Cardiac MRI for Evaluation of Radiation-Induced Cardiotoxicity in Breast Cancer Patients: A Phase II Clinical Trial

Purpose/Objective(s): In women irradiated for breast cancer (BC), a clear relationship between radiation (RT) dose and subsequent cardiac events has been documented. To date, however, no biomarkers of cardiac toxicity have been shown to identify women at risk for developing cardiac disease following BC RT. We hypothesized that early MRI (to detect early fibrosis, edema, perfusion, and volume changes) and serum biomarker changes could predict cardiac injury and risk of subsequent cardiac events. Here we report the findings of 2 clinical trials both designed to assess this hypothesis and the association between radiation dose to the heart and anatomically defined cardiac substructures with changes on early MRI in a cohort of women irradiated for left-sided BC. Materials/Methods: Women with N-/+ left-sided BC were enrolled on 2 IRB-approved clinical trials conducted at 2 institutions and baseline clinicodemographic data, including cardiac risk factors, were collected. ECG-gated steady state free precession imaging MRI was conducted pretreatment, 1 month post-, and 3-6 months’ post-treatment to quantify left and right ventricular (LV/RV) volumes and function. Pre-contrast quantitative T1- and T2-mapping to assess myocardial fibrosis and edema was also performed on all patients. Additionally, regadenos on stress perfusion mapping was performed on a subset of patients. Serum markers (cTnl, ET-1, I-6, hsCRP, cholesterol, HDL, LDL, Trig, and NT pro-BNP) were collected at the same time points. The whole heart and cardiac substructures contoured using CT and MRI were reviewed for consistency. Models were constructed using baseline risk factors (age, underlying CAD, cardiac risk, smoking, BMI, and doxorubicin exposure). Associations between MRI-measured changes and dose were evaluated and institutional equipment variances were controlled for. Results: Fifty-one women were enrolled on study. The range of mean doses to the heart was 0.85-4.69 Gy and to the LV 1.30-8.16 Gy, with mean (Dmean) heart dose 2.0 Gy. T1 time, a marker of fibrosis, changed significantly and RV ejection fraction (EF) decreased significantly with treatment, but these were not dose dependent. T2 (marker of edema) and LV EF did not significantly change. No risk factors were associated with baseline global perfusion, although higher BMI was associated with lower baseline anterior perfusion (p 0.07). Prior receipt of doxorubicin was most significantly associated with changes in cardiac perfusion after RT (decreased perfusion, p 0.059) and mean heart dose was not associated with perfusion changes. Conclusion: In these 2 prospective trials of women with left-sided BC treated with contemporary RT treatment planning, cardiac doses were very low. Although RT treatment was associated with significant changes in T1 and RV EF shortly after RT, these changes were not correlated with dose to the whole heart or any substructures. Serum biomarkers of cardiac injury after radiation are currently being analyzed, which will be folded into a subsequent analysis