Association of Left Anterior Descending Coronary Artery Calcium Progression and Radiation Dose with Major Adverse Cardiac Events in Breast Cancer

Coronary artery calcium (CAC) is associated with increased risk of major adverse cardiac events (MACE). Accelerated CAC progression has been observed in patients with breast cancer after radiotherapy (RT) and there is a relationship between left anterior descending (LAD) coronary artery RT dose and the risk of coronary events. However, there is lack of consensus on LAD dose constraints for breast RT and limited data on the extent and impact of CAC progression. Our objective was to evaluate the association of LAD dose exposure and CAC progression with the risk of MACE in patients with breast cancer following RT.Retrospective analysis of 181 patients with breast cancer treated with RT between 2008 and 2019. CAC was manually measured on RT planning and follow-up CTs (with at least one-year interval) using the Agatston method. Coronary arteries were segmented using a deep learning-based automated algorithm and dosimetric parameters collected. MACE cumulative incidence was estimated, and Fine and Gray regressions performed, accounting for non-cardiac death as a competing risk.The median follow-up following RT was 70 months (interquartile range [IQR], 53-86). The median age was 63 years (IQR, 53-72), 43% had hypertension, 40% hyperlipidemia, 8% coronary heart disease (CHD). Most had pathologic stage I-II disease (76%). RT was targeted to breast/chest wall only in 60% and included regional nodes in 40% (internal mammary chain in 4%). The most common dose/fractionation was 48-50.4 Gy/25-28 fractions (67%) and 42.6-42.7 Gy/16 fractions (30%). At the time of RT, 68 (38%) had at least moderate CAC burden (CAC >100; statin-therapy indicated), but only 29 (43%) were on statin therapy. At a median interval of 44 months (IQR, 26-63), 55% (n = 84) had CAC progression, with a median increase of 52%/year (IQR, 18-193). The median time to MACE was 68 months (IQR, 53-85), with a 5-year cumulative incidence of 7.3% (15 MACE overall). Accounting for age and CHD, there was an increased risk of MACE with LAD CAC progression (subdistribution hazard ratio [SHR] 1.02/10 CAC points; 95% confidence interval [CI] 1.01 = 1.03; p = .007) and the volume of LAD receiving 15 Gy (LAD V15 Gy; SHR 1.03/%; 95% CI, 1.01-1.06; p = .004). There was no association between mean heart dose, chemotherapy, or Her2 therapy exposure and MACE (p>.05).LAD CAC progression and LAD V15 Gy dose exposure were associated with an increased risk of MACE following RT. Accelerated CAC progression was commonly observed, however most patients were under-optimized for cardiovascular (CV) risk, with less than half of statin-eligible patients with at least moderate CAC burden on statin therapy. Together, these data support more aggressive cardiac risk mitigation approaches, including guidelines-based CV risk factor modification and optimized sparing of LAD radiation dose.