Oral Contraceptives and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

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1 Oral Contraceptives and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers Steven A. Narod, Marie-Pierre Dubé, Jan Klijn, Jan Lubinski, Henry T. Lynch, Parviz Ghadirian, Diane Provencher, Ketil Heimdal, Pal Moller, Mark Robson, Kenneth Offit, Claudine Isaacs, Barbara Weber, Eitan Friedman, Ruth Gershoni-Baruch, Gad Rennert, Barbara Pasini, Theresa Wagner, Mary Daly, Judy E. Garber, Susan L. Neuhausen, Peter Ainsworth, Hakan Olsson, Gareth Evans, Michael Osborne, Fergus Couch, William D. Foulkes, Ellen Warner, Charmaine Kim-Sing, Olufunmilayo Olopade, Nadine Tung, Howard M. Saal, Jeffrey Weitzel, Sofia Merajver, Marion Gauthier-Villars, Helena Jernstrom, Ping Sun, Jean-Sebastien Brunet Background: Oral contraceptive use has been associated with an increase in the risk of breast cancer in young women. We examined whether this association is seen in women at high risk of breast cancer because they carry a mutation in one of two breast cancer susceptibility genes, BRCA1 and BRCA2. Methods: We performed a matched case control study on 1311 pairs of women with known deleterious BRCA1 and/or BRCA2 mutations recruited from 52 centers in 11 countries. Women who had been diagnosed with breast cancer were matched to control subjects by year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of ovarian cancer. All study subjects completed a questionnaire about oral contraceptive use. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. All statistical tests were twosided. Results: Among BRCA2 mutation carriers, ever use of oral contraceptives was not associated with an increased risk of breast cancer (OR = 0.94, 95% CI = 0.72 to 1.24). For BRCA1 mutation carriers, ever use of oral contraceptives was associated with a modestly increased risk of breast cancer (OR = 1.20, 95% CI = 1.02 to 1.40). However, compared with BRCA1 mutation carriers who never used oral contraceptives, those who used oral contraceptives for at least 5 years had an increased risk of breast cancer (OR = 1.33, 95% CI = 1.11 to 1.60), as did those who used oral contraceptives before age 30 (OR = 1.29, 95% CI = 1.09 to 1.52), those who were diagnosed with breast cancer before age 40 (OR = 1.38, 95% CI = 1.11 to 1.72), and those who first used oral contraceptives before 1975 (OR = 1.42, 95% CI = 1.17 to 1.75). Conclusions: Among BRCA1 mutation carriers, women who first used oral contraceptives before 1975, who used them before age 30, or who used them for 5 or more years may have an increased risk of early-onset breast cancer. Oral contraceptives do not appear to be associated with risk of breast cancer in BRCA2 carriers, but data for BRCA2 carriers are limited. [J Natl Cancer Inst 2002;94: ] Women who inherit a germline mutation in breast cancer susceptibility genes BRCA1 or BRCA2 have a 50% 80% lifetime risk of developing breast cancer (1). The breast cancers typically occur in young women, often before 50 years of age. Although the majority of BRCA1-associated breast cancers are estrogen-receptor negative (2,3), factors that influence endogenous hormone levels appear to modify the breast cancer risk. For example, among mutation carriers, the risk of breast cancer is decreased by oophorectomy (4), and the risk of contralateral breast cancer is decreased by tamoxifen (5). By contrast, in young women with BRCA mutations, the risk of breast cancer Affiliations of authors: S. A. Narod, M.-P. Dubé, P. Sun, The Centre for Research on Women s Health, University of Toronto, Ontario, Canada; J. Klijn, Daniel den Hoed Cancer Center and Erasmus University Medical Center, Rotterdam, The Netherlands; J. Lubinski, Pomeranian Medical University, Szczecin, Poland; H. T. Lynch, Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE; P. Ghadirian, Epidemiology Research Unit, Centre hospitalier de l Université de Montréal (CHUM), Hôtel-Dieu, University of Montreal, Quebec, Canada; D. Provencher, Department of Obstetrics and Gynecology, Notre Dame Hospital, Montreal; K. Heimdal, P. Moller, Department of Cancer Genetics, Norwegian Radium Hospital, Oslo, Norway; M. Robson, K. Offit, Department of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; C. Isaacs, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC; B. Weber, Departments of Medicine and Genetics, University of Pennsylvania, Philadelphia; E. Friedman, Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel; R. Gershoni-Baruch, Institute of Genetics, Rambam Medical Center, Haifa, Israel; G. Rennert, National Cancer Control Center, Carmel Medical Center, Haifa; B. Pasini, Istituto Nazionale Tumori, Milan, Italy; T. Wagner, Department of Obstetrics and Gynecology, University of Vienna, Vienna, Austria; M. Daly, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA; J. E. Garber, Dana-Farber Cancer Institute, Boston, MA; S. L. Neuhausen, Department of Medical Informatics, University of Utah, Salt Lake City; P. Ainsworth, London Regional Cancer Center, London, Ontario, Canada; H. Olsson, H. Jernstrom, The Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden; G. Evans, St. Mary s Hospital, Manchester, U.K.; M. Osborne, Strang Cancer Prevention Center, New York; F. Couch, Mayo Clinic, Rochester, MN; W. D. Foulkes, Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal; E. Warner, Sunnybrook and Womens College Health Sciences Centre, Toronto; C. Kim-Sing, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; O. Olopade, Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL; N. Tung, Beth Israel Deaconess Hospital, Boston; H. M. Saal, Hereditary Cancer Program, Division of Human Genetics, Children s Hospital Medical Center, Cincinnati, OH; J. Weitzel, City of Hope Hospital, Duarte, CA; S. Merajver, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; M. Gauthier-Villars, Service de Genetique-Oncologique, Institute Curie, Paris, France; J.