Correspondence
Ovarian Cancer, Oral Contraceptives, and BRCA Mutations
N Engl J Med 2001; 345:1706-1707December 6, 2001
- Article
To the Editor:
Modan and colleagues (July 26 issue)1 conclude that oral contraceptives do not protect against ovarian cancer in Israeli Jewish women carrying BRCA mutations. We have shown, in two studies of Jewish and non-Jewish women with BRCA mutations, that the use of oral contraceptives was strongly protective against ovarian cancer.2,3 In our recent study, the odds ratio for ovarian cancer among women who had used oral contraceptives was 0.44 (95 percent confidence interval, 0.28 to 0.68).3
Relevant differences may exist between Jews and non-Jews, between carriers of the three founder mutations common among Jews and carriers of other predisposing mutations, or between North Americans and Israelis (including the types of contraceptive pills used). To resolve the discrepancy in results between our studies and that of Modan et al., we report the results of a new case–control study of 186 women with ovarian cancer and 186 individually matched controls, all of whom were Ashkenazi Jews with BRCA mutations. These subjects were drawn from a registry of families with cancer and from a study of patients with cancer who were not selected on the basis of family history.4 Patients had invasive ovarian cancer; controls did not, and they had both ovaries intact. Patients and controls were matched for year of birth (within one year), mutation (BRCA1 vs. BRCA2), and place of residence (Israel or North America). There were 150 pairs with BRCA1 mutations (185delAG or 5382insC), and 36 pairs with BRCA2 mutations (6174delT); 151 pairs were from North America, and 35 were from Israel. Information on oral-contraceptive use was obtained as previously described.2,3
The odds ratio for ovarian cancer among women who had used oral contraceptives was 0.54 (95 percent confidence interval, 0.35 to 0.84; P=0.005); the mean duration of use in this group was 4.8 years for controls and 4.3 years for patients. This corresponds to a reduction in risk of 4.4 percent for each year of use (P=0.056). Six percent of Israeli patients and 23 percent of Israeli controls used oral contraceptives for five years or more, as compared with 18 percent of North American patients and 25 percent of North American controls. The odds ratio for ovarian cancer in the group that had used oral contraceptives for five or more years was 0.45 among North American women (95 percent confidence interval, 0.23 to 0.87) and 0.14 among Israeli women (95 percent confidence interval, 0.02 to 1.25).
Important differences between the two studies include the source of patients (we used both those drawn from a cancer registry and those not selected with respect to family history) and controls (all of our controls were mutation carriers, as compared with 1.7 percent of those in the study by Modan et al.). Nevertheless, we believe that the main reason for the discrepant results is that the controls in the study by Modan et al. were not comparable to the subgroup of patients with BRCA mutations. The controls were matched to all the patients with invasive ovarian cancer, but patients carrying BRCA1 mutations are, on average, 7 to 10 years younger at the time of the diagnosis of ovarian cancer than women with sporadic cases.5 Thus, the controls were born appreciably earlier than the patients with BRCA mutations, and in that older generation, fewer women had had long-term exposure to oral contraceptives. In fact, in the study by Modan et al., only 8.5 percent of the Israeli controls had used oral contraceptives for five or more years, as compared with 23 percent in our study. Modan et al. attempted to adjust for the difference in the year of birth by including age (in decades) in the logistic-regression analysis, but we believe that this adjustment was inadequate. Our controls were matched for age within one year. We believe that oral contraceptives are effective in reducing the risk of ovarian cancer in women with BRCA mutations, including Jewish women.
5 ReferencesSteven A. Narod, M.D.
Ping Sun, Ph.D.
University of Toronto, Toronto, ON M5G 1N8, Canada
steven.narod@swchsc. on. ca Harvey A. Risch, M.D., Ph.D.
Yale University School of Medicine, New Haven, CT 06510-8034for the Hereditary Ovarian Cancer Clinical Study Group
1
Modan B ,Hartge P ,Hirsh-Yechezkel G , et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:235-240
Full Text | Web of Science | Medline2
Narod SA ,Risch H ,Moslehi R , et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424-428
Full Text | Web of Science | Medline3
Narod SA ,Sun P ,Ghadirian P , et al. Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 2001;357:1467-1470
CrossRef | Web of Science | Medline4
Moslehi R ,Chu W ,Karlan B , et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 2000;66:1259-1272
CrossRef | Web of Science | Medline5
Risch HA ,McLaughlin JR ,Cole DEC , et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001;68:700-710
CrossRef | Web of Science | Medline
To the Editor:
Modan et al. show how genetic testing can be used to provide clear health directives under defined circumstances. Ashkenazi Jewish women with a founder mutation in their BRCA1 or BRCA2 gene should now be told that multiparity has a protective effect against ovarian cancer but that the use of oral contraceptives does not. However, there are currently 864 known mutations, polymorphisms, or variants of BRCA1 alone. What should women who have one of these forms be told?
At least one founder mutation (185delAG) probably results in a BRCA1 protein with no activity. Other, non-founder mutations presumably code for a protein with some residual function. Because cancer is a multistep process, mutations in other genes besides BRCA1 must be involved. In fact, some BRCA1 mutations damage the body's ability to repair DNA and thereby facilitate mutations in these other genes. Thus, the use of oral contraceptives may well protect women with some non-founder mutations. All these points may help explain the discrepancies in the literature regarding factors that confer protection against ovarian cancer.
In the future it will be helpful for a clinician to know whether a woman has a BRCA mutation that results in residual function, destabilizes other genes, or requires the presence of specific mutations and whether the mutation is one of a group with similar functional consequences. The clinician can use this information to determine which studies are likely to be relevant and to assess risks more accurately. We still have a great distance to go before we arrive at the best way to deal with a BRCA-mutation carrier in the clinic, but the work of Modan et al. shows us the way.
