Abstract 6366: Pre-diagnostic circulating proteins and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Abstract Introduction: Proteomics has emerged as a potentially important research tool for identifying novel etiological biomarkers of cancer risk. To date, apart from some specific proteins such as insulin-like growth factor -1 and sex hormone binding globulin, few protein biomarkers for breast cancer risk have been established. This study aimed to identify novel plasma proteins associated with premenopausal and postmenopausal breast cancer in a case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Plasma proteins were measured using the SomaScan 7k Assay in 970 incident breast cancer cases (231 premenopausal, 739 postmenopausal) and 2, 490 female subcohort participants from the EPIC cohort. Separately in premenopausal and postmenopausal women, Prentice-weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating proteins and breast cancer risk adjusted for known breast cancer risk factors. A false discovery rate-corrected P-value <0.05 was considered statistically significant. Results: Of the 7, 363 assayed circulating proteins (aptamers), 19 were statistically significantly associated with premenopausal breast cancer risk. Of these, LEG1, KLK5, LACRT, LIPK, PIP, ADPGK, KRTAP2-4, CXCL13, LGSN, DNAJC11, SEMA4G, RLN2, FGF9, LYPD3, SHCBP1L and DEFB107A were positively associated (HRs ranged from 1.20 to 1.65 per 1 SD increment) and SUMO2, MPI, and XPNPEP1 were inversely associated with premenopausal breast cancer risk (HRs ranged from 0.56 to 0.63 per 1 SD increment). Three proteins - LEG1 (HR: 1.32; 95% CI: 1.21, 1.44), CST6 (HR: 1.31; 95% CI: 1.20, 1.44), and SAR1B (HR: 1.21; 95% CI: 1.12, 1.30) - were positively associated with postmenopausal breast cancer risk. In heterogeneity tests by menopausal status, 20 proteins were differentially associated with breast cancer risk in postmenopausal and premenopausal women. Conclusions: These findings point to potentially novel pathways and biomarkers of breast cancer development, with possible important differences by menopausal status. These results need to be replicated in other epidemiological studies. Citation Format: Yahya Mahamat-saleh, Alicia Heath, Vivian Viallon, Antonio Agudo, Giovanna Masala, Salvatore Panico, Carlotta Sacerdote, Karl Smith-Byrne, Ruth Travis, Rosario Tumino, Martijn Kolijn, Roel Vermeulen, Nicholas Wareham, Pietro Ferrari, Elio Riboli, Marc J. Gunter, Laure Dossus. Pre-diagnostic circulating proteins and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6366.