Genetic risk stratification of common diseases in breast cancer survivors: a population-based cohort study

BACKGROUND: Patients diagnosed with breast cancer are at increased risk of multiple common diseases; however, the spectrum of these diseases and the contribution of inherited genetic susceptibility remain incompletely characterized. METHODS: We evaluated 15 common diseases and tested their associations with breast cancer exposure and disease-specific polygenic risk scores in the UK Biobank (n = 254 736). Analyses were performed using cause-specific Cox proportional hazards models within a full-cohort framework, with time-updated breast cancer status, delayed entry at study recruitment, and age as the underlying time scale. RESULTS: After recruitment, incident breast cancer was diagnosed in 11 386 women (4.47%), including 2742 (24.08%) with metastatic breast cancer. Patients with breast cancer had an increased risk of 9 diseases spanning cardiovascular, metabolic, and neuropsychiatric domains (P < .003, Bonferroni corrected). Elevated risks were generally observed among patients with both early-stage and advanced breast cancer. Inherited susceptibility further stratified disease risk, with the highest risks observed among patients with breast cancer and elevated disease-specific polygenic risk scores. For example, compared with women without breast cancer, the hazard ratio for osteoporosis was 2.33 (95% CI = 2.15 to 2.52) among women with any breast cancer, 2.38 (95% CI = 2.18 to 2.59) among women with nonmetastatic breast cancer, and 2.12 (95% CI = 1.78 to 2.54) among women with metastatic breast cancer; the hazard ratio was 4.48 (95% CI = 3.99 to 5.02) among patients with breast cancer in the highest quartile of osteoporosis-specific polygenic risk scores (all P < .001). In contrast, breast cancer was not statistically significantly associated with risk of coronary artery disease. CONCLUSION: Breast cancer and inherited genetic susceptibility jointly contribute to increased risk of multiple common diseases, supporting the integration of genetic risk stratification into survivorship care.