Affiliations of authors: J. L. Rutter, S. Ebbers, J. P. Struewing (Center for Cancer Research), S. Wacholder, M. A. Tucker, P. Hartge (Division of Cancer Epidemiology and Genetics), National Cancer Institute, National Institutes of Health, Bethesda, MD; A. Chetrit, F. Lubin, Chaim Sheba Medical Center, Tel-Hashomer, Israel; J. Menczer, Edith Wolfson Medical Center, Holon, Israel.
Correspondence to: Patricia Hartge, Sc.D., Division of Cancer Epidemiology and Genetics, Epidemiology and Biostatistics Program, National Cancer Institute, Executive Plaza South, Rm. 8090, 6120 Executive Blvd., Bethesda, MD 208927246 (e-mail: hartgep{at}mail.nih.gov).
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ABSTRACT |
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INTRODUCTION |
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Although prophylactic oophorectomy is now an accepted method of ovarian cancer risk reduction for women at high risk for the disease, primary peritoneal cancers can occur after oophorectomy. Two recent reports (6,7) suggested considerable reduced risk of developing cancers of the ovary or peritoneum after preventive surgery. In a prospective study (6), 170 BRCA mutation carriers were followed for a mean of 2 years after 98 had surgery and 72 chose surveillance without surgery. Among the women who had had surgery, one developed primary peritoneal cancer after the surgery, whereas among the women in the surveillance group, one developed primary peritoneal cancer and four developed ovarian cancer. In a retrospective cohort study (7), an analysis of 551 BRCA mutation carriers assembled from clinics for women with a strong family history of breast or ovarian cancer found that six of 259 (2.3%) women had ovarian cancer at the time of their prophylactic surgery and that two women developed peritoneal cancers during the next 9 years. During the same time, 58 of 292 (20%) women who chose not to have surgery developed ovarian or peritoneal cancer. A study of high-risk Jewish women enrolled in a screening program (8) showed that 21% of BRCA1/2 mutation carriers developed ovarian or peritoneal cancers in 10 years. A potential limitation of these three studies (68) is that they predominately involved women from high-risk families, illustrated by their high rates of developing ovarian cancer.
To avoid the limitation associated with use of high-risk families, we have used a population-based design to examine the long-term associations of gynecologic surgeries on ovarian cancer risk among BRCA1/2 mutation carriers and non-carriers. We evaluated the association of prophylactic oophorectomy with ovarian or peritoneal cancer risk in the context of all of the major types of gynecologic surgeries. Using our population-based sample, we studied non-carriers and carriers of the three Ashkenazi founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) to measure the associations of the range of typical gynecologic surgeries on ovarian cancer risk and to assess how these associations vary with BRCA1 and BRCA2 mutations.
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METHODS |
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The rapid case ascertainment and control selection criteria have been described in previous reports (911). Briefly, from March 1, 1994, through June 30, 1999, a nationwide study of ovarian cancer was conducted in Israel. Study staff identified all Jewish women with pathologically confirmed epithelial ovarian cancer or primary peritoneal cancer by weekly telephone inquiries and personal contacts with the chief nurses in the 22 gynecologic departments in Israel. After they were identified, the case patients were followed. After the patient recovered from surgery, the study staff performed the interviews in the hospital. Six percent of the case patients were interviewed during chemotherapy treatment and at home.
Control women were selected from the Israeli Central Population Registry, two per case patient, and were matched for age (within 2 years), area of birth, and place and length of residence in Israel. The study protocol was approved by institutional review boards in Israel and the United States, and participants gave written informed consent. The participation response rate was 79% for case patients and 66% for control subjects.
The case definition included all epithelial ovarian cancers (n = 1036) (code 183.0 of the International Classification of Diseases, 9th revision, Clinical Modification) and peritoneal carcinomas (n = 88) (code 158.0). The primary peritoneal cancers were counted as post-bilateral oophorectomy cases only if the pathology records clearly indicated that the ovaries removed during a previous surgery were clear of cancer cells. Borderline and germ-cell ovarian tumors were excluded in the analysis because of the possibility of different etiology.
