The I-SPY Program Project advances the goals of personalized treatment in the setting of an advanced clinical trial design that facilitates continuous improvement in outcomes. In this program, we focus on women with stage 2 and 3 molecularly high-risk, early breast cancer who have the highest risk for rapid progression and death. The I-SPY2.2 program project allows us to generate a patient-centric approach to clinical drug development that optimizes individual, biomarker- targeted treatments by escalation or de-escalation of therapy based on treatment response, doing so in the context of a trial that efficiently evaluates novel potential first-line agents and treatment regimens. The lessons and insights developed in this program project will be broadly applicable beyond breast cancer to other cancers and to clinical trial design. The continuation of the I-SPY2.2 program project will provide the resources for the discovery research that ultimately will increase complete response (pCR) and prevent metastases. The proposed four projects and three shared resource cores will allow us to create strategies for combining multiple biomarker analytes from the tumor and derivatives assessed in circulation to build better and better predictive models of lack of response and poor outcome in the neoadjuvant setting and further identify ‘druggable’ targets in residual disease to alleviate resistance. The I-SPY program and the Program Project have, in effect, established a continuous improvement system for breast cancer treatment outcomes, enabling us to drive progress in precision medicine for breast cancer, importantly, using a highly patient-centric framework. The iterative process will lead to more and better targeting of therapies by leveraging biologic insights, refinement of response- predictive biomarkers, and integration of both efficacy and impact on quality of life. The combination of these elements will save lives, reduce morbidity and set the stage for improved personalization and translation to clinical practice. In the past 5 years of the I-SPY2.2 program project, we have met all of our stated aims, creating and implementing (June 2022) a novel, innovative trial design to both test novel agents and individualize care over the course of the treatment. In the subsequent five years, we will iteratively refine the processes to optimize outcomes through early de-escalation of treatment in the setting of success, and early escalation of treatment in the setting of minimal response, based on our innovations in establishing and refining quantitative breast MRI as a biomarker of response assessment. We will use integrated molecular and immune response-predictive subtypes developed in the first five years to assign treatments for targeted agents initially without standard chemotherapeutics, but then in sequence if response is not sufficient. We will randomize treatments based on the improved, response-predicted subtypes we developed to test their ability to...