ABSTRACTDedicated breast CT can eliminate tissue superposition that contributes to false-positives and false-negatives and alleviates the need for physical compression of the breast. It provides for 3D images atnear-isotropic spatial resolution that allows for viewing the breast in any orientation without the need forrepeat acquisitions. It is an emerging technology with only about five teams conducting researchworldwide. In order to develop evaluate accelerate its clinical translation and to facilitate the widespreadclinical adaptation of this technology we are collaborating with GE Global Research to develop an uprightpatient positioning geometry with advanced technological capabilities designed to eventually allow forbreast cancer screening in addition to diagnostic imaging. The technological advanced proposed includean x-ray imaging detector with reduced system (electronic) noise data readout rates improved by a factor ofat least 2 and improved spatial sampling (pixel pitch) by a factor of 2 or more; a short-scan acquisitiontrajectory with angular range not exceeding 270-degrees that will improve patient positioning; and the useof model-based iterative reconstruction techniques. All these technological advances are focused onimproving posterior coverage reducing the radiation dose to the breast so that it is similar to a standard 2-view mammography exam and improving the visualization of microcalcifications; all with an aim of making itsuitable for breast cancer screening in the future. Importantly the upright geometry allows for rapid clinicaladaptation as it allows for easy replacement of mammography and digital breast tomosynthesis systemseven in small mammography rooms and addresses the patient discomfort observed with the prone breastCT. The research is broadly organized in two phases. In the first phase all design factors and operationalparameters will be verified through physics-based numerical simulations and empirical studies using thebench-top prototype system. In the second phase we will conduct a clinical feasibility study that will recruitsubjects from two cohorts: BIRADS 4/5 and screening population to determine if the advancedtechnological approach using the upright low-dose high-resolution dedicated breast CT system improvesthe diagnostic accuracy compared to digital breast tomosynthesis. To our knowledge this will be first studyto directly compare digital breast tomosynthesis with dedicated breast CT. Thus the proposed research willdevelop an innovative design concept for unprecedented impact in breast cancer imaging that will enablebreast imaging without physical compression and at radiation dose similar to mammography. To ourknowledge a compression-free breast CT system incorporating the aforementioned features does not exist.