-S. Brunet, Algorithme Pharma, Montreal. Correspondence to: Steven A. Narod, M.D., Centre for Research on Women s Health, 790 Bay St., Rm. 750, Toronto, Ontario M5G 1N8, Canada ( steven.narod@swchsc.on.ca). See Notes following References. Oxford University Press Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002 ARTICLES 1773

2 appears to increase with pregnancy (6). Whether exogenous hormones in the form of oral contraceptives or hormone replacement therapy may also modify the risk of breast cancer in BRCA1 and BRCA2 mutation carriers is unknown. Long-term oral contraceptive use has been associated with a small increase in breast cancer risk in young women. In a metaanalysis of 54 studies (7), a relative risk of 1.24 was associated with current use of oral contraceptives (P<.001). The risk was elevated for 10 years after use of oral contraceptives was discontinued but was not influenced by a family history of breast cancer. This observation contrasts with a recent report of Grabick et al. (8) who found that oral contraceptive use increased the risk of breast cancer among women with a family history of breast cancer a threefold increased risk of breast cancer among sisters and daughters of women with breast cancer if the relatives took oral contraceptives. The increase was present only in women who had taken oral contraceptives before 1975 (when, on average, the estrogen content was higher than that in oral contraceptives produced after 1975). The BRCA status of the patients in the study by Grabick et al. (8) was unknown; however, given that the average age at diagnosis was 57 years for daughters and 60 years for sisters, it is unlikely that many of these women were BRCA mutation carriers. Although it appears that long-term use of oral contraceptives is associated with a modest increase in the risk of early-onset breast cancer in the general population, it is not known whether a similar association would be seen in BRCA mutation carriers. The issue is important because the baseline risk of breast cancer is very high in this subgroup and because hereditary breast cancer often appears in premenopausal women. Women at high risk of breast cancer may be reluctant to take oral contraceptives for fear of increasing their risk of breast cancer and may, therefore, forego the protective effects of oral contraceptives on ovarian cancer risk (9,10). The present study was conducted to examine whether the use of oral contraceptives influences the risk of breast cancer in high-risk women who carry a mutation in the BRCA1 or BRCA2 gene. SUBJECTS AND METHODS Study Population Eligible study subjects were women who were known carriers of deleterious mutations of the BRCA1 or BRCA2 gene. Eligible study subjects were identified from 52 centers in 11 countries. These women were participants in prior and ongoing clinical and research protocols at the host institutions. All study subjects received counseling and provided written consent for genetic testing for BRCA1 and BRCA2 mutations. For most women, genetic testing was initially offered to those who had been affected with breast cancer or ovarian cancer. When a BRCA1 or BRCA2 mutation was identified in a proband or her relative, genetic testing was then offered to other at-risk women in her family. The genetic testing involved several different techniques to detect BRCA1 or BRCA2 mutations. All abnormal nucleotide sequences were confirmed by direct sequencing of DNA. A subject was eligible for the current study after the molecular analysis established that she was a carrier of a pathogenic mutation. More than 95% of the mutations identified among study participants were either nonsense mutations, deletions, insertions, or small frameshifts (data not shown). Information on cancer history and contraceptive use was submitted to the data center in Toronto on a total of 4921 women who carried BRCA1 or BRCA2 mutations. We excluded women for several reasons, including incomplete oral contraceptive history (260 women) and missing information regarding ovarian cancer (10 women) or oophorectomy status (22 women), reproductive history (119 women), and age (nine women). Because oral contraceptives were introduced into general use in approximately 1960, we also excluded 61 women who were born before After these exclusions, there was a total of 4440 eligible women, including 2233 women with breast cancer (potential case subjects) and 2207 women without breast cancer (potential control subjects). Potential case subjects were selected from among the study subjects with a history of invasive breast cancer who were diagnosed from 1970 through We excluded 65 subjects