This Program Project comprises four individual projects, which propose to: implement and test imaging, pathology, and molecular biomarkers to optimize treatment switching within the I-SPY2.2 sequential multiple assignment randomized trial (SMART) adaptive framework (Project 1); refine non-invasive imaging metrics to optimize early treatment switching decisions and prognostic modeling of long-term outcomes (Project 2); characterize of the biology of non-responders using imaging and molecular analysis to inform treatment (Project 3); and develop and optimize of a portfolio of agents that matches biology of patients within the I-SPY2.2 framework (Project 4). The Bioinformatics and Biostatistics Core will act as a centralized dedicated team where the analytical goals of these projects converge. We will work closely with each of the project teams to develop project-specific analysis plans and provide analytical support. We will develop novel statistical methodologies for the complex trial designs and build predictive models across multiple modalities (imaging, pathology, molecular profiles and their combination). Our goal is to facilitate cross-project interactions to refine robust decision algorithms to optimize adaptation of treatment for individual women based on their response within the I-SPY 2.2 trial according to the quality standards necessary to evaluate experimental regimens within a regulatory evidence generation framework. Specifically, the Bioinformatics and Biostatistics Core has three aims: Specific Aim 1: To provide innovative bioinformatics and statistical modeling and analytical approaches needed by the projects to achieve their Specific Aims. Specific Aim 2: To develop SMART methods that incorporate quality of life and residual cancer burden measures into the I-SPY2.2 Program Project framework (Project 1, Aim 3). Specific Aim 3: To synthesize biomarker and drug response data within and across projects into actionable clinical information for implementation in I-SPY2.2.