and breast cancer for BRCA2 carriers than for BRCA1 carriers (10.5 years for BRCA2 carriers versus 7.2 years for BRCA1 carriers). Thirty-one percent of the BRCA2 carriers, who had an oophorectomy, underwent this procedure 15 years or more before breast cancer, compared with 21% of BRCA1 carriers. However, in the 15-year period following oophorectomy, the level of risk reduction was similar for both mutation subgroups, although the sample size of BRCA2 carriers was much smaller, and the result was of borderline significance. It is possible that the difference observed in risk of breast cancer following oophorectomy in BRCA1 versus BRCA2 carriers might reflect biologic differences in tumorigenesis. The functions of the BRCA1 and BRCA2 proteins are closely linked, however, the pathologic characteristics of BRCA1- and BRCA2-associated breast cancers are distinct and the profile of risk factors are different for the two subgroups.12,15,16 In general, exogenous hormones appear to have a less profound effect on BRCA2 carriers than on BRCA1 carriers. Similar differences are seen with breastfeeding17 and parity (Cullinane et al, The effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers, manuscript in preparation).
Prophylactic oophorectomy is associated with a low risk of operative complications,9,18 but can commonly result in the abrupt onset of menopausal symptoms. The long-term complications of early surgical menopause include an increased risk of heart disease19 and of osteoporosis20 together with a decline in libido and psychological well-being.21 Hormone replacement therapy until age 50 is often recommended to prevent these complications. However, hormone replacement therapy has not been found to reduce the risk of cardiovascular disease following natural menopause,22,23 and it is not yet known to what extent, if at all, hormone replacement diminishes the protective effect of oophorectomy on breast cancer risk (this study is currently underway).
In summary, we found a significant degree of protection against breast cancer offered by surgical oophorectomy in BRCA1 carriers, and a similar, but nonsignificant reduction in BRCA2 carriers. The protective effect may be limited to the period of 15 years following the surgery. The strongest effects were observed for early oophorectomies (before 40 years of age) and for early-onset breast cancers (diagnosed before 40 years of age) in BRCA1 carriers. On the basis of the typically early age of onset of hereditary breast cancers, we recommend that preventive oophorectomy be considered for women with BRCA1 or BRCA2 mutations aged 35 and older. This surgery is expected to prevent the majority of ovarian cancers in this high risk group as well.
Appendix
Other members of the study group who contributed patients were Fergus J. Couch, Judy E. Garber, Mary Daly, Barry Rosen, Olufunmilayo Olopade, Beth Karlan, Nadine Tung, Howard M. Saal, Jeffrey Weitzel, Charis Eng, Carrie Snyder, Michael Osborne, Jane McLennan, Ellen Warner, Wendy McKinnon, Marie Wood, David Fishman, Donna Gilchrist, Albert Chudley, Ed Lemire, Kevin Hughes, Dianne Provencher, Sofia Merajver, Noah Kauff, Mark Robson, and Wendy Meschino.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank the Canadian Breast Cancer Research Initiative for their support for this research study. SLN was supported by NIH CA74415 and Noah Kauff was supported by DAMD 17-03-1-0375.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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