diagnosed before 1970 because oral contraceptives use was infrequent in this subgroup and 47 subjects who were diagnosed with ovarian cancer before breast cancer (case subjects who were diagnosed with ovarian cancer after being diagnosed with breast cancer were eligible for the study). Furthermore, because of the strong protective effect of oophorectomy on the risk of breast cancer in BRCA carriers (4), we excluded 100 subjects who had an oophorectomy before their diagnosis of breast cancer. An attempt was made to identify a single matched control for each of the 2021 eligible breast cancer case subjects. Control subjects were women who had never had breast cancer but were known to be carriers of a mutation in the BRCA1 or BRCA2 gene. The control subject was matched to the case subject according to the gene with the mutation (BRCA1 or BRCA2), year of birth (within 2 years), and country of residence. All subjects were matched on the basis of the age of the case subject at the time of the breast cancer diagnosis. A subject was not eligible to be a control for a given case subject if she had a bilateral oophorectomy or a bilateral prophylactic mastectomy before the age of the matched case subject at the time of the breast cancer diagnosis. To be matched to a given case subject, the control had to be at least as old as the case subject at the time of diagnosis of breast cancer. A control subject with ovarian cancer was matched to a case subject with ovarian cancer; however, the age of the control subject at the time of the ovarian cancer diagnosis had to be greater than the age of the matched case subject at the time of the breast cancer diagnosis. Case subjects without ovarian cancer were matched to control subjects without ovarian cancer. Nine potential case subjects and two potential control subjects carried both a BRCA1 and a BRCA2 mutation. These subjects were eligible to be matched with a case or a control subject with either type of mutation. A total of 1311 matched case control pairs were generated for the analysis, including 981 pairs with BRCA1 mutations and 330 pairs with BRCA2 mutations. Of the case subjects (and their matched control subjects), 141 had been diagnosed with ovarian cancer. Between 1977 and 2001, case and control subjects completed a questionnaire that asked about their medical and reproductive histories, including past and current oral contraceptive use. Questionnaires were administered by each of the individual centers. They were completed by the subjects at the time of a clinic appointment or at their home at a later date. The subjects were asked at what age they began using an oral contraceptive, if they currently used an oral contraceptive, at what age they stopped 1774 ARTICLES Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002

3 taking an oral contraceptive, and the total duration of oral contraceptive use. No information was requested about the specific hormonal contraceptive formulation used. Subjects from Canada, Poland, Israel, and most U.S. sites completed a common questionnaire. However, subjects from other European countries and from several U.S. centers completed a similar, but not identical, instrument. For this study, only oral contraceptive use by case and control subjects before the time of the diagnosis of breast cancer in the matched case subject was considered. Additional variables of interest included ethnicity, smoking history (ever/never a regular smoker), parity, and ages at first and last live births. Only births that occurred before the onset of breast cancer in the case subject were considered. Only living women were eligible to participate in this study. This restriction was made because mutation testing can be done only if a blood sample is available and because of the difficulty in obtaining accurate information about oral contraceptive use from surrogate sources. For the case subjects, an average of 8.2 years had elapsed from the date of the breast cancer diagnosis when the questionnaire was completed. Data Analysis A matched case control analysis was performed. The mean duration of oral contraceptive use in the case and control subjects was compared by using Student s t test. This test statistic was also used for all other continuous variables. Univariate odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression. A multivariable analysis was also carried out by using conditional logistic regression controlling for parity and ethnicity. Parity was defined as zero, one, two, three, or more than three live births. Ethnicity/race was defined as French-Canadian, Jewish, other white, black, other nonwhite, or missing. All statistical tests were two-sided. The SAS statistical package, version 8.1 (SAS Institute, Cary, NC) was used for all analyses. Because there were a few instances in which the case and control subjects were from the same family, the confidence intervals surrounding the estimates were adjusted accordingly by using the robust sandwich estimator in SAS. RESULTS Study Subjects We identified a total of 1311 matched pairs for the case control analysis. The case and control subjects were similar with respect to the date of questionnaire completion, date of birth, current age, ethnicity, and country of residence (Table 1). There were no statistically significant