Data Collection
In-person interviews were conducted, and samples for BRCA1 and BRCA2 founder mutation screening were obtained from blood or paraffin-embedded tumor tissue (from the case patients) or by buccal cell collection (from the control subjects), as previously described (9). Most of the case patients were interviewed in the hospital within 46 days after their gynecologic surgery. The interview included questions on menstrual, reproductive, medical, and dietary histories. Past gynecologic surgeries were self-reported. Abstraction of medical records of these surgeries was performed and validated for 109 of 275 (40%) of the subjects. Of the 109, 95 (87%) were in agreement. We do not know whether such close agreement would characterize all self-reports of gynecologic surgeries, but close agreement between self-reports and medical records has been reported elsewhere (12,13).
Laboratory Methods
Laboratory procedures to detect the BRCA1 and BRCA2 founder mutations have been described elsewhere (9). Briefly, we used a multiplex polymerase chain reaction assay containing reagents to detect all three founder mutations within one reaction tube, and analyzed the results with an Applied Biosystems model 310 genetic analyzer and Genescan software (Applied Biosystems, Foster City, CA). Founder mutation screening results were obtained from 847 of 891 (95%) of case patients. Buccal cell collection on the control subjects was initiated midway through the study, and we were able to collect samples from 968 of 2268 control subjects. We successfully tested 790 (81.6%) samples for founder mutations.
Statistical Methods
We compared history of gynecologic surgeries among case patients and control subjects using descriptive statistics and estimated odds ratios (ORs) and the 95% confidence intervals (CIs) from logistic regression models. All analyses were adjusted for age in decades, ethnicity, parity, and oral contraceptive use, unless otherwise noted. In analyses designed to estimate the association with gynecologic surgery in carriers or non-carriers separately, we used as case patients either carriers only or non-carriers only from among the women with ovarian cancer, and as control subjects all the non-diseased women, whether they tested as carriers or non-carriers or were untested, as in our previous report (9). This approach gives unbiased estimates of the effects if the history of gynecologic surgery is independent of carrier status, conditional on other terms in the model (14). The unconditional assumption may not hold, for example, if family history of cancer encouraged gynecologic surgery. By conditioning on family history of cancers of the breast and ovary, we reduce the chance that the independence assumption is materially violated. All statistical tests were two-sided and were performed using SAS version 8.2 software (SAS Institute, Cary, NC) and BMDP Version 1990 Statistical Software (BMDP Software, Los Angeles, CA).
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RESULTS |
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Of the eligible case patients, 1124 (84.8%) were interviewed, and their characteristics are shown in Table 1. Of the 1124 case patients, 88 had ovarian or peritoneal and 18 had fallopian tube primary cancers. More than 70% of the case patients were of Ashkenazi origin, with the remainder of non-Ashkenazi (23.6%) or mixed (5.7%) ancestry. Of the 1124 case patients, 277 were excluded from DNA mutation analysis: 226 case patients did not provide a sample or refused consent for BRCA1/2 testing, and DNA from 51 case patients was of poor quality. Thus, we analyzed DNA from 847 case patients. Of these patients, 187 carried a founder BRCA1 mutation, 64 carried a founder BRCA2 mutation, two carried a founder mutation in both genes, and 598 were non-carriers of the founder mutations (Table 1
). As shown in a previous report (9), there were no statistically significant differences in age at diagnosis or ethnic origin between those who were tested for the founder mutations and those who were not.
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DISCUSSION |
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It is possible that levels of risk reduction depend on the specific location of the mutation. Mutations falling within the so-called "ovarian cancer cluster region" of BRCA2, such as the 6174delT mutation, are associated with an increased risk of ovarian cancer compared with mutations located in other regions of the BRCA2 gene (19). None of the 64 BRCA2 6174delT carrier case patients in this study reported having had a bilateral oophorectomy. Larger numbers of carriers with different BRCA2 mutations must be studied to understand their magnitude of risk reduction following surgery and whether that effect is specific to peritoneal cancers.
We also observed a decreased risk of developing ovarian cancer among BRCA1 and BRCA2 mutation carriers who had other gynecologic surgeries involving the uterus, ovaries, and fallopian tubes. The overall magnitude of the risk reduction we observed in carriers who had previous gynecologic surgery (OR = 0.63, 95% CI = 0.50 to 0.79) was similar to the association seen in non-carriers (OR = 0.66, 95% CI = 0.50 to 0.88) and similar to that seen in a previous prospective study of the risk of ovarian cancer among the general population (12). Our results are also consistent with a report regarding the effects of tubal ligation on ovarian cancer risk in a clinic-based series of prevalent BRCA1 mutation-positive ovarian cancer case patients who were compared with women without ovarian cancer (20).
