Oral Contraceptives and the Risk of Hereditary Ovarian Cancer
Steven A. Narod, M.D., Harvey Risch, M.D., Ph.D., Roxana Moslehi, M.Sc., Anne Dørum, M.D., Susan Neuhausen, Ph.D., Hakan Olsson, M.D., Diane Provencher, M.D., Paolo Radice, Ph.D., Gareth Evans, M.D., Susan Bishop, M.Sc., Jean-Sébastien Brunet, M.Sc., Bruce A.J. Ponder, M.D., Ph.D., Jan G.M. Klijn, M.D., for The Hereditary Ovarian Cancer Clinical Study Group
Background Women with mutations in either the BRCA1 or the BRCA2gene have a high lifetime risk of ovarian cancer. Oral contraceptivesprotect against ovarian cancer in general, but it is not knownwhether they also protect against hereditary forms of ovariancancer.
Methods We enrolled 207 women with hereditary ovarian cancerand 161 of their sisters as controls in a case–controlstudy. All the patients carried a pathogenic mutation in eitherBRCA1 (179 women) or BRCA2 (28 women). The control women wereenrolled regardless of whether or not they had either mutation.Lifetime histories of oral-contraceptive use were obtained byinterview or by written questionnaire and were compared betweenpatients and control women, after adjustment for year of birthand parity.
Results The adjusted odds ratio for ovarian cancer associatedwith any past use of oral contraceptives was 0.5 (95 percentconfidence interval, 0.3 to 0.8). The risk decreased with increasingduration of use (P for trend, <0.001); use for six or moreyears was associated with a 60 percent reduction in risk. Oral-contraceptiveuse protected against ovarian cancer both for carriers of theBRCA1 mutation (odds ratio, 0.5; 95 percent confidence interval,0.3 to 0.9) and for carriers of the BRCA2 mutation (odds ratio,0.4; 95 percent confidence interval, 0.2 to 1.1).
Conclusions Oral-contraceptive use may reduce the risk of ovariancancer in women with pathogenic mutations in the BRCA1 or BRCA2gene.
Approximately 10 percent of cases of invasive epithelial ovariancancer are hereditary, occurring predominantly in women withgerm-line mutations in the BRCA1 or the BRCA2 gene (unpublisheddata). The lifetime risk of ovarian cancer is approximately45 percent among women with BRCA1 mutations and 25 percent amongthose with BRCA2 mutations.1,2,3
Current strategies for reducing the risk of ovarian cancer inwomen carrying BRCA1 or BRCA2 mutations include prophylacticoophorectomy and ultrasound screening, but the extent of riskreduction associated with either of these procedures is notknown.4 A third potential strategy is chemoprevention. The riskof ovarian cancer is reduced by 50 percent or more in unselectedwomen with long-term use of oral contraceptives.5,6 An oralcontraceptive agent is appealing as a possible preventive treatment,because these agents are well tolerated and their side effectsare known. To evaluate the potential benefit of oral-contraceptiveuse in women at high risk for ovarian cancer, we studied 207patients with BRCA1 or BRCA2 mutations and ovarian cancer and161 of their sisters, who served as controls.
Methods
Subjects
The patients were 207 women born between 1925 and 1960 in whominvasive epithelial ovarian cancer had been diagnosed and whowere found by molecular testing to carry a germ-line mutationin either the BRCA1 or the BRCA2 gene (Table 1). They were identifiedin three ways. Sixteen were women in whom ovarian cancer hadbeen diagnosed in Ontario, Canada, after January 1, 1995. Twenty-sixwere Ashkenazi Jewish women with a history of ovarian cancerwho were identified from the gynecology–oncology recordsof 11 hospitals in North America. One hundred sixty-five werewomen identified by members of the Breast Cancer Linkage Consortium:37 from the United Kingdom, 39 from other European countries,67 from the United States, and 22 from Canada. The women's averageages at the time of diagnosis in the three groups were 49, 52,and 49 years, respectively.
Table 1. Characteristics of Patients with Ovarian Cancer and Control Women.
All living sisters of the patients who were born between 1925and 1960 were eligible to be control subjects. The use of thesewomen as controls ensured that the geographic and ethnic characteristicsof the patients and the control women would be similar. Furthermore,the sisters had the same a priori familial risk of ovarian canceras the patients; that is, before the diagnosis of breast orovarian cancer in the latter, both a patient and her sisterwould have had the same risk of ovarian cancer on the basisof family history alone. Fifty-one of the patients had no sisters,and no information on family history was available for another12 patients. The remaining 144 patients had a total of 328 sisters.Of these, 167 sisters were not studied because they had died,had ovarian cancer (these women were invited to be study patients),were born before 1925 or after 1960, were too ill to respond,or were unwilling to be questioned. Thus, there were 161 controlwomen, or 0.8 per patient (range, 0 to 7).
