Background: Environmental chemical exposures and metabolic profiles may influence breast cancer risk, particularly during windows of susceptibility, such as the menopausal transition. However, few studies have specifically examined environmental exposures during menopause and their potential link to postmenopausal breast cancer. Leveraging a large-scale Swedish cohort, this study aims to address this gap.

Objective: To investigate associations between chemical exposomics and metabolomic biomarkers in plasma (measured at age 50) and subsequent risk of postmenopausal breast cancer.

Methods: We selected 500 breast cancer cases (diagnosed at ≥55 years) and 500 matched controls from the large prospective cohort of the Northern Sweden Health and Disease Study (NSHDS) and the research infrastructure PREDICT. Plasma samples (n=1,000) are currently being analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS) using a hybrid chemical exposomics workflow that combines targeted quantification of prespecified contaminants with parallel untargeted discovery-driven profiling. Additionally, a panel of 250 clinically relevant metabolic biomarkers (including cholesterol, fatty acids, lipids, and inflammatory markers) is already available and will be included in association models. Aside from using standard methods to estimate Odds Ratios between chemical exposure profiles and breast cancer risk, we will also evaluate multiple exposures in analyses of mixtures. All multivariate models will adjust for established breast cancer risk factors, including BMI, smoking, alcohol, physical activity, socioeconomic factors, and family cancer history, obtained from health records and national registers.

Expected Impact: This study is expected to provide insights into how exposures during menopause may impact postmenopausal breast cancer risk, informing future prevention strategies and precision risk assessment.