BACKGROUND Estrogen is involved in both bone metabolism and breast cancer proliferation. However, evidence about the risk of breast cancer according to women's bone mineral density (BMD) is scarce, and little is known about their causal associations. METHODS Women participating in the UK Biobank cohort were used to investigate the association between BMD and the risk of breast cancer using Cox regression models. Instrumental variants associated with estimated BMD (eBMD) were extracted from genome‐wide association studies with European ancestry. Logistic regression was used to calculate the genetic association with breast cancer in the UK Biobank and 2‐sample Mendelian randomization (MR) analyses to assess their causal associations with breast cancer. Finally, the pleiotropic conditional false discovery rate (cFDR) method was conducted to further detect common genetic variants between BMD and breast cancer. RESULTS Compared with the general population, postmenopausal women with BMD T scores <−2.5 had a lower risk of breast cancer (hazard ratio [HR], 0.77; 95% CI, 0.59‐1.00), and this effect was stronger in women with fracture (HR, 0.31; 95% CI, 0.12‐0.82). In MR analysis, no causal associations between eBMD and breast cancer were observed. The cFDR method identified 63 pleiotropic loci associated with both BMD and breast cancer, of which CCDC170, ESR1, and FTO might play crucial roles in their pleiotropy. CONCLUSIONS An association between BMD and the risk of postmenopausal breast cancer in the UK Biobank was observed, whereas no evidence supported their causal association. Instead, their association could be explained by pleiotropic genetic variants leading to the pathology of osteoporosis and breast cancer.

Background: We aimed to identify factors associated with false-positive recalls in mammography screening compared with women who were not recalled and those who received true-positive recalls. Methods: We included 29,129 women, aged 40 to 74 years, who participated in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) between 2011 and 2013 with follow-up until the end of 2017. Nonmammographic factors were collected from questionnaires, mammographic factors were generated from mammograms, and genotypes were determined using the OncoArray or an Illumina custom array. By the use of conditional and regular logistic regression models, we investigated the association between breast cancer risk factors and risk models and false-positive recalls. Results: Women with a history of benign breast disease, high breast density, masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have mammography recalls, including both false-positive and true-positive recalls. Further analyses restricted to women who were recalled found that women with a history of benign breast disease and dense breasts had a similar risk of having false-positive and true-positive recalls, whereas women with masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have true-positive recalls than false-positive recalls. Conclusions: We found that risk factors associated with false-positive recalls were also likely, or even more likely, to be associated with true-positive recalls in mammography screening.

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Background Risk assessment is important for breast cancer prevention and early detection. We aimed to examine whether common risk factors, mammographic features and breast cancer risk prediction scores of a woman were associated with breast cancer risk for her sisters. Methods We included 53,051 women from the KARMA study. Established risk factors were derived using self-reported questionnaires, mammograms, and SNP genotyping. Using the Swedish Multi-Generation Register, we identified 32,198 sisters of the KARMA women (including 5,352 KARMA participants and 26,846 non-participants). Cox models were used to estimate the hazard ratios of breast cancer for both women and their sisters, respectively. Results A higher breast cancer polygenic risk score, a history of benign breast disease, and higher breast density in women were associated with an increased risk of breast cancer for both women and their sisters. No statistically significant association was observed between breast microcalcifications and masses in women and breast cancer risk for their sisters. Furthermore, higher breast cancer risk scores in women were associated with an increased risk of breast cancer for their sisters. Specifically, the hazard ratios for breast cancer per 1 standard deviation increase in age-adjusted KARMA, BOADICEA, and Tyrer-Cuzick risk scores were 1.16 (95% CI = 1.07 to 1.27), 1.23 (95% CI = 1.12 to 1.35) and 1.21 (95% CI = 1.11 to 1.32), respectively. Conclusion A woman’s breast cancer risk factors are associated with her sister's breast cancer risk. However, the clinical utility of these findings requires further investigation.