differences in mean parity or in age at last birth, but a small difference was observed in mean age at first live birth (Table 2). Risk of Breast Cancer Associated With Oral Contraceptive Use Table 1. Comparison of case and control subjects with BRCA mutations* Variable Control subjects (N 1311) Case subjects (N 1311) Date of interview, mean year ± SD ± ± 2.0 Date of birth, mean year ± SD ± ± 10.3 Current age, mean ± SD 46.2 ± ± 10.0 Breast cancer, mean ± SD Year of diagnosis ± 6.9 Age at diagnosis 39.1 ± 8.1 Ovarian cancer, No. (%) No 1170 (89.2) 1170 (89.2) Yes 141 (10.7) 141 (10.7) Mutation, No. (%) BRCA1 981 (74.8) 981 (74.8) BRCA2 330 (25.2) 330 (25.2) Country of residence, No. (%) United States 600 (45.8) 600 (45.8) Canada 299 (22.8) 299 (22.8) Israel 101 (7.7) 101 (7.7) Poland 88 (6.7) 88 (6.7) The Netherlands 79 (6.1) 79 (6.1) Norway 59 (4.5) 59 (4.5) Italy 37 (2.8) 37 (2.8) U.K. 15 (1.1) 15 (1.1) Austria 15 (1.1) 15 (1.1) Sweden 14 (1.1) 14 (1.1) France 4 (0.3) 4 (0.3) Ethnicity, No. (%) Black 14 (1.1) 28 (2.1) French Canadian 97 (7.4) 99 (7.6) Jewish 391 (29.8) 414 (31.6) Other non-whites 6 (0.5) 11 (0.8) Other whites 801 (61.1) 754 (57.4) Missing 2 (0.1) 5 (0.4) *One BRCA2 carrier case subject was matched to a BRCA1/BRCA2 carrier control subject, four BRCA1/BRCA2 carrier case subjects were matched to BRCA1 carrier control subjects, and four BRCA1/BRCA2 carrier case subjects were matched to BRCA2 carrier control subjects. SD standard deviation. Where mean ages or years are given, the digit after the decimal place refers to tenths of a year. Table 2. Comparison of reproductive factors and smoking histories in case and control subjects with BRCA mutations Variable Control subjects Case subjects P value* Parity, No. (%) (20.6) 254 (19.4) (12.7) 191 (14.6) (36.7) 500 (38.1) (30.1) 366 (27.9).23 Parity, mean ± SD 2.0 ± ± Age at first live birth, mean ± SD 24.2 ± ± Age at last live birth, mean ± SD 28.7 ± ± Smoking history, No. (%) 717 (54.7) 689 (52.6).27 Ever 509 (38.8) 551 (40.0).10 Missing 85 (6.5) 71 (5.4).25 *All P values are univariate and were derived by using Student s t test. SD standard deviation. Oral contraceptives had been used by 69.7% of the case subjects and by 68.0% of the control subjects. Among all study participants, the average duration of oral contraceptive use was 3.9 years for the case subjects and 3.6 years for the control subjects (P.15). Among those who used oral contraceptives, the average duration of use was 5.3 years for the case subjects and 5.0 years for the control subjects (P.27). We examined the relationship between the risk of breast cancer and oral contraceptive use by multivariable conditional logistic regression (Table 3). Compared with those who had never used oral contraceptives, the OR of breast cancer for ever users of oral contraceptives was 1.18 (95% CI 1.01 to 1.38) for BRCA1 mutation carriers and 0.93 (95% CI 0.72 to 1.21) for Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002 ARTICLES 1775

4 Table 3. Association between breast cancer risk and oral contraceptive use stratified by BRCA mutation Variable Odds ratio (95% CI) P P trend Oral contraceptive use BRCA1 mutation carriers.03 Ever 1.20 (1.02 to 1.40) BRCA2 mutation carriers.68 Ever 0.94 (0.72 to 1.24) Duration of use, y BRCA1 mutation carriers (0.92 to 1.31) (1.11 to 1.67) (0.99 to 1.64) (0.91 to 1.87).15 BRCA2 mutation carriers (0.67 to 1.20) (0.56 to 1.91) (0.75 to 1.78) (0.71 to 2.56) *All P values were calculated using a multivariable conditional logistic regression model, adjusting for ethnicity and parity. P trend is based on increments of 5 years of exposure. CI confidence interval. BRCA2 mutation carriers. After adjusting for parity and ethnicity, the ORs were 1.20 (95% CI 1.02 to 1.40) for BRCA1 mutation carriers and 0.94 (95% CI 0.72 to 1.24) for BRCA2 mutation carriers (Table 3). Use of oral contraceptives appeared to have different effects among BRCA1 and BRCA2 mutation carriers. Because there was no evidence of an increased risk of breast cancer for BRCA2 mutation carriers and because the BRCA2 subgroup was relatively small (330 matched pairs), additional analyses were restricted to BRCA1 mutation carriers. Among BRCA1 mutation carriers, the ORs for breast cancer risk increased with duration of contraceptive use (Tables 3 and 4). For each additional year of oral contraceptive use, the OR increased by a factor of 1.02 (95% CI 1.00 to 1.03; P.02) relative to subjects who never used oral contraceptives. Compared with BRCA1 mutation carriers who never used oral contraceptives, the adjusted OR was 1.10 (95% CI 0.92 to 1.31 for those who used oral contraceptives for less than 5 years (P.30) and 1.33 (95% CI 1.11 to 1.60) for those who used oral contraceptives for 5 or more years (P.002). The overall mean age at breast cancer diagnosis was 38.6 years among the BRCA1 mutation carriers. The effect of oral contraceptives appeared to be greater for early-onset breast cancer than for breast cancers diagnosed after age 40, but the confidence intervals for the age-specific estimates are wide (Table 5). The multivariate OR for ever use of oral contraceptives was 1.38 (95% CI 1.11 to 1.72) for BRCA1 carriers who were diagnosed with breast cancer before age 40 and 0.96 (95% CI 0.75 to 1.24) for BRCA1 carriers who