Multinuclear MRI to Monitor Breast Cancer Therapy

Project Summary Neoadjuvant chemotherapy (NACT) is administered to treat locally advanced invasive breast cancer by shrink- ing inoperable tumors, and to enable breast-conserving surgery. About 30% of patients have inadequate NACT response, but are not immediately identified by standard imaging such as mammography, ultrasound, or struc- tural magnetic resonance imaging (MRI), and are therefore subjected to unnecessary toxicity and thwarted from customized treatment. An imaging method for early assessment of tumor response to NACT is still needed to identify non-responders that may be candidates for alternative therapy. Our hypothesis is that, in responding pa- tients, cancer cell damage induced by NACT can be characterized by loss of ion homeostasis through changes in pH, membrane depolarization and dysregulation of transmembrane ion transporters. This loss of homeostasis immediately manifests as variations in the intracellular sodium concentration and cellular volume fraction, and po- tentially the cellular microenvironment itself. We therefore propose to implement a new quantitative multinuclear MRI (QMM) protocol, where structural information from proton (1H) MR fingerprinting (MRF) acquired with both CE (T1 pre/post contrast) and dynamic CE (pharmacokinetics) methods, and metabolic information from sodium (23Na) MRF will be acquired simultaneously on a clinical system at 3 T. We will also develop a QMM-based imaging biomarker model that combines the metabolic metrics related to ion homeostasis with the structural and pharmacokinetic metrics to assess changes in cancer cell viability during early NACT as a predictor of therapy response. Specific aim 1: Quantitative multinuclear MRI (QMM) protocol for breast imaging at 3 T. (1.a) To build a 1H/23Na multichannel RF coil for bilateral breast MRI at 3 T. (1.b) To optimize a multinuclear fingerprinting (MNF), which consists of a simultaneous 1H/23Na MRF acquisition. MNF will be acquired with 2 echo times to separate water and fat signals using the Dixon method (Dixon MNF), before and after Gadolinium contrast enhancement (CE MNF), and also during dynamic CE (DCE MNF). (1.c) Optimization of the QMM protocol, which includes diffusion tensor imaging (DTI), CE MNF, DCE MNF, and Dixon MNF. Specific aim 2: Longitudinal application of QMM in patients with breast cancer during NACT. (2) Longitudinal study in patients with triple negative breast cancer (TNBC) that undergo standard clinical NACT regimen, who will be scanned: (1) baseline (pre-NACT), (2) within 1 week of the 1st cycle, (3) within 1 week of the 2nd cycle. Specific aim 3: To develop biomarker model for prognosis of therapy efficiency from QMM data. (3.a) To develop an imaging biomarker model of breast cancer response to therapy based on the combination of metabolic, pharmacokinetic, and structural metrics from the QMM protocol. (3.b) To determine which combinations of biomarkers from the model are best predictor of pathological response after NACT.