Environmental Exposures, Reproductive Windows, and Social Drivers of Young-Onset Breast Cancer

PROJECT SUMMARY Young-onset breast cancer (YOBC), diagnosed in women <50 years old, is increasing in incidence by 1-2% annually in the U.S. and is associated with worse outcomes compared to breast cancer (BC) diagnosed later in life. Most YOBC cases occur in women without inherited genetic risk, highlighting the need to better understand environmental, reproductive, and social drivers of the disease. Emerging evidence suggests that exposures during vulnerable life stages such as puberty, pregnancy, and the postpartum period may have lasting effects on BC risk. Concurrent shifts in reproductive timing (e.g., delayed childbirth) and rising environmental exposures (e.g., air pollution, pesticides, ‘forever chemicals’ in water, lack of greenspace access) may contribute to this trend, particularly in socially disadvantaged populations. Methods: We will conduct a population-based, matched case-control study using data from the Healthy Oregon Project (HOP), a mobile health research platform with >50,000 participants statewide. YOBC cases (n=600) and age and race-matched controls (n=1,200) identified from the HOP will complete detailed surveys on reproductive history (e.g., age at menarche, parity, age at first/last birth, lactation); residential addresses and age/year at key life stages: (1) menarche, (2) each pregnancy and postpartum period, and (3) pre- diagnosis window for cases and a matched age window for controls, and current period; and social factors (e.g., education, healthcare access). Geocoded residential addresses will be linked to environmental datasets on PM2.5, pesticides, agricultural and urban greenspace, and PFAS to quantify environmental exposures during each key reproductive time window and pre-diagnosis window (cases) or current period (controls). Specific Aims: We propose to: 1) Evaluate the effects of environmental exposure mixtures during key reproductive life stages using quantile g-computation. This approach will allow us to assess the cumulative/overall impact of environmental exposure mixtures and the relative contribution of individual environmental exposure component at each time window on YOBC risk. We will compare the magnitude and direction of environmental [mixture] risk estimates between reproductive life stages and the pre- diagnosis period to identify the most critical window of vulnerability; 2) Determine how social drivers influence YOBC risk via environmental exposures and reproductive factors using structural equation modeling (SEM). We hypothesize that environmental exposures during hormonally sensitive life stages interact synergistically with reproductive timing to increase YOBC risk, with a prediction that earlier life exposures playing the most significant role, and that social disadvantage amplifies these risks. This study will identify modifiable, time-sensitive environmental exposures and provide insight into how social and reproductive factors may compound these risks, informing future YOBC prevention strategies, particularly among socioeconomically and environmentally vulnerable populations.