This work will apply novel, noninvasive structural and functional magnetic resonance imaging (MRI) methods to patients with mild and moderate breast cancer-related lymphedema (BCRL) for the first time to test fundamental hypotheses about relationships between lymphatic compromise and imaging biomarkers that may portend disease progression and individualized therapy response. BCRL is a chronic, debilitating disease caused by lymphatic flow obstruction in the legs, arms, and shoulder regions. Lymphedema secondary to mastectomy and radiation therapy is a growing health concern and has been reported to occur, on average, in 20% of women within three years after breast cancer treatment and in as many as 94% of women five years after breast cancer treatment. While there is no cure for lymphedema, it has been shown that behavioral adjustments and aggressive therapeutic management of patients in early or subclinical disease stages can prevent or reduce long-term impairment. However, very limited information is available for identifying patients at highest risk for lymphedema. Several specialized imaging methods have demonstrated that reduced lymphatic flow velocity and related lymphatic contractility impairment may portend lymphedema risk, however these approaches require radioactive tracers and/or exogenous contrast agents, are generally only available in specialized centers, and are not performed in routine patient management. We have very recently demonstrated that arterial spin labeling (ASL), a popular and noninvasive MRI method for measuring blood flow, can be adapted to measure flow of lymphatic fluid to axillary lymph nodes, and furthermore that lymphatic velocities reported using this technique are consistent with similar measures using exogenous contrast agents. Additionally, we have shown that chemical exchange saturation transfer (CEST) MRI can be used to characterize interstitial protein accumulation in patients in preclinical BCRL stages prior to limb volume changes. Importantly, both spin labeling and CEST utilize standard MRI equipment available at most hospitals and therefore can easily be disseminated to clinical or research centers seeking to expand their abilities to characterize lymphatic compromise. Here, we propose to assess the ranges of lymphatic flow velocities and interstitial protein accumulation in healthy individuals (Aim 1) and BCRL patients in preclinical, mild, and moderate stages of impairment (Aim 2), and finally to assess how lymphatic system compromise changes in response to manual lymphatic drainage therapy and to what extent lymphatic flow velocity and interstitial protein accumulation may predict lymphedema progression (Aim 3). This work will for the first time apply a noninvasive, multi-modal MRI protocol, which has demonstrated clinical potential in neuroscience, liver, and breast applications, to the human lymphatic system to better characterize lymphatic dysfunction and lymphedema risk in the growing breast cancer survivor population.
Lymphedema is a chronic, debilitating disease caused by lymphatic flow obstruction and lymphedema secondary to mastectomy with radiation therapy has been reported to occur in as many as 94% of breast cancer survivors. However, owing to a lack of methodology for sensitively identifying lymphatic system compromise, there are important gaps in our knowledge regarding which patients are at highest risk and how and when therapies should be applied to minimize impairment. Here, principles of arterial spin labeling (ASL) and chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI), two popular and noninvasive methods for measuring blood flow and biochemical profiles in brain, breast, and liver, are applied to assess internal measures of lymphatic system dysfunction in multiple stages of impairment and in response to therapy.