Data on mutations were available for 95 of the 161 control women.According to molecular testing, 53 were carriers of the sameBRCA1 or BRCA2 mutations as their sisters, and 42 were not carriers.Ideally, the group of control women would have been restrictedto mutation-positive women who did not have ovarian cancer andhad not undergone oophorectomy at the age at which ovarian cancerwas diagnosed in their sisters. However, this approach was impractical,because there were only 42 unaffected mutation-positive sisterswho had both ovaries at the time of the diagnosis of ovariancancer in their sisters. Women with a history of breast cancerwere not excluded from the study; 63 of the patients (30 percent)and 29 of the control women (18 percent) had a previous diagnosisof breast cancer.
Analysis of Mutations
Mutation analysis was performed by several established detectiontechniques, and all mutations were confirmed by direct sequencingof DNA samples. For the women in Ontario, DNA samples were screenedby the protein-truncation test for mutations in exons 10 and11 of BRCA1 and exon 11 of BRCA2.7 The Ashkenazi Jewish womenwere screened for three founder mutations, two in BRCA1 (185delAGand 5382insC) and one in BRCA2 (6174delT).8 The women in thegroup identified by the Breast Cancer Linkage Consortium werescreened for mutations by techniques routinely used in the participatinglaboratories. These techniques included direct sequencing ofDNA, heteroduplex analysis, single-strand conformation analysis,and allele-specific oligonucleotide hybridization. In everywoman, the actual sequence variant in BRCA1 or BRCA2 was establishedby direct sequencing of DNA.
Study Protocol
The patients and control women were asked about their reproductivehistories, methods of contraception (including use of oral contraceptiveagents and tubal ligation), and history with respect to oophorectomy.The women were asked at what age they first took an oral contraceptive,at what age they stopped, and the total duration of oral-contraceptiveuse. No information was requested about the specific oral contraceptiveagent taken. Two patients had undergone unilateral oophorectomyfor a benign condition before the diagnosis of ovarian cancer.Among the control women, 72 had undergone oophorectomy (5 unilateraland 67 bilateral). The average age at the time of bilateraloophorectomy was 45 years.
Statistical Analysis
The mean duration of oral-contraceptive use in the patientsand control women was compared by the nonparametric Wilcoxontwo-sample test. Odds ratios were estimated by unconditionallogistic-regression analysis with control for other covariates,including geographic area of residence (United States, Canada,United Kingdom, or elsewhere in Europe), year of birth, parity,and age at delivery of a first child. The last three variableswere included as continuous terms.
To control for possible confounding effects of ethnic group,a separate matched analysis was performed. Patients were matchedwith their sisters, and conditional logistic regression formatched sets (with variable ratios of patients to controls)was performed. This analysis was based on 89 case–controlpairs, because patients with no sisters were excluded. All statisticaltests were two-sided.
Results
The characteristics of the 207 patients with ovarian cancerand the 161 controls were similar (Table 1). Fifty percent ofthe patients and 70 percent of the control women reported ahistory of oral-contraceptive use (P<0.001). The averageduration of oral-contraceptive use for the patients was fouryears, significantly less than the average duration for thecontrol women (six years; P=0.01).
Among the 207 patients, 179 had BRCA1 mutations and 28 had BRCA2mutations. Among the 161 control women, 53 were known to havemutations (50 had BRCA1 mutations and 3 had BRCA2 mutations)and 42 were known to be noncarriers; the remaining 66 were nottested. In these three subgroups of women, a history of oral-contraceptiveuse was reported by 77 percent, 64 percent, and 67 percent,respectively (as compared with 50 percent of the patients).The average duration of use was also greater for each of thethree subgroups of control women (five, five, and seven years,respectively) than for the patients (four years). Because theduration of oral-contraceptive use was similar in the threesubgroups of control women, and because of the small sizes ofthose subgroups, they were combined for most of the multivariateanalyses. The pattern of oral-contraceptive use did not differsignificantly between the control women who had undergone bilateraloophorectomy (69 percent; mean duration of use, five years)and those with both ovaries (72 percent; mean duration of use,six years; P=0.37).
The odds ratios for ovarian cancer associated with oral-contraceptiveuse according to unconditional logistic-regression analysisare shown in Table 2. The risk of ovarian cancer decreased withthe duration of use (multivariate P for trend, <0.001). Womenwho took an oral contraceptive agent for six or more years hada reduction in risk of 60 percent. The reduction in risk wassimilar for carriers of the BRCA1 and BRCA2 mutations. The oddsratio for carriers of the BRCA1 mutation who had used oral contraceptives,as compared with those who had not, was 0.5 (95 percent confidenceinterval, 0.3 to 0.9), and that for carriers of the BRCA2 mutationwas 0.4 (95 percent confidence interval, 0.2 to 1.1). Adjustmentsfor parity, age at the delivery of a first child, and age atthe delivery of a last child did not significantly change themagnitude of the odds-ratio estimates associated with oral-contraceptiveuse.
