Discovering plasma proteins associated with breast cancer incidence in postmenopausal women in the Atherosclerosis Risk in Communities study

Background: Plasma proteomic data can be used to discover breast cancer risk biomarkers beyond established risk factors. Discovery using a large-scale platform in a diverse population is needed. Methods: We investigated 4712 plasma proteins and breast cancer risk among postmenopausal women in a prospective cohort analysis in the Atherosclerosis Risk in Communities study. Proteins were measured by SomaScan 5K Assay. Incident cases were ascertained primarily from state cancer registries. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox regression adjusting for risk factors and applied the Benjamini-Hochberg method to control false discovery. We determined whether the statistically significant proteins were confirmed in a case-cohort study within the European Prospective Investigation into Cancer and Nutrition. Results: After median follow-up of 23.3years, 340 of 4403 women had an incident breast cancer. Two proteins were statistically significantly associated after P value adjustment: per doubling, the hazard ratio of breast cancer was 1.45 (95% CI = 1.23 to 1.70; P=7.47*10⁻⁶, P _adjusted=.0370) for protein LEG1 homolog and 2.52 (95% CI = 1.66 to 3.83; P=1.50*10⁻⁵, P _adjusted=0.0371) for adenosine diphosphate (ADP)–dependent glucokinase. Results were consistent in a lagged analysis and among Black (28.1%) and White women. In the European Prospective Investigation into Cancer and Nutrition, both associations were confirmed (protein LEG1 homolog: HR=1.24, 95% CI = 1.14 to 1.35; P=9.79*10⁻⁷; ADP–dependent glucokinase: HR=1.13, 95% CI = 1.03 to 1.23; P=.01). Conclusion: We identified 2 plasma proteins associated with increased breast cancer risk over the longer term in postmenopausal women; both were confirmed in an independent cohort. If further validated, these plasma protein biomarkers could be considered for utility in current risk stratification tools.