We examined effects of obesity and lifetime exercise patterns on postmenopausal breast cancer risk according to family history in a large population‐based case control study conducted in Los Angeles County, California, because we hypothesized that both factors would affect risk through similar mechanistic pathways, and that their effects would be stronger among women with a family history. We studied 1,883 postmenopausal breast cancer case subjects and 1,628 postmenopausal control subjects ranging in age from 55–72 years. Cases were diagnosed with incident breast cancer in the late 1980s and 1990s. Controls were individually matched to case subjects on age, ethnic origin and neighborhood. In‐person interviews determined known breast cancer risk factors including: height, weight, lifetime exercise, and family history of breast and other cancers. Breast cancer risk was raised among women who had at least 1 first‐degree relative with breast cancer (odds ratio [OR] = 1.68; 95% confidence interval [CI] = 1.36–2.08). Risk increased with increasing levels of body‐mass index (wt‐kg/ht‐m²) (p‐trend = 0.005). Breast cancer risk was reduced among women who maintained, on average, 17.6 metabolic equivalent of energy expenditure (MET)‐hr of activity/week from menarche onward (OR = 0.66; 95% CI = 0.48–0.90). Body‐mass index, adjusted for lifetime exercise, was strongly associated with breast cancer risk among women with a positive family history of breast cancer (p‐trend < 0.0001), but only weakly associated among women with no family history (p‐trend = 0.08; homogeneity of trends p = 0.0005). In contrast, the risk reduction associated with exercise activity, adjusting for body‐mass index, was limited to women without a family history of breast cancer (p‐trend = 0.001; homogeneity of trends p = 0.005). Body‐mass index and exercise activity, both modifiable risk factors for breast cancer, seem to have differential effects depending on a woman's family history of breast cancer, and may impact risk through different biological mechanisms.

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