CORRESPONDENCE

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

Geertruida H. de Bock, Rob A. E. M. Tollenaar, Hadewych Papelard, Theodora P. M. Vliet Vlieland, Peter Devilee, Cornelis J. Cornelisse, Jan P. Vandenbroucke

Affiliations of authors: G. H. de Bock (Department of Medical Decision Making), R. A. E. M. Tollenaar (Department of Surgery), H. Papelard (Departments of Medical Decision Making and Surgery), T. P. M. Vliet Vlieland (Department of Rheumatology), P. Devilee (Department of Human and Clinical Genetics), C. J. Cornelisse (Department of Pathology), J. P. Vandenbroucke (Department of Epidemiology), Leiden University Medical Center, Leiden, The Netherlands.

Correspondence to: G. H. de Bock, Ph.D., Department of Medical Decision Making, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (e-mail: G.H.de_ Bock{at}LUMC.NL).

Narod et al. (1) reported that, among BRCA1 mutation carriers, women who used oral contraceptives might have an increased risk of early-onset breast cancer. They call for independent verification, preferably among women who are not selected through familial aggregation. We believe that it might also be of interest to assess the combined effect of the BRCA1 mutation and oral contraceptive use, and the separate effects of the mutation and of oral contraceptive use on breast cancer risk, each comparison relative to the risk in those having neither risk factor for breast cancer.

From 1984 until 1996, all primary invasive breast cancer patients who were surgically treated at the Leiden University Medical Center were asked to provide a blood sample for research purposes, regardless of age or family history. This request was approved by the Medical Ethics Committee. For patients aged younger than 50 years at diagnosis and for whom leukocyte DNA was available (n = 183) (2), data on current oral contraceptive use were obtained by a questionnaire mailed to 162 patients alive on June 1, 1997; 111 patients responded. For all other patients with breast cancer, current oral contraceptive use was verified from their medical records. For control subjects, data regarding expected oral contraceptive use were derived from a national random sample of 1971 women aged 19–49 years who had been interviewed in 1990 (i.e., the halfway point for patient accrual) regarding their current use of contraceptives (3). For our analysis, we assumed that the frequencies of oral contraceptive use among control subjects were the same, irrespective of BRCA1 mutation status, and we multiplied these frequencies with the expected population frequencies of BRCA1 germline mutations (4) to calculate the expected frequency of all combinations of oral contraceptive use and BRCA1 mutation status among the general population.

Oral contraceptive use was known for eight BRCA1 mutation carriers and for 175 non-carriers. At the time of breast cancer diagnosis, two BRCA1 mutation carriers and 30 non-carriers had used oral contraceptives. This leads to a multiplicative synergy index (5) of 1.61 (95% confidence interval [CI] = 0.31 to 8.37). The index indicates that the relative risk of oral contraceptive use is equal or, at most, slightly greater among BRCA1 mutation carriers than among non-carriers. The separate and combined effects of oral contraceptive use on the risk of breast cancer among women with and without BRCA1 mutations are shown in Table 1Go. The odds ratios suggest that oral contraceptive use is in itself a weak risk factor for breast cancer but increases the risk of breast cancer in BRCA1 mutation carriers from 35-fold (95% CI = 16- to 79-fold) to 58-fold (95% CI = 15- to 236-fold).


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Table 1. Odds ratios (ORs) for the development of breast cancer associated with using oral contraceptives in carriers (n = 8) and non-carriers (n = 175) of BRCA1 mutations in an unselected population*
 
Our results support the notion that the relative risk of oral contraceptive use might be similar among BRCA1 mutation carriers and non-carriers—or at most slightly higher among carriers—but that oral contraceptive use clearly leads to a much higher total risk among women with BRCA1 mutations. We realize that our numbers are small and reflect only current use. However, most previous studies also assessed an elevated risk with current use, and the Collaborative Group on Hormonal Factors in Breast Cancer analysis of 54 studies found no difference in the relative risk associated with oral contraceptives between subgroups and, moreover, not in the subgroup of women with affected family members, where we would expect to find most BRCA1 mutation carriers (6). A small overall relative risk associated with oral contraceptive use is likely, given the known epidemiologic data, but even small relative risks will have much larger consequences among BRCA1 mutation carriers because these women already have an elevated risk resulting from the mutation.

REFERENCES

1 Narod SA, Dube MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2002;94:1773–9.[Abstract/Free Full Text]

2 de Bock GH, Tollenaar RA, Papelard H, Cornelisse CJ, Devilee P, van de Vijver MJ. Clinical and pathological features of BRCA1 associated carcinomas in a hospital-based sample of Dutch breast cancer patients. Br J Cancer 2001;85:1347–50.[ISI][Medline]

3 Central Department of Statistics of The Netherlands. Enkele vormen van geboortenregeling. Centraal Bureau voor de Statistiek. [In Dutch.] Statistisch Jaarboek 1998;491.

4 Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 1995;57:1457–62.[ISI][Medline]

5 Khoury MJ, Flanders WD. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls! Am J Epidemiol 1996;144:201–13.

6 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. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996;347:1713–27.[ISI][Medline]

7 Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955;19:251–3.[Medline]



             
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