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BACKGROUND: Greater body mass index (BMI), a measure of overall adiposity, is associated with a higher risk of postmenopausal breast cancer. The role of central adiposity, often measured by waist circumference, is less well understood, especially among premenopausal women. The objective of the current study was to examine multiple measures of adiposity in relation to breast cancer in a prospective cohort study. METHODS: A total of 50,884 Sister Study cohort participants aged 35 to 74 years were enrolled from 2003 through 2009. Inclusion criteria for the cohort included having a sister previously diagnosed with breast cancer. Trained study personnel measured height, weight, and waist and hip circumference during a home visit and study participants completed a detailed questionnaire. Using Cox regression analysis, we estimated multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer risk associated with adiposity measurements, considering tumor subtype and menopausal status. RESULTS: In total, 2009 breast cancers were diagnosed during follow-up (mean=5.4 years). Weight, BMI, waist circumference, and waist-to-hip ratio were found to be positively associated with overall breast cancer risk and HRs were greater among postmenopausal women, those with hormonally responsive tumors, and women who were not currently using postmenopausal hormones. In models that adjusted for BMI, waist circumference associations persisted among both postmenopausal women (81-88 cm vs <= 80 cm: HR=1.16 [95% CI 1.01-1.35] and > 88 cm vs <= 80 cm: HR=1.30 [95% CI 1.10-1.54]) and premenopausal women (81-88 cm vs <= 80 cm: HR=1.56 [95% CI 1.19-2.04] and > 88 cm vs <= 80 cm: HR=1.30 [95% CI 0.91-1.87]). CONCLUSIONS: Findings from this large, prospective study with examiner-measured body size indicate that waist circumference is independently and positively associated with both premenopausal and postmenopausal breast cancer risk. (c) 2015 American Cancer Society.