Bernard Friedenson, Ph.D.
University of Illinois, Chicago, Chicago, IL 60612
molmeddoc@yahoo.com Author/Editor Response
The authors reply:
To the Editor: As Friedenson notes, ideally, clinical advice should be individualized to reflect a patient's mutation. But even with the relatively high prevalence of founder mutations among Israeli Jews, the number of women with each specific mutation is too small to allow a separate assessment of the effect of reproductive factors that has any degree of precision. A better understanding of the functional consequences of these rare mutations is probably required before we will be able to provide tailored clinical advice.
As Narod et al. note, in our case–control study involving the total population of Israeli Jews, our finding of an absence of evidence that the use of oral contraceptives protects against ovarian cancer among women with BRCA1 and BRCA2 mutations differs from the findings of their clinic-based study. They speculate that the reason for the discrepancy is that the disease is diagnosed at a much younger age in women who have a mutation than in women who do not have a mutation, and consequently, few carriers in our study had a long duration of oral-contraceptive use. In fact, the average age at diagnosis was less than three years younger in carriers than in noncarriers. Adjustment for age in pentads instead of decades made only a trivial difference in our findings; the reduction in risk for each five years of use changed from 1.0 percent (95 percent confidence interval, –23 to 27 percent) to 3.5 percent (95 percent confidence interval, –25 to 24 percent).
The pattern observed in Israeli carriers is most appropriately compared with the pattern observed in Israeli noncarriers. In particular, our results concerning the use of oral contraceptives and parity in noncarriers are strikingly similar to those of other case–control studies of ovarian cancer, even though the average duration of use is shorter in Israel than in other populations. Indeed, a test of interaction showed that the reduction in the risk of ovarian cancer conferred by the use of oral contraceptives was significantly less in carriers than in noncarriers.
Both our study and that of Narod et al. have limitations, but the proposal of Narod et al. that age differences are the source of the discrepancy in results does not appear to be correct. Methodologic differences in the identification of patients and the selection of controls or differences in the timing and level of oral-contraceptive use among women seen at clinics for high-risk women may explain the discrepant results. We regard the population-based framework of our study as a strength. Probably, as we wrote, only “additional research can resolve the discrepancy.”
Baruch Modan, M.D.
Tel Aviv University, Tel Aviv 69978, Israel
bmodan@gertner.health. gov. il Sholom Wacholder, Ph.D.
National Cancer Institute, Bethesda, MD 20892-7244for the National Israeli Ovarian Cancer Study Group
- Citing Articles (14)
Citing Articles
1
Andrea Tinelli, Antonio Malvasi, Giuseppe Leo, Daniele Vergara, Maurizio Pisanò, Mariangela Ciccarese, Vincenzo Emanuele Chiuri, Vito Lorusso. (2010) Hereditary ovarian cancers: from BRCA mutations to clinical management. A modern appraisal. Cancer and Metastasis Reviews 29:2, 339-350
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Jane C. Figueiredo, Robert W. Haile, Jonine L. Bernstein. (2009) Oral contraceptives and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Current Breast Cancer Reports 1:3, 139-147
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David J. Hughes. (2008) Use of association studies to define genetic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Familial Cancer 7:3, 233-244
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Karen H. Lu. (2008) Hereditary gynecologic cancers: differential diagnosis, surveillance, management and surgical prophylaxis. Familial Cancer 7:1, 53-58
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Rebecca Byler Dann, Joseph L. Kelley, Kristin K. Zorn. (2007) Strategies for Ovarian Cancer Prevention. Obstetrics and Gynecology Clinics of North America 34:4, 667-686
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Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Cezary Cybulski, Ping Sun, Anna Tulman, Steven A. Narod, Jan Lubinski. (2006) Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Research and Treatment 95:2, 105-109
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Tal Grenader, Tamar Peretz, Meyer Lifchitz, Linda Shavit. (2005) BRCA1 and BRCA2 germ-line mutations and oral contraceptives: to use or not to use. The Breast 14:4, 264-268
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Antonis C. Antoniou, David E. Goldgar, Nadine Andrieu, Jenny Chang-Claude, Richard Brohet, Matti A. Rookus, Douglas F. Easton. (2005) A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genetic Epidemiology 29:1, 1-11
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K. Tiller, B. Meiser, L. Gould, K. Tucker, T. Dudding, J. Franklin, M. Friedlander, L. Andrews. (2005) Knowledge of risk management strategies, and information and risk management preferences of women at increased risk for ovarian cancer. Psycho-Oncology 14:4, 249-261
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A S Whittemore, R R Balise, P D P Pharoah, R A DiCioccio, I Oakley-Girvan, S J Ramus, M Daly, M B Usinowicz, K Garlinghouse-Jones, B A J Ponder, S Buys, R Senie, I Andrulis, E John, J L Hopper, M S Piver. (2004) Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. British Journal of Cancer 91:11, 1911-1915
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Helen E. Roberts. (2004) Gynaecological cancer and the contraceptive pill. The Obstetrician & Gynaecologist 6:2, 75-79
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Luis Robles-d
az, Deborah J Goldfrank, Noah D Kauff, Mark Robson, Kenneth Offit. (2004) Hereditary ovarian cancer in Ashkenazi Jews. Familial Cancer 3:3-4, 259-264
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Steven A. Narod. (2002) MODIFIERS OF RISK OF HEREDITARY BREAST AND OVARIAN CANCER. Nature Reviews Cancer 2:2, 113-123
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