Table 2. Association between Oral-Contraceptive Use and Risk of Ovarian Cancer.
The results of the matched analysis were very similar to thoseshown in Table 2. The odds ratios for ovarian cancer were 0.9(95 percent confidence interval, 0.4 to 2.1), 0.4 (95 percentconfidence interval, 0.2 to 1.2), and 0.3 (95 percent confidenceinterval, 0.1 to 0.7) for oral-contraceptive use for less thanthree years, three to less than six years, and six or more years,respectively (P=0.02).
Among the 63 patients who had had breast cancer in additionto ovarian cancer, the average duration of oral-contraceptiveuse was five years, as compared with four years among thosewho had not had breast cancer. The average duration of oral-contraceptiveuse was six years among the 29 control women who had had breastcancer and among those who had not had breast cancer.
Discussion
In this multicenter case–control study, the use of oralcontraceptives was associated with a significant reduction inthe risk of ovarian cancer among women with a mutation in theBRCA1 or BRCA2 gene. The reduction in risk was 20 percent forup to three years of use, rising to 60 percent for six or moreyears of use.
The magnitude of the protective effect of oral contraceptivesin carriers of BRCA1 and BRCA2 mutations is consistent withthat previously found in the general population. In a meta-analysisof 12 case–control studies of oral-contraceptive use andthe risk of ovarian cancer in the United States,9 the risk decreasedwith increasing length of oral-contraceptive use. In the sixpopulation-based studies, the risk reduction was 34 percentfor those who had ever used oral contraceptives and 70 percentfor those with six or more years of use. In the six hospital-basedstudies, the corresponding risk reductions were 30 percent and45 percent, respectively.
The strengths of the present study are that the cases of ovariancancer were identified through a large international consortium,all patients with ovarian cancer were confirmed carriers ofmutations, and the control group consisted of sisters of thepatients. We think the smaller size of the control group iscounterbalanced by the similarity of the control women to thepatients, because by definition they shared the same familyhistory, were members of the same ethnic group, and were fromthe same geographic region.
Ashkenazi Jewish women were somewhat overrepresented among thepatients and French-Canadian women among the controls. Thesedifferences reflect the average family size of women from thetwo ethnic groups, rather than the willingness of the sistersof the patients to participate. On average, a Jewish woman had1.2 sisters, and a French-Canadian woman had 4.5 sisters. Inother respects, the patients and control women were well matched.
The ideal control group for this study might be sisters of thepatients who still had both their ovaries and who carried thesame mutation but in whom ovarian cancer had not developed bythe age at which it was diagnosed in their sisters. Unfortunately,we could not identify sufficient numbers of control women withthese characteristics, and we therefore extended the controlgroup to include all unaffected living sisters of the patients.Nevertheless, more of the sisters with and without mutationsin BRCA1 or BRCA2 than patients had used oral contraceptives.The extent of misclassification introduced by the inclusionof sisters without mutations is likely to be minimal, giventhe similarity of the results of the analysis based on all controlwomen and on only sisters with mutations. Furthermore, if theuse of oral contraceptives protects against ovarian cancer,then a higher proportion of women with mutations who did nothave ovarian cancer would have been expected to have taken oralcontraceptives. This was true: 77 percent of the control womenwith mutations had taken oral contraceptives, as compared with64 percent of those without mutations.
Our study included control women who had undergone oophorectomy.Fewer of these women might have taken oral contraceptives thanexpected if the oophorectomy was performed before menopause.However, there was little difference in the frequency of useof oral contraceptives between control women who had had theirovaries removed and those who had not. Selection bias of thistype should lead to underestimation of the magnitude of therisk reduction associated with oral-contraceptive use.
Adjustment for parity, the presence or absence of tubal ligation,and ages at the delivery of a first and last child did not influencethe protective effect of oral-contraceptive use. Increasingparity appears to be protective against hereditary ovarian cancer,as it is for ovarian cancer in the general population.9 Thereare no other known risk factors for ovarian cancer that arelikely to have been confounders in the present study.
A limitation of this study is that it included only living womenwith ovarian cancer as case patients. This was true becauseof the difficulty of ascertaining whether deceased patientshad carried mutations and of obtaining an accurate history ofcontraceptive use in interviews with surrogates. If oral-contraceptiveuse is associated with a higher case fatality rate for ovariancancer, then this selection strategy will exaggerate the protectiveeffect of oral contraceptives. On average, the women in ourstudy stopped using oral contraceptives 17 years before thediagnosis of ovarian cancer, and only 12 women had taken anoral contraceptive agent during the 5-year period before diagnosis.