were diagnosed with breast cancer at age 40 or older. Case subjects took oral contraceptives for an average of 3.2 years before age 30, whereas control subjects took oral contraceptives for 2.9 years (P.03). After age 30, case subjects and control subjects took oral contraceptives for a mean of 0.7 years.42 (P.99). The OR for breast cancer risk associated with ever use of oral contraceptives before age 30 was 1.29 (95% CI 1.09 to 1.52). Compared with BRCA1 mutation carriers who never used an oral contraceptive, for each additional year of oral contraceptive use before age 30, the OR for the risk of breast cancer increased by 3% (OR 1.03, 95% CI 1.01 to 1.05). Compared with BRCA1 mutation carriers who never used oral contraceptives, those who began oral contraceptive use after age 30 were not at increased risk of breast cancer (OR 0.75, 95% CI 0.54 to 1.04) (P.08). We also considered the risk of breast cancer associated with recent use of oral contraceptives. There was a statistically nonsignificant trend with time since last use, with no apparent increased risk of breast cancer for women who recently took oral contraceptives. By contrast, women who stopped taking oral contraceptives 10 or more years earlier had a statistically significant increase in risk of breast cancer (OR 1.59, 95% CI 1.30 to 1.94; P<.001 (Table 4). We next examined the effect of oral contraceptive use before the first pregnancy. A total of 19.9% of the case subjects and 20.0% of the control subjects were nulliparous, and case subjects were 23.9 years old and control subjects were 24.4 years old at the time of their first live birth. Among women with one or more live births, 43.6% of case subjects and 43.6% of control subjects took an oral contraceptive before the first pregnancy (OR 1.20, 95% CI 0.95 to 1.52). Among women who took oral contraceptives, the average duration of oral contraceptive use before the first pregnancy was 2.6 years for case subjects and 2.6 years for control subjects (P.95). It has been suggested that oral contraceptives in use before Table 4. Association between breast cancer risk and oral contraceptive use in BRCA1 mutation carriers* Oral contraceptives variable Odds ratio (95% CI) Overall P P trend Contraceptive use.03 Ever 1.20 (1.02 to 1.52) Recent use of oral contraceptive Stopped >10 years ago 1.59 (1.30 to 1.94) <.001 Stopped within 6 10 years ago 1.10 (0.87 to 1.38).44 Stopped within 1 5 years ago 1.03 (0.81 to 1.32).81 Recent use 0.83 (0.66 to 1.04).11 Age at first use, y < (1.11 to 1.67) (1.10 to 1.64) (0.77 to 1.37) (0.54 to 1.04).08 Age at last use, y (0.84 to 1.56) (1.08 to 1.63) (0.98 to 1.47) (0.91 to 1.35) <.001 *All P values were calculated using a multivariable conditional logistic regression model, adjusting for ethnicity and parity. For duration of use, the overall P value is for a linear trend associated with increments of 5-year exposure. Recent use of oral contraceptive is defined as use within 1 year of the age at diagnosis of the matched case subject. 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5 Table 5. Association between breast cancer risk and ever use of oral contraceptive among BRCA1 mutation carriers, stratified by other factors* Ever used oral contraceptives Odds ratio (95% CI) P Year of birth (0.82 to 1.53) (0.91 to 1.57) (0.94 to 1.59).14 Year of diagnosis (1.16 to 3.40) (0.94 to 1.70) (0.90 to 1.36).32 Age at diagnosis, y < (1.11 to 1.72) (0.73 to 1.28).82 > (0.50 to 1.64).76 *All P values were calculated using a multivariable conditional logistic regression model, adjusting for ethnicity and parity. For each subgroup, the referent groups were those who never used oral contraceptives. CI confidence interval had a higher estrogen content than more recent formulations, and therefore may pose a greater risk. More case subjects (38.8%) than control subjects (33.6%) reported first oral contraceptive use before 1975 (OR 1.42, 95% CI 1.17 to 1.75; P<.001). The average cumulative duration of oral contraceptive use before 1975 was 1.2 years for case subjects and 0.9 years for controls (P.003). The average cumulative duration of oral contraceptive use after 1975 was 2.7 years for case subjects and 2.6 years for controls (P.67). Effects of Country of Residence, Ethnicity, and Smoking To reduce the potential effect of differences in the patterns of oral contraceptive use by country, we matched case and control subjects by country of residence. The use of oral contraceptives varied substantially by country (Table 6). Some variation in the effect of oral contraceptive use on breast cancer risk was observed with place of residence. For women residing in North America, the OR associated with 5 or more years of contraceptive use was 1.61 (95% CI 1.28 to 2.02), whereas for women who resided in Europe, the OR was 0.76 (95% CI 0.54 to 1.08), and for those in Israel, the OR was 1.71 (95% CI 0.91 to 3.21). Ethnicity also appeared to influence the effect of oral contraceptives on breast cancer risk because the OR was greater for Jewish ever users (OR 1.37, 95% CI 1.11 to 1.68) than for non-jewish ever users (OR 1.11, 95% CI 0.94 to 1.31). Among women who use oral contraceptives, the primary determinant of circulating levels of estrogen and progesterone is the dose of estrogen in the contraceptive (Jernstrom H: unpublished data). Among women who do not use oral contraceptives, several factors, including smoking, influence estrogen levels. We observed an associated between oral contraceptive use and smoking histories. The average duration of oral contraceptive use was 4.1 years in smokers compared with 3.3 years in nonsmokers (P<.001). However, after adjusting for smoking history in the multivariable analysis, the effect of oral contraceptives on breast cancer risk was not modified. Effects of Ovarian Cancer Diagnosis A small proportion (12.5%) of the study participants had been diagnosed with ovarian cancer. Because case subjects and control subjects were matched for history of ovarian cancer, it was possible to assess the effect of oral contraceptives in this subgroup. Among matched pairs with ovarian cancer, the OR for breast cancer risk associated with 5 or more years of contraceptive use was 3.29 (95% CI 1.61 to 6.73) and was higher than that for women with no history of ovarian cancer (OR 1.21, 95% CI 1.00 to 1.47). Effect of Time Since Diagnosis We studied prevalent case subjects of breast cancer and found that an average of 8.2 years had elapsed between the time of diagnosis and completion of the questionnaire. Therefore it is possible that if past oral contraceptive use is associated with breast cancer survival, then our results may not be representative of all incident cases of breast cancer in BRCA1 mutation carriers. However, there was no difference in the ORs associated with oral contraceptive use for women who completed the questionnaire within 5 years of their breast cancer diagnosis (OR 1.26, 95% CI 0.98 to 1.64) and those who completed the questionnaire 5 or more years after their breast cancer diagnosis (OR 1.13, 95% CI 0.93 to 1.37). Thus, survivorship bias is not a likely explanation for these findings. DISCUSSION Our study was conducted to examine whether oral contraceptive use increases the risk of breast cancer among women who Table 6. Geographic distribution of oral contraceptive use in case and control subjects with BRCA1 mutations* Ever users (%) Age at first use (mean ± SD) Duration of use (mean ± SD) Country No. of pairs Control Case Odds ratio (ever use) Control Case Control Case United States ± ± ± ± 5.0 Canada ± ± ± ± 4.5 U.K ± ± ± ± 4.1 Norway ± ± ± ± 3.5 Sweden ± ± ± ± 7.4 Italy ± ± ± ± 3.9 France ± ± 5.8 The Netherlands ± ± ± ± 5.5 Austria ± ± ± ± 4.7 Poland ± ± ± ± 1.1 Israel ± ± ± ± 5.8 *Case and control subjects were matched according to age at the time of breast cancer diagnosis and country of residence. Number of pairs refers to the number of matched case and control subjects from each country. Within each country, the odds ratio is for ever versus never users. SD standard deviation. Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002 ARTICLES 1777

6 carry a BRCA1 or BRCA2 mutation. Among BRCA1 mutation carriers who took oral contraceptives for 5 years or more, there was a statistically significant increase in breast cancer risk (OR 1.33, 95% CI 1.11 to 1.60; P.002) relative to BRCA1 mutation carriers who never took oral contraceptives. This risk increase was greater in selected subgroups. Modest increases in the risk of breast cancer were observed for women who were diagnosed with breast cancer before age 40 (Table 5), for women diagnosed with breast cancer before 1980 (Table 5), for women who used an oral contraceptive before age 30 (Table 4), and for women who used an oral contraceptive before The OR for breast cancer associated with 5 years of oral contraceptive use was 1.38 (95% CI 1.11 to 1.72) for women diagnosed before age 40 and 0.91 (95% CI 0.50 to 1.64) for women diagnosed after age 50 (Table 5). The risk of breast cancer also varied with the age at which oral contraceptives were first used. Case subjects were more likely to use oral contraceptives at some time before age 30 than were controls (OR 1.29, 95% CI 1.09 to 1.54; P.003) but were less likely to use oral contraceptives after age 30 (OR 0.75, 95% CI 0.54 to 1.04; P.08) (Table 4). We did not observe a statistically significant increase in breast cancer risk in BRCA2 carriers, but this subgroup was small, and further studies should be done to confirm these observations. Why oral contraceptives should be a risk factor for breast cancer when used before age 30 but not thereafter is not known. It is possible that this is chance variation because of our limited study size. A more likely possibility is that oral contraceptives may have different effects on the incidence of new cancers and the progression of existing cancers. One alternative possibility is that risk factors for breast cancer change with age. For example, differences in estrogen receptor status or in other pathologic features of the cancers may be present in different age groups, which may affect the responsiveness of the cancer to oral contraceptives. Another possibility is that use of oral contraceptives in the perimenopausal period reduces irregularity in menstrual cycle length, the frequency of ovulations, and levels of reproductive hormones, all of which may influence the risk of breast cancer. The observation that oral contraceptive use is a risk factor specifically for breast cancer diagnosed before age 40 is consistent with our previous observation that