Abstract
IMPORTANCE: Evidence suggests that breast density and body mass index (BMI) are strong breast cancer risk factors; however, their interactive associations are unknown. Elucidation of these interactive associations may help to increase understanding of the causes of breast cancer and find effective interventions for susceptible subgroups. OBJECTIVE: To explore the association of the interaction of mammographic breast density and BMI with breast cancer risks among premenopausal and postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational cohort study used population-based data of the Korean National Cancer Screening Program embedded in the National Health Insurance Service database to evaluate the breast cancer risk of 3 248 941 premenopausal cancer-free women and 4 373 473 postmenopausal cancer-free women aged 40 years or older who underwent mammographic screening between January 1, 2009, and December 31, 2013, and were followed up until December 31, 2018. Statistical analysis was performed from June 1 to July 15, 2021. EXPOSURES: Breast Imaging Reporting and Data System (BI-RADS)-defined breast density (with a scale from 1 to 4, where 1 indicates almost entirely fat, 2 indicates scattered fibroglandular densities, 3 indicates heterogeneously dense tissue, and 4 indicates extremely dense tissue) and BMI levels classified according to the World Health Organization Asia-Pacific Region classification. MAIN OUTCOMES AND MEASURES: Adjusted relative risk (aRR) of breast cancer during the follow-up period and interactions in additive and multiplicative scales. The study end point was the development of breast cancer. RESULTS: Of 3 248 941 premenopausal women (mean [SD] age, 44.6 [4.3] years) and 4 373 473 postmenopausal women (mean [SD] age, 59.6 [8.4] years) aged 40 years or older, 34 466 cases of breast cancer were identified among the premenopausal women, and 30 816 cases of breast cancer were identified among the postmenopausal women. Increased breast density was associated with an increased risk of breast cancer in both premenopausal and postmenopausal women across the BMI categories. Among premenopausal women, those in BI-RADS category 4 had an approximately 2-fold higher risk of breast cancer irrespective of BMI (all women: aRR, 2.36 [95% CI, 2.24-2.49]; underweight: aRR, 1.80 [95% CI, 1.25-2.59]; normal weight: aRR, 2.10 [95% CI, 1.93-2.28]; overweight: aRR, 2.47 [95% CI, 2.27-2.68]; obese: aRR, 2.87 [95% CI, 2.49-3.32]) than those with underweight status and in BI-RADS category 1. However, an association between BMI and the risk of breast cancer was found only in the postmenopausal women in all breast density categories compared with underweight women with BI-RADS category 1 (BI-RADS category 4, all women: aRR, 2.91 [95% CI, 2.78-3.04]; underweight: aRR, 2.74 [95% CI, 1.89-3.98]; normal weight: aRR, 3.05 [95% CI, 2.82-3.30]; overweight: aRR, 2.85 [95% CI, 2.67-3.04]; obese: aRR, 2.52 [95% CI, 2.22-2.88]). When the combined associations of breast density and BMI with the risk of breast cancer were considered, a high breast density and high BMI had a significant positive interaction on the additive scale for both premenopausal and postmenopausal women, especially the latter (premenopausal women: adjusted relative excess risk due to interaction, 0.53 [95% CI, 0.35-0.71]; postmenopausal women: adjusted relative excess risk due to interaction, 1.68 [95% CI, 1.26-2.10]). CONCLUSIONS AND RELEVANCE: This study suggests that breast density and BMI interact synergistically to augment breast cancer risk, with a stronger association found among postmenopausal women. Both factors should be incorporated into risk stratification in a population-based screening for public health significance. Women with overweight or obesity and dense breast tissue might benefit from tailored early screening strategies to detect breast cancer.