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    Genetics of Breast and Ovarian Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Introduction

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    Reproductive and menstrual history

    In general, breast cancer risk increases with early menarche and late menopause and is reduced by early first full-term pregnancy. In BRCA1 and BRCA2 mutation carriers, results have been conflicting and may be gene dependent. No consistent significant associations have been observed.[15,17,18,19] Evidence suggests that reproductive history may be differentially associated with breast cancer subtype (i.e., triple-negative vs. ER-positive breast cancers). In contrast to ER-positive breast cancers, parity has been positively associated with triple-negative disease, with no association with ages at menarche and menopause.[20]

    Oral contraceptives

    Oral contraceptives (OCs) may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with OC use did not vary in relationship to a family history of breast cancer.[21]

    OCs are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers. Although the data are not entirely consistent, a meta-analysis concluded that there was no significant increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers.[22] However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.06-2.04).[22] (Refer to the Reproductive factors section in the Clinical management of BRCA mutation carriers section of this summary for more information.)

    Hormone replacement therapy

    Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.21-1.49) for women who had used HRT for 5 or more years after menopause.[23] The WHI, a randomized controlled trial (NCT00000611) of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[24,25] Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR, 1.24; 95% CI, 1.02-1.5, P <. 001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women's Study in the United Kingdom.[26] The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR, 0.77; 95% CI, 0.59-1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.[27]

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