pregnancy is a risk factor for breast cancer in young BRCA carriers but has no apparent effect on the risk of breast cancer diagnosed after age 40 (6). The effects of ionizing radiation on breast cancer risk also appear to be greater for women with early exposure and for women with early-onset breast cancer (11). Compared with unexposed women, women exposed to the atomic bomb blast experienced a 14-fold increase in risk of breast cancer occurring before age 35 but only a twofold increase in risk of breast cancer occurring at age 35 or older. In addition, women who were exposed to radiation before age 20 experienced a much greater increase in breast cancer risk than women who were exposed after age 20, and women who were older than 40 years experienced almost no increase in risk (11). Together, these studies support the notion that certain genetic and environmental risk factors may have a greater impact on cancer risk in younger women. There has been a temporal change in the formulations of oral contraceptives in common use over the past several decades, and recent formulations may pose less of a hazard. Data from previous studies suggest that contraceptive use before 1975 was particularly hazardous (8). The duration of oral contraceptive use before 1975 was statistically significantly longer for case subjects than for control subjects (1.2 years versus 0.9 years; P.003). However, the difference in duration of use after 1975 was much smaller between the two groups (2.7 years versus 2.6 years; P.67). To some extent, this difference may explain why past use was found to be a greater risk factor than current use. However, these data do not explain why there was an effect seen in North America and Israel but not in Europe. It should be noted that we do not have specific information regarding the formulations used in the different countries. The principal strength of our study is that it is based on a large sample of known BRCA carriers. The study involved 1311 matched pairs selected from a total of approximately 5000 documented mutation carriers and is by far the largest such study to date. Previous studies addressing the effect of oral contraceptives on the risk of hereditary breast cancer have either been very small (12) or have used family history as a surrogate for hereditary cancer (8). Our matching strategy resulted in the generation of case and control groups that were similar in most respects (Table 1). We believe that matching and exclusion provided the benefit of minimizing confounding effects. Oral contraceptive use is strongly dependent on birth cohort; for example, among our control subjects, the average duration of use was 1.9 years for women born before 1940 and 3.4 years for women born between 1940 and There was also substantial variation in oral contraceptive use by country (Table 6). By matching case and control subjects by year of birth and country of residence, it was possible to eliminate potential spurious effects of oral contraceptive use associated with calendar period and country of residence. Because oophorectomy is associated with both fertility and breast cancer risk, women with a previous oophorectomy were excluded from this study. There are several limitations to our study. First, we studied prevalent cases drawn from families with breast cancer. In theory, a better study design might be a population-based study of incident cancer cases of hereditary breast cancer. However, such a study would require genetic testing of unselected breast cancer case subjects (approximately 2% of all case subjects are carriers) and would either be very small or prohibitively expensive. Prospective studies of healthy carriers are a possibility the incidence of breast cancer is approximately 2 per 100 per year in BRCA carriers (13,14) and, therefore, if 1000 healthy carriers were followed for 10 years, we would expect to identify 200 incident cases of breast cancer. However, with the dissemination of tamoxifen, oophorectomy, and mastectomy as riskreducing measures, it is likely that cohort studies will yield fewer case subjects. Our case subjects were interviewed an average of 8.2 years after diagnosis. Because we used prevalent rather than incident cancers, any relationship between past oral contraceptive use and tumor-specific survival may result in a bias in the estimate of the odds ratio. Second, our study was based on familial cancer cases, which may not be representative of all mutation carriers in the population. It is possible that the results would differ if unselected case subjects were to be used, but the great majority of women who are currently undergoing genetic testing do so because of a family history of cancer. Our subjects originated from 52 genetics centers in 11 countries and carried a wide range of mutations. With the exception of the four countries that contributed fewer 1778 ARTICLES Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002

