Primary and secondary objectives
The primary objective of this study is to investigate and compare the prognostic value of cardiac MRI parameters (native and postcontrast T1 mapping, ECV, right ventricular (RV), LV systolic function, and global longitudinal strain of LV) for cardiotoxicity. The endpoint is MACEs.
The secondary objectives are to determine the temporal relationships between contractile dysfunction and microstructural injury over a four-year period using cardiac MRI across all patients and by subgroup analysis according to treatment (e.g., chemotherapy regimen, targeted therapy agents, and radiation dose) and to compare the diagnostic accuracy of MRI, echocardiography or multigated acquisition (MUGA) by subgroup analysis.
Inclusion criteria
Patients ≥18 years of age are considered eligible if, following the initial oncology consultation, breast cancer is diagnosed and related therapeutic plans are formulated. All subjects will agree to participate by giving both verbal and written informed consent. This prospective study was approved by the institutional review board of Yonsei University College of Medicine.
Exclusion criteria include prior mammoplasty, history of other cancers, confirmed benign breast disease, poor image quality due to uncontrolled breast holding, arrhythmia, or patients with contraindications to MRI (i.e., claustrophobia, estimated glomerular filtration rate (eGFR) < 30).
Cardiac MRI protocol
A standardized breast and cardiac MR examination will be performed with 3 T MR scanners with an 8-channel breast coil (GE MRI 750w, GE Healthcare, Milwaukee, WI, USA). Because breast MRI is performed with the patient in a prone position, peripheral pulse gating will be applied for cardiac imaging.
The cardiac protocol includes pre- and postcontrast T1 mapping, T2 mapping, and cine imaging of both ventricular myocardia. Motion-corrected native T1 and postcontrast T1 and T2 mapping images will be acquired at the end of diastole in the short axis orientation of mid LV using a FIESTA-based 3(3)5 MOLLI sequence. Post-contrast T1 images will be acquired 15 min after the bolus injection of the contrast agent (0.1 mmol/kg body weight of gadolinium-based contrast agent, Gadobutrol 604.76 mg/ml).
The imaging parameters for the 2D FIESTA cardiac cine MRI will be set as follows: flip angle = 45°, repetition time (TR) = 3.0 ms, echo time (TE) = 1.1 ms, field of view (FOV) = 390 × 390 mm, matrix = 160 × 192, measured pixel size = 2.4 × 2.0 mm, slice thickness = 8 mm (2 mm gap between adjacent slices), number of slices = 9, temporal resolution = 60 ms, and ASSET factor = 2.
The specific scan parameters for T1 mapping will be set as follows: flip angle = 35°, TR = 2.8 ms, TE = 0.9 ms, FOV = 300 × 300 mm, matrix = 160 × 128, delay time (TD) = 220 ms, measured pixel size = 1.9 × 2.3 mm, slice thickness = 8 mm, and acquisition window = 361 ms.
The specific scan parameters for FSE-based black blood T2 mapping will be set as follows: TR = 1 RR; total echo train length (ETL) = 16; FOV = 300 × 300 mm; matrix = 160 × 128; measured pixel size = 1.9 × 2.3 mm; slice thickness = 8 mm; 4 echoes with effect TEs = 11.3, 33.9, 56.5, and 79.1 ms; acquisition window = 91 ms; and ASSET factor = 2.
Sequential short axis cine imaging will be performed including the entire ventricular myocardium in addition to standard long-axis views using the 2D FIESTA sequence. The specific scan parameters will be set as follows: flip angle = 45°, TR = 3.0 ms, TE = 1.1 ms, FOV = 390 × 390 mm, matrix = 160 × 192, measured pixel size = 2.4 × 2.0 mm, slice thickness = 8 mm (2 mm gap between adjacent slices), number of slices = 9, temporal resolution = 60 ms, and ASSET factor = 2.
The sequences for breast MR examination include a three-plane localizing sequence, axial T2-weighted fast-spin- echo and T2-stimulated inversion recovery (STIR) sequence, and diffusion-weighted imaging before contrast administration. 3D dynamic postcontrast-enhanced (DCE) images and a T1-weighted 3D delayed postcontrast sequence will be acquired in the sagittal plane after contrast injection.
Native T1 and T2 images will be acquired between T2-STIR and diffusion images, while postcontrast T1 images will be acquired after delayed postcontrast images. Cine images will be acquired before dynamic images. Precontrast T1 and T2 mapping images will be acquired before DWI imaging, and postcontrast T1 mapping imaging will be performed after dynamic contrast imaging. The hematocrit (Hct) levels of the patients will be acquired on the day of cardiac MRI.
Cardiac MRI analysis
Both ventricular volumes and systolic function
All MR images will be analyzed using cvi42 image analysis software (Circle Cardiovascular Imaging Inc., Calgary, AB, Canada). Short-axis cine images will be analyzed using semi-automated contouring of the endocardial and epicardial borders of both ventricles at end-diastole and end-systole to calculate both ventricular function (i.e., RV, LV end-diastolic volume (RVEDV, LVEDV), end-systolic volume (RVESV, LVESV), cardiac output, stroke volume, RVEF, and LVEF).
T1 and T2 mapping analysis
One native T1, one postcontrast T1, and one T2 mapping image acquired on the mid LV will be transferred to the software. A region of interest (ROI) will be freely drawn on the septum. Images with severe artifacts will be coded and removed from the analysis.
Mean segmental native T1, T2, and postcontrast T1 values are calculated for each patient. ECV values are calculated using the mean values of native and postcontrast T1 and hematocrit, as previously established [
13].
Myocardial strain analysis
Feature tracking analysis will also be performed using cvi42 software. The long axis and short-axis cine images will be loaded onto the software. Endocardial and epicardial borders of the LV in both the long- and short-axis views were semi-automatically delineated in the end-diastolic phase. The feature software automatically measured the global longitudinal strain in the two-dimensional (2D) longitudinal directions. Analysis of interobserver agreement in regard to MRI measurements will be performed.