If tamoxifen is the appropriate agent to test as a chemopreventive, then the issue becomes identification of women at risk for definitive clinical trials. Family history is probably the best-recognized risk factor for breast cancer. An inherited gene mutation is thought to account for 5%-10% of breast cancer cases.116,117 Although infrequent, these mutations are significant since they are associated with a lifetime risk of breast cancer of 50%-80%,118,119 beginning at a young age. At present, two predisposition genes, BRCA1, located on chromosome 17q21,120 and BRCA2, located on chromosome 13q12-13,121 have been identified, both of which are inherited in an autosomal dominant pattern.
Most women with a family history of breast cancer do not have the genetically transmitted form of the disease, and their risk is much less than that seen in women who have inherited a predisposing gene. The cumulative probability that a 30-year-old woman with a mother and sister with breast cancer will develop breast cancer by the age of 70 is between 7% and 18%.122,123 While this risk increases as the number of relatives with breast cancer increases, the probability of cancer development if both a mother and a sister have bilateral breast cancer is only 25%.123,124 The cumulative risk of breast cancer in women with a family history rarely exceeds 30%, making it critically important to distinguish those women with hereditary breast cancer from those with a family history of the disease.
Breast cancer is clearly related to endogenous hormones, and numerous studies have linked breast cancer risk to age at menarche, menopause, and first pregnancy. Although the absolute age-specific incidence of breast cancer is higher in postmenopausal than premenopausal women,125 the absolute rate of rise of the curve is greatest up to the time of menopause, then slows to one-sixth of that seen in the pre-menopausal period. Further support for the promotional role of estrogen in breast cancer comes from observations that early menarche,126 late menopause,127 nulliparity, and late age at first birth128 all increase the risk of breast cancer development. An increased number of ovu-latory cycles is suggested to be the common mechanism of increased risk.
Other hormonal risk factors have been suggested but are not as well established. Abortion, whether spontaneous or induced, has been reported by some to increase risk,129,130 while oth ers have found no relationship between abortion and breast cancer.131,132 Studies of the effect of lactation on breast cancer risk have also been inconclusive,133,134 but recent studies have suggested that a long duration of lactation reduces breast cancer risk in premenopausal women.135 Physical activity in adolescence is reported to decrease risk, perhaps due to a higher rate of anovulatory cycles;136,137 but an increased level of physical activity later in life has not been shown to reduce breast cancer risk.138 Post-menopausal obesity increases risk,139 perhaps due to increased peripheral estrogen production; but this relationship between weight and risk is not observed in premenopausal women.
The effects of exogenous hormones in the form of oral contraceptives and hormone-replacement therapy (HRT) on breast cancer risk have been studied extensively. Overall, there is no convincing evidence of increased risk with use of oral contraceptives.140 Some studies have suggested that long-term use of oral contraceptives in young women prior to first pregnancy may increase risk.141,142 Two meta-analyses of the effect of HRT demonstrated small, but statistically significant, increases in risk.143,144 The Iowa Women's Health Study found that the duration of HRT was directly associated with risk of invasive carcinoma with a favorable histology, with a relative risk (RR) of 1.81 for HRT taken at less than 5 years vs. an RR of 2.65 for HRT taken at greater than 5 years.145 Although hormonal risk factors are clearly implicated in the pathogenesis of breast cancer, most of them are associated with an RR of less than 3; therefore, the presence of a single hormonal risk factor is insufficient to classify a woman as high-risk.
Environmental factors have also been linked to breast cancer. A large amount of attention has been directed to the role of diet in the etiology of breast cancer. This link is suggested by the large international variation in breast cancer incidence and the observation that national per capita fat consumption correlates with breast cancer incidence and mortality.146 Prospective studies, however, of diet and breast cancer risk have failed to identify a relationship with 10 years of follow-up.147 The lack of a relationship between dietary fat intake and cancer risk within the context of a Western diet is confirmed by a pooled analysis of seven cohort studies involving a total of 337,816 women, which demonstrated no difference in incidence in women in the lowest and highest quintiles of fat intake.148
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