It is important to establish whether the risk of breast cancerin women with BRCA1 or BRCA2 mutations is influenced by oral-contraceptiveuse, especially if oral contraceptives are to be recommendedto healthy carriers as chemopreventive agents. Oral-contraceptiveuse has been associated with a small increase in the risk ofbreast cancer in young9 and older10 women. In a large meta-analysis,current use of oral contraceptives was associated with a relativerisk of 1.2 for breast cancer, and past use was associated witha relative risk of 1.1. However, there was no increased riskin the subgroup of women with a family history of breast cancer(defined as having a mother or sister affected). In one studyof Jewish women with breast cancer, the frequency of long-termoral-contraceptive use was higher among women who had a BRCA1or BRCA2 mutation than among women without a mutation.11 Wefound no difference in the history of oral-contraceptive usebetween women who had had breast cancer and those who had not,but our study was not specifically designed to evaluate thisissue.
Our data suggest that the administration of an oral contraceptiveagent should be considered as part of a program of preventionfor women with BRCA1 or BRCA2 mutations who have not had ovariancancer. However, our data do not allow us to address the specificformulation to be recommended or the age at which treatmentshould begin.
Supported by grants from the National Institutes of Health (1R01CA63682, CA63678, CA57601, CA61231, and CA55914), the NationalCancer Institute of Canada Breast Cancer Initiative, the Departmentof the Army (DAMD17-94-J-4299 and DAMD 17-94-J-4260), the CanadianGenetic Diseases Network, the Canadian Breast Cancer Foundation(Ontario chapter), the Fonds de la Recherche en Santédu Québec, the Women's Cancer Program of the Dana–FarberCancer Institute, and the Norwegian and Dutch Cancer Societies.
* Other members of the study group are listed in the Appendix.
Source Information
From the Centre for Research on Women's Health, Women's College Hospital, University of Toronto, Toronto (S.A.N., S.B., J.-S.B.); the Department of Epidemiology and Public Health, Yale University, New Haven, Conn. (H.R.); the Department of Medical Genetics, University of British Columbia, Vancouver, Canada (R.M.); the Unit of Medical Genetics, Norwegian Radium Hospital, Oslo, Norway (A.D.); the Department of Medical Informatics, University of Utah, Salt Lake City (S.N.); the Department of Oncology, Lund University, Lund, Sweden (H.O.); the Department of Obstetrics and Gynecology, Notre Dame Hospital, Montreal (D.P.); the Istituto Nazionale Tumori, Milan, Italy (P.R.); the Department of Medical Genetics, St. Mary's Hospital, Manchester, United Kingdom (G.E.); and the Cancer Research Campaign Genetic Epidemiology Unit, Cambridge University, Cambridge, United Kingdom (B.A.J.P.). Jan G.M. Klijn, M.D. (Department of Medical Oncology, Rotterdam Cancer Institute, Rotterdam, the Netherlands), was also an author.
Address reprint requests to Dr. Narod at the Centre for Research on Women's Health, Women's College Hospital, 790 Bay St., Rm. 750a, Toronto, ON M5G 1N8, Canada.
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Appendix
Other members of the Hereditary Ovarian Cancer Clinical StudyGroup are as follows: Montreal: W. Foulkes, P. Tonin, J. Rosenblatt,P. Ghadirian, C. Perret, A.-M. Mes-Masson, and B. Godard; Toronto:B. Rosen, D. Cole, J. McLaughlin, J. Murphy, L. Bradley, I.Fan, J. Abrahamson, and E. Warner; Philadelphia: T. Rebbeck,B. Weber, F. Couch, M. Daly, A. Godwin, and J. Wagner-Costalos;Washington, D.C.: C. Lerman and B. Peshkin; Durham, N.C.: A.Futreal and J. Lancaster; Chicago: O. Olopade and S. Cummings;Salt Lake City: L. Cannon-Albright and L. Steele; Boston: J.Garber and N. Tung; Omaha, Nebr.: H. Lynch, J. Lynch, C. Snyder,and C. Durham; Los Angeles: B. Karlan; New Hyde Park, N.Y.:D. Smotkin; New York: A. Fields, D. Russo, and K. Antman; Cambridge,United Kingdom: D. Ford and D. Easton; Lyons, France: G. Lenoir,O. Serova, and S. Mazoyer; Rotterdam, the Netherlands: E. Meijers-HeijBoerand L. Verhoog; Manchester, United Kingdom: F. Laloo; Lund,Sweden: O. Johannson and A. Borg; and Oslo, Norway: P. Moller.
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