PROJECT SUMMARY/ABSTRACT Objective: We will develop an advanced photoacoustic computed tomography (PACT) breast imaging system capable of detecting anatomical and functional changes in breast cancer treated with neoadjuvant therapy (NAT). Significance: NAT improves outcomes in breast cancer patients by increasing the likelihood of breast conservation, providing important prognostic information, and enabling adaptive therapy such as change in systemic treatment and de-escalation of surgery in exceptional responders. As such, identification of responders enables personalized cancer treatment. Challenges: Current breast imaging does not sufficiently detect breast cancer treatment response. Standard of care (SOC) breast imaging technology either assesses anatomical details or metabolic function, not both. In addition, ionizing radiation, exogenous contrast agents, and patient perceived discomfort and inconvenience usually restrict imaging frequency required for timely evaluation of response. For example, although dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is considered the SOC in breast imaging, this test is limited by the need for intravenous heavy metal contrast, duration of study, patient discomfort, and high resource costs while delivering only moderate accuracy in detection of NAT response. As such, there is no reliable,non-invasive, cost-effective imaging method to identify treatment response.PACT is an emerging technology with great potential to address these problems by imaging both function and anatomy without exogenous contrast. Solutions: Capitalizing on our experience and success in building two PACT breast imaging systems, we propose the construction and clinical testing of an innovative PACT imaging system that integrates the two previous systems to enable both anatomical and functional imaging. The Dual Mode PACT (DM-PACT) will combine dual-sided light delivery, large-view detection aperture, and dense acoustic sampling for rapid functional and high-resolution anatomical imaging to assess treatment-related responses in breast cancer. The imaging features generated by the DM-PACT will be first characterized and correlated with the histopathological results of the resected breast cancer specimens from patients treated with NAT. A diagnostic model using the imaging features will be trained and tested in a larger group of breast cancer patients treated with NAT. We will compare the performance of DM-PACT with the performance of SOC DCE-MRI in treatment response discrimination. The success of this project will result in imaging technology that directs response- driven, personalized breast cancer treatment plans.