Abstract Background: Individual environmental contaminants have been associated with breast cancer; however, evaluations of multiple exposures simultaneously are limited. The USPA has constructed an environmental quality index (EQI), which contains county-level environmental exposure data across five overarching environmental domains (air, water, land, sociodemographic, and built environment). Unfortunately, the links made between breast cancer and the EQI are lacking because these analyses used total breast cancer incidence quantities, masking potential associations between EQI domains and specific stages of disease. In this study, we investigated if multiple exposures in broad EQI domains was associated with incidence of breast cancer, stratified by stage. Methods: The EQI data was linked to county-level age-standardized incidence rates (SIRs) obtained from the North Carolina Central Cancer Registry/NC CCR (2010-2014), a reporting system for all cancer cases diagnosed in residents of the state. Incidence rates and SIRs of total, in situ, localized, regional, and distant breast cancers were evaluated stratified by rural-urban status. Associations between county-level age-adjusted cancer incidence rates for each summary stage were assessed using general linear models (SAS 9.3), linear models with a continuous outcome with a p-value cutoff for statistical significance set at p< 0.05. We also evaluated incidence rates by summary stage comparing across rural versus urban counties using Mann-Whitney rank tests, since not all stages were normally distributed, confirmed by the D’Agostino-Pearson normality test. Results: In counties with poor environmental quality compared to those with good environmental quality, total breast cancer incidence was higher by 10.82 cases per 100,000 persons (95%CI: 2.04, 19.60, p=0.016). This association was most pronounced for localized breast cancer (β=5.59, 95%CI: 0.59, 10.58, p=0.029). Higher incidence of early-stage disease (carcinoma in situ β=5.25, 95%CI: 2.34, 8.16, p=0.001 and localized breast cancer β=6.98, 95%CI: 2.24, 11.73, p=0.004) and total breast cancer (β=11.44, 95%CI: 3.01, 19.87, p=0.008) occurred in counties with poor land quality, especially urban counties. Overall, NC counties averaged 21.6% percent African American (AA) which is higher than the US national average of 12.6% at the time of the U.S. 2010 Census. The percentage of AA in each county in bivariate analyses was associated with increased incidence of regional (incident cases 0.12 cases per % increase in AA population, 95% CI 0.01, 0.22, p=0.022) and distant breast cancers (incident cases 0.06 per % increase in AA population, 95% CI 0.02, 0.10, p=0.003) (Table 1). In addition, in stratified models, associations persisted and were strengthened in urban county models for regional breast cancer and in rural county models for distant breast cancer. Conclusions: Environmental quality is variable across NC akin to variability across the US, as the interquartile range (25th-75th percentile) of total EQI in NC is -0.187 to 0.734 while the interquartile range is –0.606 to 0.706 for the US (USEPA), making NC EQI analyses generalizable to a number of states and counties across the U.S., although what drives poor environmental quality varied by region and by county. Our analyses indicate significant associations between EQI and breast cancer incidence, which differ by breast cancer stage and urbanicity, identifying a critical need to assess cumulative environmental exposures in the context of cancer stage. Funding: Duke Cancer Institute seed grant (GRD, KH) as part of the P30 Cancer Ctr grant; Duke Environmental Health Scholars Award and NIEHS T32-ESO21432-05 (LMG). Table 1. Generalized linear model estimates and associated p-values for county characteristics, per 1% increase. Results are stratified by breast cancer stage and urbanicity. Bolded text indicates statistically significant estimates (p<0.05) Citation Format: Larisa M Gearhart-Serna, Hillary Hsu, Oluwadamilola (Lola) Fayanju, Brittany Mills, Kate Hoffman, Gayathri R Devi. Cumulative Environmental Quality is Associated with Differential Breast Cancer Incidence by Summary Stage and Urbanicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-12.