Among all study participants, we observed that women reporting a bilateral oophorectomy had an almost 90% lower cancer risk. The reduced risk was similar regardless of the age at surgery or whether surgery was performed during or after reproductive years. Similar to a report by Hankinson et al. (12), our study provides evidence that ovarian cancer risk associated with previous gynecologic surgery persisted beyond 10 years. This long-lasting effect suggests that surveillance alone (i.e., detection that accompanies surgery) could not explain the effect and that risk of developing cancer may actually be lower than that detected.
Our study has several strengths. First, our study uses a well-defined population at risk, namely the population of Israel from 1994 through 1999 with complete ascertainment of case patients, a high response rate, specific, well-defined mutations, the use of incident rather than prevalent case patients, and the availability of extensive data on reproductive and other risk factors. Second, the decisions regarding surgery generally predated the knowledge of BRCA1/2 mutations and were before the routine use of surgery to prevent cancers in carriers. Third, it was possible to evaluate the associations of different types of gynecologic surgery on cancer risk in the Israeli Jewish populationpatterns found to be typical of those reported in many population studies. It was also possible to compare patterns in the subset of women who carried BRCA1/2 mutations with patterns in women who did not. Our analysis did not rely on the very small number of carrier controls we identified. Comparing the patterns of multiple surgical associations between carriers and non-carriers provides a broader base of evidence to detect whether surgical intervention operates similarly in carriers and non-carriers.
Our study has several limitations. First, unlike a prospective clinical cohort study, our study relies on self-reports of surgery and routine classification of the primary origin of the tumor as ovary, tubal, or peritoneal. In a woman with both ovarian and peritoneal involvement, the likelihood of assigning the peritoneum as the primary site is influenced by the presence of ovaries. In our large population series, 80 peritoneal cancers were noted in women who had ovaries. Second, even in this large study, the number of women with a specific mutation was not large, so the confidence intervals are wide. For example, only two of the BRCA2 mutation carriers in this study had had a tubal ligation. Third, women in our study may harbor a non-founder mutation. Because non-founder mutations seldom occur in Ashkenazi women (21), we repeated the analysis with restriction to Ashkenazi participants. We found no substantial difference in the risk estimates (data not shown). Finally, like our earlier report (9), this analysis relies on an unverified assumption regarding independence between genetic and behavioral factors, conditional on family history of cancer. We note that the confidence intervals we report are still too narrow because they do not take remaining uncertainty about this assumption into account (14).
Although the relation between gynecologic surgery and reduced risk of ovarian cancer in general is well established (2225), the underlying mechanisms are not completely clear. Gynecologic surgeries such as tubal ligation, hysterectomy, and/or unilateral oophorectomy may reduce the risk of ovarian cancer by reducing the number of ovulations. Studies in the 1970s and 1980s suggested that menstrual disorders, including reduced ovulation and accelerated onset of menopause, often occurred after tubal ligation, which may have been a direct result of a reduced blood supply to the ovaries (2629) and lower gonadotropin levels that act by stimulating the ovarian surface epithelium (30). This proposed mechanism applies directly to hysterectomy and unilateral oophorectomy, but it is unclear whether current tubal ligation procedures would substantially decrease blood flow to the ovaries. An alternative mechanism could be that tubal ligation procedures occlude the fallopian tube, thereby blocking passage of potential environmental carcinogens (e.g., talc) to the ovary, where they would otherwise induce an inflammatory response and subsequent malignant transformation (31).
Various investigations have assessed whether the lower ovarian cancer risk seen following gynecologic surgery reflects screening that accompanies the surgery. For instance, women may have been found unexpectedly to have ovarian cancer at the time of tubal ligation or hysterectomy surgery, or some may have had abnormal ovaries removed that may have otherwise become malignant. The published data do not, however, support such a screening hypothesis. For example, one prospective study (12) found that the reduced risk associated with hysterectomy persisted at least 15 years after the procedure (relative risk = 0.62, 95% CI = 0.31 to 1.22); another (25) showed persistently reduced risk 30 years after surgery. Both reports (12,25) suggest that the risk reduction is unlikely to be the result of a screening effect alone.
