Some women with genetic susceptibility to breast cancer face elevated risk from oral contraceptive use. (Digests).

Among women with mutations of the breast cancer susceptibility gene BRCA1, certain patterns of oral contraceptive use increase the odds of the disease. (1) In a multicenter case-control study, women with a BRCA1 mutation who were ever-users of oral contraceptives had 20% higher odds of having had breast cancer than never-users. However, the odds were elevated only for certain groups of ever-users: women who had used oral contraceptives before age 30, women who had used them for at least five years and women who had first used them before 1975. Additionally, the odds were raised among ever-users only if their cancer had been diagnosed before they reached age 40. In contrast, women with a BRCA2 mutation did not have increased odds of breast cancer if they had used oral contraceptives, but the smaller number of women in this group limited analyses.

Women with BRCA1 and BRCA2 mutations have an elevated risk of breast cancer. To determine if oral contraceptive use further increases this risk, investigators studied women from eight European countries, Canada, the United States and Israel who had known mutations of one or both genes. The women had been identified by genetic testing prompted by a diagnosis of breast or ovarian cancer in themselves or a female relative. The investigators paired women-who had had invasive breast cancer diagnosed during 1970-2001 (cases) with women who had never received a diagnosis of this cancer (controls); they matched each pair for year of birth, country of residence, BRCA gene mutated and history of ovarian cancer.

Women were excluded from the study if they had missing data or had been born before 1920. Potential cases were excluded if they had undergone oophorectomy before their diagnosis of breast cancer or if ovarian cancer was diagnosed before breast cancer; potential controls were excluded if they had had bilateral oophorectomy or bilateral prophylactic mastectomy before the age at which their matched case received her breast cancer diagnosis.

Study participants completed questionnaires asking details about their medical and reproductive histories, including their use of oral contraceptives. The relative odds of breast cancer were determined by multivariate conditional logistic regression.

Analyses were based on 1,311 matched pairs of women. In 75% of the pairs, the mutated gene was BRCA1; in 11%, the women had ovarian cancer. On average, women with and without breast cancer were both about 46-47 years old and had had two live births. Women with breast cancer were significantly older at the time of a first birth, but the difference was small (24.6 vs. 24.2 years); the vast majority of women were white. About four in 10 women in each group reported having smoked regularly at some time. The women with breast cancer had been, on average, 39 years old at the time of diagnosis. Nearly equal proportions of women with and without breast cancer had ever used oral contraceptives (70% and 68%, respectively), and the average duration of use among ever-users was similar (5.3 and 5.0 years).

After ethnicity and number of live births were taken into account, women with a BRCA1 mutation who had ever used oral contraceptives had a significant 20% increase in the odds of breast cancer relative to those who had never used them. The odds increased by 2% with each year of use. In contrast, among women with a BRCA2 mutation, ever-users did not have elevated odds of breast cancer relative to never-users, although analyses were limited by the small number of women with BRCA2 mutations.

Only certain patterns of oral contraceptive use were associated with significantly elevated odds of breast cancer in women with BRCA1 mutations. Women who had used oral contraceptives before age 30 had a 29% increase in odds relative to never-users, and the odds increased by 3% with each year of use before this age. Women who had used oral contraceptives for five or more years had a 33% increase in odds, and women who had used them before 1975 (when oral contraceptives had a higher estrogen content) had a 42% increase in odds. No associations emerged between the odds of breast cancer and use at later ages, for shorter durations or in more recent time periods.

The odds of breast cancer in women with a BRCA1 mutation also increased with the time elapsed since discontinuation of oral contraceptive use. Ever-users who had stopped use 10 or more years earlier had a 59% increase in odds relative to never-users; the odds of disease were not elevated among women who had used oral contraceptives more recently. Further analyses revealed that ever-use was associated with the likelihood of disease only among women who learned of their cancer before age 40 (increasing the odds by 38%) or during 1970-1979 (doubling the odds).

While acknowledging that earlier studies have yielded conflicting results, the investigators contend that their findings "support the use of short-term oral contraceptives as a measure for reducing ovarian cancer risk in BRCA carriers." More specifically, they conclude, "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."

REFERENCE

(1.) Narod SA et al., Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers, Journal of the National Cancer Institute, 2002, 94(23): 1773-1779.