Relation of Contraceptive and Reproductive History to Ovarian Cancer Risk in Carriers and Noncarriers of BRCA1 Gene Mutations
V. McGuire1 ,
A. Felberg1,
M. Mills1,
K. L. Ostrow2,
R. DiCioccio2,
E. M. John3,
D. W. West3 and
A. S. Whittemore1
1 Departments of Health Research and Policy and Medicine, Stanford University School of Medicine, Stanford, CA.
2 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY.
3 Northern California Cancer Center, Union City, CA.
Received for publication January 7, 2004; accepted for publication May 26, 2004.
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ABSTRACT
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In the general population, ovarian cancer risk is inversely associated with oral contraceptive use, tubal ligation, and childbearing. Among carriers of BRCA1 gene mutations, the data are conflicting. The authors identified women diagnosed with incident invasive epithelial ovarian cancer in the San Francisco Bay Area of California from March 1997 through July 2001. They compared the contraceptive and reproductive histories of 36 carrier cases and 381 noncarrier cases with those of 568 controls identified by random digit dialing who were frequency matched to cases on age and race/ethnicity. In both carriers and noncarriers, reduced risk was associated with ever use of oral contraceptives (odds ratio = 0.54 (95% confidence interval (CI): 0.26, 1.13) for carriers and 0.55 (95% CI: 0.41, 0.73) for noncarriers), duration of oral contraceptive use (risk reduction per year = 13% (p = 0.01) for carriers and 6% (p < 0.001) for noncarriers), history of tubal ligation (odds ratio = 0.68 (95% CI: 0.25, 1.90) for carriers and 0.65 (95% CI: 0.45, 0.95) for noncarriers), and increasing parity (risk reduction per childbirth = 16% (p = 0.26) for carriers and 24% (p < 0.001) for noncarriers). These data suggest that BRCA1 mutation carriers and noncarriers have similar risk reductions associated with oral contraceptive use, tubal ligation, and parity.
contraceptives, oral; genes, BRCA1; mutation; ovarian neoplasms; parity; sterilization, tubal
Abbreviations:
Abbreviations: CI, confidence interval; PTT, protein truncation test; SSCP, single-strand conformation polymorphism.
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INTRODUCTION
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Epithelial ovarian cancer is the most fatal gynecologic cancer, with 5-year relative survival rates in the United States of 53 percent overall and only 31 percent for women diagnosed with advanced disease (1). Strategies for controlling the disease through prevention and early detection are limited. Risk is highest among women who have first-degree relatives with ovarian cancer or early-onset breast cancer (24). This association is due largely to familial coinheritance of germ-line mutations in either of the breast cancer tumor suppressor genes, BRCA1 or BRCA2. Estimates of ovarian cancer risk by age 70 years among BRCA1 mutation carriers range from 16 percent to 40 percent (57). Comparable risk estimates among BRCA2 mutation carriers are lower (1120 percent) and vary with the position of the mutation within the gene (8, 9). Nevertheless, both sets of risk estimates are considerably higher than the 1 percent risk by age 70 years observed in the general population (6).
A large body of consistent evidence has identified several factors related to birth control and childbearing that are inversely associated with ovarian cancer risk. These include oral contraceptive use, tubal ligation, number of childbirths, and, among the parous, duration of breastfeeding (10, 11). However, the evidence concerning these factors has been less consistent for BRCA1 and BRCA2 mutation carriers.
Oral contraceptive use has been associated with reduced risk among carriers, with similar risk reductions being observed in carriers of BRCA1 mutations and carriers of BRCA2 mutations (12, 13). In support of this protective association, other investigators have found reduced risk associated with oral contraceptive use among women with a family history of breast cancer or ovarian cancer (14). However, a population-based Israeli study in which ovarian cancer patients were genotyped for three BRCA mutations common among Ashkenazi Jews (two in BRCA1 and one in BRCA2) found no evidence of reduced risk associated with oral contraceptive use among mutation carriers (15). This study found tubal ligation to be associated with reduced ovarian cancer risk for carriers of the three Ashkenazi BRCA mutations (16), while other studies have found reduced risk among carriers of one type of mutation but not the other (17, 18).
The evidence concerning parity and ovarian cancer risk in carriers has also been inconsistent. Parity has been inversely associated with risk among carriers of the three Ashkenazi BRCA mutations (15) but has been found to be positively associated with risk among women who carry any pathogenic mutation in either gene (12). The data on this question among women with a family history of breast or ovarian cancer are also inconsistent: Parity has been associated with reduced risk in some studies (1820) but unassociated with risk in others (2, 21).
