Metabolic Sodium MRI to Assess Early Response of Breast Cancer to Neoadjuvant Chemotherapy

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Project Summary Neoadjuvant chemotherapy (NACT) is administered to treat invasive breast cancer before surgery. NACT offers the opportunity to evaluate tumor response to treatment in aggressive disease, and guide additional therapies for patients with inadequate response. Although methods such as dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) and diffusion weighted imaging (DWI) can detect subsequent structural change in tumors (size, cellularity), insight on the tumor's metabolic response could inform patient care at an early stage in the treatment program. We propose to develop metabolic breast sodium (23Na) MRI to assess the metabolic response to NACT as soon as possible. Sodium MRI is based on the direct detection of endogenous sodium ions (Na+) in tissues, and allows a quantitative assessment of ion homeostasis, that is vital for cell viability. We propose to develop our technique at 7 T in order to generate 23Na images with adequate resolution to characterize small lesions common in breast cancer. Our hypothesis is that cell damage induced by NACT can be characterized by loss of ion homeostasis in the abnormal cells forming the malignant tumor, through dysregulation of their trans-membrane ion transporters, leading ultimately to cancer cell death and subsequent tumor shrinkage. As a consequence, large variations of Na+ concentrations inside the cancer cells are induced, which can be quantified with 23Na MRI. Measuring variations of both intracellular sodium concentration C1 (cell damage) and extracellular volume fraction 2 (cell death, inflammation) with 23Na MRI will give new metabolic information on the early effects of NACT, before tumor size reduction occurs. Our goal is to develop a 23Na MRI method to measure two new metabolic imaging biomarkers of loss of homeostasis (C1 and 2), and assess the efficacy of NACT in breast cancer as early as possible. Ultimately, the benefit for the patient would be the possibility of tailored breast cancer therapy. Specific aims are: AIM 1, Methodological development of metabolic 23Na MRI. (1.a) To build a dual-tuned multichannel radiofrequency coil (with 13 23Na-channels and 1 1H-channel per breast) that will allow bilateral breast 1H/23Na MRI at 7 T. (1.b) To optimize data acquisition and image reconstruction to generate 23Na images of the breast with 2.5-3 mm resolution in 7 min. We will perform DCE MRI for comparison. (1.c) To develop a software to quantify C1 and 2 based on 23Na MRI data and a model of cancer cells. A mechanistic model of loss of ion homeostasis due to NACT will also be developed in order to interpret the results. Reproducibility and repeatability will be assessed. AIM 2, Application of 23Na MRI to assess response of breast cancer to NACT. (2.a) To scan 12 patients with triple-negative breast cancer undergoing AC-T therapy (2 months of Adriamycin + Cyclophosphamide, then 3 months of Taxol): at baseline (pre-NACT); after the first AC cycle (2 weeks); after AC treatment (2 months); after complete NACT (5 months, pre-surgery). (2.b) To compare C1, 2, and tumor size at all 4 time-points. Using statistical analysis and the mechanistic model, we will assess which measurements are best predictors of the outcome at the end of AC treatment, and of NACT.