Project Summary/Abstract Radiotherapy is essential to achieve durable disease control for breast cancer patients. However, despite several decades of research and development in imaging and radiotherapy techniques, breast radiotherapy remains crude due to the lack of viable methods to accurately isolate, immobilize, localize and target the breast. Subsequently, the success of tumor control is at the cost of both acute and chronic toxicities that adversely affect the patients’ quality of life and potentially introduce life-threatening complications decades after the curative treatment. The challenge in providing accurate breast imaging and therapy is due to the unique biomechanical properties of the breast, which is an external organ with no internal skeletal support. As a result, its shape varies substantially with the patient's posture. In the supine position, which is the most stable and common position for radiotherapy, the breast rests on the chest wall, resulting in its close proximity to the chest wall, lung, heart, and other vital organs, which creates an undesirable geometry for radiotherapy. Yet, existing devices for supine breast setup not only provide poor support and immobilization but also adversely interfere with imaging and therapy X-rays. Patients treated in the prone position experience new problems, including the lower setup reproducibility, increased cardiac dose due to heart descending, the difficulty to tolerate, and incompatibility with nodal treatment. To attain the desirable prone breast geometry and avoid drawbacks associated with this posture, a more effective method to lift the breast from the chest wall and to image the breast in the supine position is urgently needed for precision image-guided breast radiotherapy. To achieve the first goal, a pneumatically powered multi-gait soft robot, BreastBot, will be developed and optimized to support and immobilize the breast in the supine position. The BreastBot will be fabricated in several generic form factors to minimize the cost but personalized for each breast via an individualized actuation sequence. The feasibility of BreastBot has been demonstrated using single gait prototypes on volunteers and phantoms. To achieve the second goal, which is to image the BreastBot immobilized breast for image-guided radiotherapy, avoid imaging dose to the patient's body, and achieve a higher image quality, a novel supine ceiling-mounted breast CT will be developed. The following four aims are proposed for image-guided supine breast radiotherapy. Aim 1: Optimization of a breast setup soft robot (BreastBot) for supine breast setup. Aim 2: Development of a ceiling-mounted CBCT for breast image- guided radiation therapy. Aim 3: Specific Aim 3: End-to-end integration, validation, and observational patient study.