Some of the inconsistent findings may reflect different types of selection or recall bias arising in the different study designs. Some data were obtained from population-based case-control studies, while others were obtained by comparing the attributes of affected and unaffected women in families seen at high-risk cancer clinics. To address the need for clarification of potential risk reductions associated with birth control and reproductive characteristics in mutation carriers, we used a population-based case-control design to identify women with and without ovarian cancer and genotyped the ovarian cancer cases for BRCA1 mutations. We evaluated risk in carriers and noncarriers in relation to oral contraceptive use, tubal ligation, parity, and breastfeeding.
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MATERIALS AND METHODS
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Study population
Patients with epithelial ovarian cancer diagnosed between March 1, 1997, and July 31, 2001, were identified through the Greater Bay Area Cancer Registry, which is operated by the Northern California Cancer Center as part of the National Cancer Institutes Surveillance, Epidemiology, and End Results Program. We used rapid case ascertainment to identify cases within 1 month of diagnosis. Eligible patients were those diagnosed at age 2064 years with invasive or low-malignant-potential epithelial ovarian cancer who resided in one of six San Francisco Bay Area counties (Alameda, Contra Costa, Marin, San Francisco, San Mateo, and Santa Clara). Of the 915 eligible patients, 24 (2.6 percent) were not contacted because their physicians refused permission; 209 (22.8 percent) refused to participate, had died, or could not be located; and 682 (74.6 percent) were interviewed. Of these, 579 (84.9 percent) provided a blood or mouthwash sample for DNA extraction.
Control women were identified through random digit dialing and were frequency matched to cases on race/ethnicity and 5-year age group. Of 1,041 controls randomly selected for the study, 746 (71.7 percent) completed the telephone screening interview, 162 (15.5 percent) refused to participate, and 133 (12.8 percent) could not be located. Of 689 control women who met the eligibility criteria (i.e., no prior history of breast cancer or ovarian cancer), 626 (91 percent) completed the detailed family history and epidemiology questionnaires and 585 (85 percent) provided a blood or mouthwash sample.
Each eligible subject received an introductory letter and telephone call inviting her to participate in the study. Structured personal interviews were conducted, and blood or buccal mouthwash samples were taken by trained interviewers/phlebotomists in subjects homes or other convenient locations. The interview elicited information on demographic and reproductive factors, medical history, and use of tobacco and alcohol. Research was conducted with protocols approved by the institutional review boards of the Stanford University School of Medicine (Stanford, California) and the Roswell Park Cancer Institute (Buffalo, New York).
Laboratory analysis
Samples of heparinized peripheral blood or buccal mouthwash rinse were shipped to the Roswell Park Cancer Institute. Genomic DNA was isolated from leukocytes of peripheral blood using the Puregene Kit (Gentra Systems, Minneapolis, Minnesota). Genomic DNA was also isolated from exfoliated buccal cells according to the method of Lum and Le Marchand (22).
BRCA1 mutation testing was conducted for all ovarian cancer patients who provided DNA from peripheral blood or mouthwash samples. We amplified the entire coding region of the BRCA1 gene (exons 2, 3, and 524) and splice junctions using 41 primer pairs. Individual amplification products of each DNA sample were screened for DNA variations by single-strand conformation polymorphism (SSCP) analysis (23, 24). DNA variations in exon 11 of the BRCA1 gene were also assessed by protein truncation test (PTT) (25). Placental DNA served as a normal, standard control for DNA variant screening by SSCP or PTT. (Primer structures and conditions for DNA amplification, SSCP, and PTT are available upon request by e-mail (richard.dicioccio{at}roswellpark.org).) Amplification products with DNA variants detected by SSCP or PTT were purified for direct DNA sequencing to identify mutations (25). Patients were considered mutation carriers if their test results showed a pathogenic mutation according to the criteria described on the website of the Breast Informatics Consortium (http://www.research.nhgri.nih.gov/bic/). Such mutations include frameshift or nonsense mutations, splice-site mutations predicted to cause aberrant splicing, large deletions or duplications, and missense mutations in the ring-finger domain of the gene.