7 than 20 matched sets, the results of the study were similar across countries (Table 6). Third, we studied a relatively young group of breast cancer patients. The mean age at breast cancer diagnosis in our case subjects was 39.1 years due, to some extent, to our exclusions and our matching strategy (there were relatively few control subjects available to match to the older case subjects), and they may not be representative of all cases of BRCA-associated breast cancer. The mean age at breast cancer diagnosis of the 710 women who were not included in the study was 45.0 years. Fourth, because this was a retrospective study, history of oral contraceptive use was dependent on patient recall, and the exact formulation or estrogen content was not known. It is possible that there is some inaccuracy in the recall of past oral contraceptive use, although it is unlikely that results based on the ever use/never use variable are inaccurate. Finally, ours is a single study, and multiple subgroup evaluations were made. It is important that our findings be verified in an independent population. We have previously shown that oral contraceptives protect against ovarian cancer in BRCA1 and BRCA2 mutation carriers (9,10), but there has been a contradictory report as well (15). Use of oral contraceptives for 5 years was associated with a statistically significantly decreased risk of ovarian cancer of approximately 60% (9). We did not observe a statistically significant increase in breast cancer risk associated with use of oral contraceptives for less than 5 years or in women who first used oral contraceptives after We therefore support the use of short-term oral contraceptives as a measure for reducing ovarian cancer risk in BRCA carriers. For women with BRCA1 mutations, consideration of the use of oral contraceptives should be discussed in light of anticipated preventive surgery to reduce the risk of breast or ovarian cancer. For example, women who undergo bilateral mastectomy but who have two ovaries intact should be good candidates for oral contraceptives, but women who undergo bilateral oophorectomy but not mastectomy may not benefit. Women who undergo a prophylactic oophorectomy are at risk of primary peritoneal cancer, and it remains to be determined whether oral contraceptives reduce the risk of peritoneal cancer in carriers of BRCA mutations. It is also important that the woman s age be considered if an oral contraceptive is to be prescribed. In particular, it appears that oral contraceptive use after age 30 is not likely to increase the risk of breast cancer among BRCA1 mutation carriers and can be used safely to reduce the risk of ovarian cancer. REFERENCES (1) Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Lancet 1994;343: (2) Johannsson OT, Idvall I, Anderson C, Borg A, Barkardottir RB, Egilsson V, et al. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997;33: (3) Karp SE, Tonin PN, Begin LR, Martinez JJ, Zhang JC, Pollak MN, et al. Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women. Cancer 1997;80: (4) Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Lynch HT, et al. Reduction in breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 1999;91: (5) Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen S, et al. Tamoxifen and the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers. Lancet 2000;356: (6) Jernstrom H, Lerman C, Ghadirian P, Lynch HT, Weber B, Garber J, et al. Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 1999;354: (7) Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347: (8) Grabick DM, Hartmann LC, Cerhan JR, Vierkant RA, Therneau TM, Vachon CM, et al. Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 2000;284: (9) Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, Olsson H, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339: (10) Narod SA, Sun P, Ghadirian P, Lynch H, Isaacs C, Garber J, et al. Tubal ligation and the risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations. Lancet 2001;357: (11) Tokunaga M, Land CE, Tokuoka S, Nishimori I, Soda A, Akiba S. Incidence of female breast cancer among atomic bomb survivors, Radiat Res 1994;138: (12) Ursin G, Henderson BE, Haile RW, Pike MC, Zhou N, Diep A, et al. Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 1997; 57: (13) Meijers-Heijboer H, van Geel B, van Putten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345: (14) Liede A, Karlan BY, Baldwin RL, Platt LD, Kuperstein G, Narod SA. Cancer incidence in a population of Jewish women at risk of ovarian cancer. J Clin Oncol 2002;20: (15) Modan B, Hartge P, Hirsch-Yechezkel G, Chetrit A, Lubin F, Beller U, et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. New Engl J Med 2001; 345: NOTES Supported by the Canadian Breast Cancer Research Initiative; the Canadian Breast Cancer Foundation (Ontario Chapter); the Canadian Genetics Diseases Network; Public Health Service grants RO and CA74415 from the National Institutes of Health, Department of Health and Human Services; grant RPG CCE from the American Cancer Society and the Kirby Foundation; the Utah Cancer Registry; and the Utah State Department of Health. We thank B. Rosen, B. Karlan, D. Fishman, N. Lindor, A. Chudley, D. Gilchrist, W. McKinnon, M. Wood, C. Eng, G. Mills, K. Hughes, S. Baldinger, M. K. Dabney, and E. Lemire for submission of data on their patients and C. Springate, D. Hanna, A. Liede, J. Everett, K. Huelsman, H. Meijers-Heijboer, E. Crepin, and L. Steele for help with data collection. Manuscript received January 4, 2002; revised August 14, 2002; accepted September 23, Journal of the National Cancer Institute, Vol. 94, No. 23, December 4, 2002 ARTICLES 1779