PROJECT ABSTRACT Lymphedema is a debilitating, life-long iatrogenic sequalae of cancer treatment which is becoming an important survivorship issue due to improved cancer survival. Patients with inflammatory breast cancer (IBC), a highly aggressive form of breast cancer, require systemic therapy, surgery, and radiation therapy for oncological control. These treatments place them at the highest risk of developing lymphedema, with approximately 50% developing it within 12 months following surgery. Therefore, developing strategies to predict and prevent treat lymphedema would significantly impact the well-being of patients with IBC. General strategies for treating lymphedema include physical therapy and the continuous use of compression garments, and surgical treatments have recently been introduced that can provide some improvement in the swelling and symptom burden. Given the incomplete outcomes of these interventions, especially for a high-risk group like IBC patients, focus has recently shifted to risk-reducing surgeries. Immediate lymphatic reconstruction (ILR) of lymphatic vessels at the time of axillary lymphadenectomy (ALND) has resulted in significantly lower rates of lymphedema among breast cancer patients for patients who received ILR. Unfortunately, none of the studies on ILR have focused on IBC patients, or have investigated longitudinal outcome measures, which would enable comprehensive outcome assessment, including identification of potential biomarkers. We propose a single-arm, clinical trial investigating the impact of ILR on the development of lymphedema in IBC patients at a single, high-volume center specializing in treatment of IBC patients. We hypothesize that ILR in patients with IBC is preventative against lymphedema development as defined by objective clinical threshold measurements, and prevents changes in lymphatic architecture and pumping characteristic of lymphedema visualized using near-infrared fluorescence lymphatic imaging (NIRFLI), as well as functional alterations in peripheral blood immune cells associated with lymphedema development. This hypothesis will be addressed in the following Specific Aims: (1) to determine the incidence of clinical lymphedema in IBC patients following ILR; (2) to establish a longitudinal, dynamic, imaging-based profile of IBC patients following ILR using NIRF-LI to provide real-time visualization and objective characterization of changes in lymphatic vessel architecture and function; and (3) to identify a blood-based, inflammation-related signature of lymphedema in patients with IBC through longitudinal analysis of serum samples from our clinical trial cohort, using an inflammatory cytokine/ chemokine array. The proposed trial will allow objective assessment of lymphatic vessel anatomy and functional changes in lymphedema, as well as to define immune characteristics that correlate with lymphedema development. If successful, this work would provide impetus to change the surgical standard-of-care for patients with IBC and help direct highest risk patients to specialized treatment centers for surgical intervention.

PROJECT NARRATIVE This clinical trial is focused on prevention of lymphedema by immediate lymphatic reconstruction (ILR) at the time of ALND in patients treated for inflammatory breast cancer (IBC), who have almost double the rate of lymphedema compared with the overall breast cancer patient population, to improve the quality-of-life in cancer survivors. The study proposal will determine the incidence of clinical lymphedema in IBC patients following ILR, establish a longitudinal, dynamic, imaging-based profile of changes in lymphatic vessel architecture and function following ILR using near-infrared fluorescence lymphatic imaging (NIRF-LI), and characterize longitudinal changes in serum inflammatory cytokines/ chemokines following this surgery, comparing these metrics in patients that develop lymphedema following ILR with those that do not. If successful, our work would provide impetus to change the surgical standard-of-care for patients with IBC and help direct the highest risk patients to specialized treatment centers for surgical intervention.