Statistical analysis
The present analysis was restricted to the 417 case women with invasive epithelial ovarian cancer who were tested for BRCA1 mutations and the 568 control women who had not undergone bilateral oophorectomy. Each subjects personal characteristics were assessed at a reference date, defined as the date of diagnosis for cases and the date of interview for controls. We conducted separate analyses comparing the attributes of carrier cases with those of controls and the attributes of noncarrier cases with those of controls. For each of these two analyses, we estimated odds ratios and 95 percent confidence intervals using conditional logistic regression, with the data stratified on race/ethnicity (White, non-White) and 5-year age group (26). We also included age as a continuous variable in all regression analyses to adjust for any residual confounding. The regression analyses were implemented using SAS statistical software (27). All statistical tests were two-tailed. Patients with tumors of low malignant potential were excluded from this analysis.
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RESULTS
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Table 1 shows the demographic and personal characteristics of control women and cases, by BRCA1 mutation carrier status. Compared with noncarrier cases, carrier cases were more likely to have been diagnosed before age 50 years, to be single, to be of Ashkenazi Jewish descent, and to have a positive family history of ovarian cancer or early-onset breast cancer. Regardless of carrier status, cases were less likely than controls to be parous, to have used oral contraceptives, and to have undergone tubal ligation.
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TABLE 1. Characteristics of women with invasive epithelial ovarian cancer and control women, by BRCA1 gene mutation carrier status, San Francisco Bay Area, 19972001
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Table 2 summarizes the pathologic attributes of the patients cancers by BRCA1 mutation status. BRCA1 carriers were more likely than noncarriers to be diagnosed with serous tumors and less likely to be diagnosed with endometrioid cancers.
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TABLE 2. Histologic characteristics of women with invasive epithelial ovarian cancer, by BRCA1 gene mutation carrier status, San Francisco Bay Area, 19972001
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Table 3 presents odds ratios and confidence intervals for ovarian cancer risk in relation to oral contraceptive use, tubal ligation, and parity, by cases carrier status. Odds ratio estimates for carriers were similar to those for noncarriers. The odds ratio associated with use of oral contraceptives for at least 1 year, as compared with less than 1 year, was 0.54 (95 percent confidence interval (CI): 0.26, 1.13) among carriers and 0.55 (95 percent CI: 0.41, 0.73) among noncarriers. The odds ratio associated with use of oral contraceptives for 7 or more years, as compared with less than 1 year, was 0.22 (95 percent CI: 0.07, 0.71) among carriers and 0.43 (95 percent CI: 0.30, 0.63) among noncarriers. The data showed statistically significant trends of decreasing risk with increasing duration of use for both carrier groups. Risk reductions were 13 percent per year (p = 0.01) in carriers and 6 percent per year (p < 0.001) in noncarriers.
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TABLE 3. Risk of invasive epithelial ovarian cancer according to oral contraceptive use, tubal ligation, and parity, by BRCA1 gene mutation carrier status, San Francisco Bay Area, 19972001
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A history of tubal ligation was associated with decreased risk of similar magnitudes in the two carrier groups, although the reduction was statistically significant only in noncarriers. The odds ratio associated with having a tubal ligation was 0.68 (95 percent CI: 0.25, 1.90) among carriers and 0.65 (95 percent CI: 0.45, 0.95) among noncarriers.
Table 3 also shows reduced risk associated with parity in the two carrier groups. The odds ratio associated with having at least one full-term pregnancy (
36 weeks gestation) was 0.64 (95 percent CI: 0.30, 1.39) among carriers and 0.46 (95 percent CI: 0.34, 0.63) among noncarriers. Increasing parity was associated with reduced risk in both carrier groups, but the trend was statistically significant only in noncarriers. Trends of decreasing risk with increasing age at first full-term pregnancy were noted in both carrier groups (data not shown), but the trend in carriers was not statistically significant, and the trend in noncarriers was only marginally significant.
Risk was unrelated to age at menarche, body mass index, breastfeeding, and hormone replacement therapy, regardless of carrier status (data not shown).
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DISCUSSION
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In this population-based case-control study of epithelial ovarian cancer in women with and without BRCA1 mutations, we found that carriers and noncarriers had similar ovarian cancer risk reductions associated with oral contraceptive use, tubal ligation, and parity. Among mutation carriers, we found reduced risk associated with oral contraceptive use and greater risk reduction with increasing duration of use. The risk reductions of 46 percent for ever users and 78 percent for long-term users are similar to reductions noted among noncarriers in this study and among all women (regardless of carrier status) in previous studies. For example, in a pooled analysis of six population-based case-control studies of oral contraceptives and epithelial ovarian cancer in the United States, the risk reduction associated with ever use was 34 percent and that associated with 6 or more years of use was 70 percent (28). These findings are consistent with the inverse association noted among BRCA1 and BRCA2 mutation carriers seen in familial cancer clinics (13, 17), but they are inconsistent with the absence of association found among carriers of the three Ashkenazi BRCA1 and BRCA2 mutations in a population-based study conducted in Israel (15). This latter inconsistency, if not due to chance or bias, may reflect differences in characteristics of either the populations at risk or the types of mutations studied.
