PROJECT SUMMARY – Project 1 Screening mammography results in lower breast cancer mortality by reducing the incidence of advanced breast cancer. Advanced cancer occurs in about 22% of routinely screened women diagnosed with breast cancer, with advanced cancer rates more than 2-fold higher in Black vs. White women. We have identified advanced cancer rate as a key screening outcome because it best discriminates who has the highest risk of breast cancer death. Identifying women at increased advanced cancer risk and targeting them with effective screening strategies could reduce breast cancer mortality. Thus, Project 1 aims to advance a new risk-based screening paradigm that identifies women’s absolute advanced cancer risk to inform screening intensity and supplemental imaging decisions. Aim 1) Using Breast Cancer Surveillance Consortium data on screening exams from women aged 40-74 years, and advanced breast cancers, we will develop, evaluate, and validate new risk prediction models to identify women at high risk of advanced breast cancer. We will combine clinical breast cancer risk factors, self-reported race/ethnicity, imaging features, and Artificial Intelligence output to estimate cumulative 6-year advanced cancer risk using novel discrete time survival models incorporating modern data-adaptive modeling approaches for annual and biennial screeners and examine model predictive equity by race/ethnicity. Aim 2) We will statistically emulate a randomized trial within a causal inference framework to evaluate annual vs. biennial mammography screening on breast cancer mortality among the general screening population according to advanced cancer risk. Aim 3) Three established breast cancer simulation models will be used to evaluate the long-term benefits (breast cancer deaths averted, and life years gained) and harms (e.g., false positives and biopsies) of population-level screening strategies that target mammography frequency (annual, biennial) and supplemental MRI based on advanced cancer risk. This proposal will answer: 1) Which women undergoing screening mammography are at high risk of advanced cancer and require an alternative strategy to biennial mammography, and which women are at low risk and can be screened less often? 2) What advanced cancer risk levels require annual mammography vs. biennial mammography for similar reductions in breast cancer mortality? 3) Does a risk-based screening strategy using advanced cancer risk to inform screening frequency and modality improve outcomes compared to an agebased strategy? Therefore, this project will provide evidence to guide women and providers towards equitable screening strategies based on advanced cancer risk to maximize screening benefits while minimizing harms.