Project Summary/Abstract Breast Cancer Related Lymphedema affects 1.2 million patients in the United States and has no cure. The symptoms of lymphedema include fatigue, tightness, pain, and life-threatening infections. However, two-thirds of women undergoing breast cancer treatment with the highest risk factors for developing lymphedema do not develop the disease. While there is no explanation for this finding, one hypothesis is that normal anatomic variations of the lymphatic system pre-dispose certain women to developing lymphedema after breast cancer treatment. Specifically, the main back-up lymphatic pathway of the arm, the Mascagni-Sappey (MS) pathway, is variably present in cadaver studies and avoids areas that are usually damaged with breast cancer treatment. Moreover, when present in these cadaver studies, the MS pathway has variable anatomic connections which can impact its ability to drain the arm effectively. We hypothesize that, utilizing modern imaging techniques, we can define the anatomy of the MS pathway and its variations in normal women and in breast cancer survivors who have undergone high risk breast cancer treatment and did not develop lymphedema. Utilizing this information, we will be able to predict which variations predispose women to develop lymphedema. Finally, we will develop a novel method of non-invasive intra- operative optical imaging to assess the function of this pathway during breast cancer operations to predict the patient's risk of developing lymphedema. The ability to evaluate real-time lymphatic function would allow cancer teams to implement preventive interventions in high risk patients. As the most common cause of lymphedema in the United States is secondary to cancer procedures, this model of lymphedema prevention could be widely applied to the treatment of other high risk cancer populations including gynecologic cancers, urologic cancers, skin cancers, and sarcomas.