Women whose sisters or mothers have had breast cancer are at increased risk of developing the disease, and an examination of data from a multigenerational family study suggests that their risk is further elevated if they use oral contraceptives.1Overall, among sisters and daughters of women with breast cancer, those who had ever used the pill had 3.3 times the breast cancer risk of those who had never used this method; the relative risk increased if breast or ovarian cancer occurred more than once among blood relatives. The elevated risk associated with pill use appeared only among women who had taken oral contraceptives during or before 1975; after that year, all oral contraceptives introduced to the market contained less than 50 mcg of estrogen.

The study, which took place between 1991 and 1996, followed up families of 462 women who had had breast cancer diagnosed between 1944 and 1952. Researchers conducted telephone interviews with 6,150 adult relatives of these women: 394 sisters and daughters (first-degree relatives), 3,002 nieces and granddaughters (second-degree), and 2,754 women who had married into the families. Interviews covered participants' cancer history and risk factors for breast cancer, including ever-use of oral contraceptives and the ages at which pill use began and ended.

Overall, 239 participants had had breast cancer--38 sisters and daughters, 115 granddaughters and nieces, and 86 women who had married into families of the original cohort. They had ranged in age from 25 to 83 at diagnosis; the average age was 57 years.

Fifty-one percent of participants had ever used the pill, and 7% were using it at the time of the study. On average, ever-users had taken the pill for seven years. Women who had used oral contraceptives were more likely than never-users to be premenopausal at interview, less likely to have had an oophorectomy and more likely to have smoked cigarettes; they also were slightly better educated than never-users. First-degree relatives of women with breast cancer were less likely to have used the pill (23%) than were other relatives (51-55%), and they began and ended use at later ages.

In analyses adjusting for age and birth cohort, sisters and daughters who had used the pill had a significantly greater risk of breast cancer than never-users (relative risk, 3.3). Oral contraceptive use did not influence the risk among other relatives of women in the breast cancer cohort. In no relationship category was duration of pill use, age at first use, or duration since either first or last use significantly associated with women's breast cancer risk.

The researchers further examined the effect of pill use in families they classified as high-risk--namely, those in which multiple blood relatives had had breast or ovarian cancer. (They included the latter because mutations in the same genes may affect the risk of both diseases). In the 132 families with three or more occurrences of these diseases, ever-use of the pill was again associated with an elevated breast cancer risk for sisters and daughters (relative risk, 4.6), but not for other relatives. The same pattern was seen among the 35 families in which at least five blood relatives had had breast or ovarian cancer, and the relative risk for first-degree relatives who had used the pill was even higher (11.4). Adjustment for a range of potentially confounding factors--parity; age at first birth, menarche and menopause; oophorectomy; smoking; and educational attainment--had essentially no effect on the results.

Finally, because the amount of hormones contained in oral contraceptives has been substantially reduced since 1975, the researchers examined the risk of breast cancer according to the period in which women used oral contraceptives. To maximize the power of these analyses, the investigators considered participants' closest affected relative rather than their relationship to the woman in the original breast cancer cohort. In these analyses, ever-use of the pill was associated with breast cancer risk only for one group of women: those who had a first-degree relative with breast cancer and who had used the pill before 1975 (relative risk, 3.3).

While the investigators note that their study has several advantages over previous work on the relationship between pill use and breast cancer risk, they also acknowledge that it has limited ability to elucidate the influence of current low-dose oral contraceptive formulations. However, they suggest that women with a first-degree family history of breast cancer who used early formulations of the pill "may want to be particularly vigilant regarding appropriate breast cancer screening practices."

The author of an editorial accompanying the study concludes that high-risk women should avoid the pill, "but at the price of forgoing an attractive option for reducing ovarian cancer risk."2 These trade-offs, she writes, highlight the need for pill use to be considered on an individual basis, taking into account a woman's particular risks, alternative strategies for reducing the risk of cancer and other benefits of using this method. Clinicians have an important role to play, the editorial concludes, by "helping [women] to evaluate the evidence, with its gaps and uncertainties, in the context of patients' own preferences."--D. Hollander


1. Grabrick DM et al., Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer, Journal of the American Medical Association, 2000, 284(14):1791-1798.

2. Burke W, Oral contraceptives and breast cancer: a note of caution for high-risk women, editorial, Journal of the American Medical Association, 2000, 284(14):1837-1838.