We also found reduced ovarian cancer risk to be associated with tubal ligation among BRCA1 mutation carriers, although the 32 percent risk reduction did not achieve statistical significance. Similar risk reductions have been reported for carriers of BRCA1 mutations but not BRCA2 mutations (17) and for carriers of BRCA2 mutations but not BRCA1 mutations (18). The Israeli case-control data indicated risk reductions of 30 percent in association with tubal ligation among both carriers and noncarriers of the three Ashkenazi BRCA mutations (16). Risk reductions of similar magnitudes have been reported in all women regardless of mutation status (28, 29).
The present data suggest that BRCA1 mutation carriers and noncarriers have similar reductions in ovarian cancer risk associated with parity, although the trends achieved statistical significance only for parity in noncarriers. Similar parity-related risk reductions were found among Israeli carriers of the Ashkenazi BRCA mutations (15). In contrast, a clinic-based study reported a 40 percent increased risk among parous BRCA1 mutation carriers as compared with nulliparous carriers (12).
The present study had several strengths. These included a well-defined population at risk (namely, female residents of the San Francisco Bay Area during the period March 1997July 2001), complete ascertainment of cases, a high study participation rate, specific well-defined pathogenic mutations of BRCA1, the inclusion of incident rather than prevalent cases, and the availability of extensive data on personal characteristics elicited from the participants themselves, rather than proxies, in structured interviews using a single standardized questionnaire instrument. Moreover, decisions concerning birth control methods and childbearing typically predated knowledge of the existence of germ-line BRCA mutations and their roles in breast and ovarian cancer risk. Indeed, few if any case participants knew their own BRCA1 mutation status. Finally, it was possible to compare the distributions of birth control methods and reproductive characteristics in carrier patients directly with those in noncarrier patients. Comparison of these two distributions provides a direct source of evidence concerning whether the attributes have similar effects in carriers and noncarriers.
The study also had some limitations. First, the number of carrier patients was small, so the confidence intervals were wide. Nevertheless, the data for carriers showed a statistically significant risk reduction associated with long-term use of oral contraceptives and a statistically significant trend of decreasing risk with increasing duration of oral contraceptive use. Second, we did not test the control women for BRCA1 mutations, which precluded an ideal comparison of attributes in carrier cases and carrier controls. Such a comparison is infeasible, however, because BRCA1 mutations are so rare in the US population that one would expect fewer than one in 500 control women to be carriers (30). Third, the noncarrier case group contained some unidentified BRCA1 carriers (since the laboratory detection methods have imperfect sensitivity) and unidentified BRCA2 mutation carriers (since we did not evaluate BRCA2 mutations). However, such carriers would comprise at most a small minority of noncarrier cases, and their presence would have little effect on the inferences.
In conclusion, the present data support the hypothesis that oral contraceptive use and tubal ligation reduce ovarian cancer risk among carriers of BRCA1 mutations. These birth control methods provide preventive options that are alternative or supplemental to and less invasive than prophylactic oophorectomy. However, any benefit of oral contraceptive use for carriers ovarian cancer risks must be weighed against its possible adverse effects on their breast cancer risks (3133). On the basis of the data presently available, women with BRCA1 mutations might consider oral contraceptive use in light of any planned prophylactic surgery. Women with intact ovaries who undergo prophylactic mastectomy are good candidates for oral contraceptives, while those who undergo prophylactic oophorectomy but not mastectomy may not benefit.
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ACKNOWLEDGMENTS
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This research was supported by grants UO1 CA71966 and CA16056 from the National Institutes of Health. The latter grant helps to maintain the Biopolymer Facility at the Roswell Park Cancer Institute, which assisted in the synthesis of primers and in DNA sequencing. The recruitment of controls by the Northern California Cancer Center was supported in part by grant UO1 CA69417 from the National Institutes of Health.
The authors acknowledge the expert technical support of Alexandra Nachaev, Karen Head, and John Mikula.
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NOTES
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Correspondence to Dr. Valerie McGuire, Department of Health Research and Policy, HRP Redwood Building, Room T213C, Stanford University School of Medicine, Stanford, CA 94305-5405 (e-mail: vmcguire{at}stanford.edu). 
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