Cardiac Toxicity is Not Increased 25 Years After Treatment of Early-stage Breast Carcinoma With Mastectomy or Breast Conservation Therapy From the National Cancer Institute Randomized Trial

Assessment of late cardiac toxicity from the National Cancer Institute (NCI) randomized trial of breast conservation therapy (BCT) versus modified radical mastectomy (MRM). Two hundred forty-seven stage I-II breast cancer pts treated from 1979-1987 at NCI were randomized to BCT (45-48.6 Gy whole breast, 15-20 Gy boost) or MRM. Node positive pts received doxorubicin and cyclophosphamide. One hundred two pts were alive at 25.7 yrs, and 50 pts (26 BCT, 24 MRM) participated in this prospective IRB-approved study with a detailed cardiac history, exam, cardiac labs, 3T cardiac MRI (CMR) to evaluate for anatomic and functional abnormalities, and CT angiogram to evaluate for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden. Imaging was assessed by a single experienced cardiologist blinded to randomization arm. Pt characteristics, exam findings, and labs were similar between arms, although MRM pts trended to have higher systolic blood pressures (SBP, 139 mmHg vs. 127 mmHg) and rates of diabetes (12.5% vs. 3.8%, p = 0.27). Among BCT pts, radiation central lung distance >3 cm was similar for right- versus left-sided tumors (35.7% vs. 50.0%, p = 0.48). Cardiac interventions (CABG or PCI) occurred in 4 MRM and 3 BCT pts. Two pts had prior myocardial infarction (MI) and one had heart failure (all MRM pts). Framingham 10-yr risk of MI was similar between arms (BCT 5.1 vs. MRM 5.7%). CMR showed lower ventricular mass in BCT pts (91 vs. 110 gm, p = 0.02) that was not significant after adjusting for SBP. Diastolic function, including peak filling rate (p = 0.29) and diastolic volume recovery (p = 0.28), was similar between arms. Other CMR findings, including peak midwall strain and chamber mass, volume and function, were similar between arms. No pt had evidence of myocardial fibrosis. One pt in each arm had pericardial thickening. Among BCT pts, cardiac structure and function were similar for right or left tumors. Median CAC was similar in both arms (BCT 25 [IQR 0, 86] vs. MRM 0 [IQR 0, 354] p = 0.65). BCT pts had no increase in visible atherosclerosis (HR = 1.12, p = 0.80) or luminal stenosis >50% (HR = 0.64, p = 0.62). Prevalence, severity and distribution of atherosclerosis were not different in BCT pts for right- or left-sided radiation, including LAD (close proximity to the chest wall, received the highest RT dose) (38.9% vs. 33.3%, p = 0.73). Chemotherapy pts trended towards more visible atherosclerosis independent of randomization arm (HR = 2.4, p = 0.07). This is the first study to report comprehensive late cardiac outcomes after randomization for breast cancer therapy. Based on this study, in the era of 3D planning, pts treated with breast radiation therapy do not have a higher risk of long-term cardiac morbidity compared with MRM pts.