In 2016, we initiated the first large-scale clinical trial to personalize screening based on individual risk, which varies significantly among women. The WISDOM Study is a multi-center, randomized comparative effectiveness trial to determine if personalized screening recommendations based on a woman’s individual breast cancer risk is as safe and causes fewer morbidities than the current US approach of annual screening for all women. In the intervening time, there have been a number of important advances in breast cancer risk assessment. In particular, there is evidence that models of risk can not only predict a woman’s risk for breast cancer, but can predict risk for specific breast cancer subtypes. This Project will extend the WISDOM Study for a period of five years, integrating models of risk that predict specifically for the development of fast-growing and slow-growing cancers. Women with high-risk for fast- growing cancers will be recommended earlier and more frequent screening with more sensitive imaging methods. Women at high risk for slow-growing cancers will be offered endocrine risk reduction. In order to compare the impact of this subtype-specific approach on screening outcomes, we will first acquire and determine the subtype of cancers that arose in the original WISDOM cohort as well as the new cohort assessed with subtype-specific models. The primary aim is to determine if the subtype-specific models indeed enrich for the type of tumor detected (fast or slow-growing). We will see if this approach increases the efficiency of screening (cancers/1000 women screened) compared to the reported rates from the BCSC model. We will also compare whether the fast and slow prediction increases the fraction of fast-growing cancers that are screen detected compared to the first cohort in WISDOM prior to subtype tumor prediction. The secondary aims include the fraction of women at high-risk for slow growing tumors that take up risk reducing interventions and whether those that do develop fewer cancers. As well, we will look to reduce morbidity of screening. Project 1 will implement and help validate advanced cancer and subtype-specific risk models that integrate family history, mammography (2D and 3D)-based artificial intelligence algorithms and refined polygenic risk scores developed from large external cohorts. A collaboration with the leadership of the CISNET/MISCAN model of breast cancer screening will allow us to evaluate the potential healthcare impacts of these new subtype-specific risk models to determine whether they should be adopted as part of subtype specific risk prediction models. The goal is to increase health care value of screening by the end of this P-01. Extending the utility of the existing WISDOM infrastructure represents exceptional value for a ground-breaking research program that will significantly advance our understanding of the potential for risk-based approaches to impact breast cancer screening outcomes. WISDOM’s team is ...