Few non-surgical options to reduce ovarian cancer risk are available to high-risk women. Routine screening with ultrasound and antibody tests have not yet been shown to be effective. Oral contraceptive use was reported to be associated with reduced risk in a clinic-based series of BRCA mutation carriers (32), but this finding was not confirmed in our population-based casecontrol study (9). Thus, tubal ligation, hysterectomy, and/or unilateral oophorectomy may be options for BRCA mutation carriers who seek a means of reducing their risk of ovarian cancer. This option may be desirable to genetically at-risk women who have completed childbearing but who want to avoid complete bilateral oophorectomy and the possible morbidities associated with it. For example, premenopausal women may want to reduce their need for hormone replacement therapy. These are complicated decisions, in part because women who carry a germline mutation in BRCA1/2 have an increased risk not only of ovarian cancer but also of breast cancer. Regardless, prophylactic oophorectomy is an option for at-risk women despite the possibility of subsequent occurrence of primary peritoneal cancers.
Gynecologic surgeries may offer some reduction in risk of breast cancer. Tubal ligation does not seem to reduce breast cancer risk, but other gynecologic procedures, such as hysterectomy, unilateral oophorectomy, and bilateral oophorectomy do (33,34). The reduction in breast cancer risk may be related to the altered exposure to endogenous ovarian hormones following hysterectomy and oophorectomy. Furthermore, long-term hormone replacement therapy may increase risk of breast cancer (35), although at least one recent report found that BRCA1 mutation carriers who had a prophylactic oophorectomy showed no increased breast cancer risk with hormone replacement therapy use (36).
Taken together, the current evidence suggests that gynecologic surgeries can reduce risk of ovarian cancer in carriers of BRCA1/2 mutations. Bilateral oophorectomy may remove most of the risk, other surgeries that remove ovarian tissue may halve the risk, and hysterectomy and tubal ligation may modestly reduce the risk. Clinical decisions for ovarian cancer risk reduction in BRCA mutation carriers will necessarily involve the balancing of potential benefits and harms for each individual woman faced with this difficult decision.
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NOTES |
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Supported in part by Public Health Service grant RO1 CA61126-01-03 (to Chaim Sheba Medical Center, Tel-Hashomer, Israel) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and by support services contract MS NO2-CP-81005 with Information Management Services, Silver Spring, MD, and contracts NO2-CP-60534 and NO2-CP-91026 with Westat, Rockville, MD.
We thank Mary McAdams for statistical assistance and Drs. Mark Greene and Robert Hoover for critical review of this manuscript.
We are deeply indebted to the members of the National Israel Ovarian Cancer Group: Marco Altaras, M.D., Shmuel Anderman, M.D., Shaul Anteby, M.D., Jack Atad, M.D., Amiran Bar-Am, M.D., Uzi Beller, M.D., Moshe Ben Ami, M.D., Gilad Ben-Baruch, M.D., Yehuda Ben-David, M.D., Izhar Ben-Shlomo, M.D., Haim Biran, M.D., Angela Chetrit, B.Sc., Shlomit Cohan, M.D., Ram Dgani, M.D., Yehudit Fishler, C.T.R., Ami Fishman, M.D., Eitan Friedman, Ph.D., Ofer Gemer, M.D., Ruth Gershoni, M.D., Galit Hirsh-Yechezkel, B.Sc., David Idelman, M.D., Rafael Katan, M.D., Yuri Kopilovic, M.D., Efrat Lahad, M.D., Liat Lerner Geva, M.D., Hanoch Levavi, M.D., Tal Levi, M.D., Albert Levit, M.D., Beatriz Lifschiz-Mercer, M.D., Zohar Liviatan, M.D., Flora Lubin, M.Sc., R.D., Jacob Markovich, M.D., Joseph Menzcer, M.D., Baruch Modan, M.D. (Chairman), Hedva Nitzan, R.N., M.P.H., Moshe Oettinger, M.D., Tamar Peretz, M.D., Benjamin Piura, M.D., Shulamit Rizel, M.D., David Schneider, M.D., Adi Shani, M.D., Michael Shtark, M.D., Mariana Shteiner, M.D., Zion Tal, M.D., Chaim Yaffe, M.D., Ilana Yanai, M.D., Shifra Zohar, M.D., Ahuva Zoltan, R.N., B.A., and Yuri Kopilovic, M.D.
1 Editors note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
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Manuscript received October 17, 2002; revised April 28, 2003; accepted May 8, 2003.
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