Breast Cancer Radiation Therapy and the Risk of Acute Coronary Events: Insights From a Process-Oriented Model

Abstract

Acute coronary events (ACEs) are considered the most important side effect of radiation therapy (RT) for breast cancer, but underlying mechanisms still have to be identified. Process-oriented models mathematically describe the development of disease and provide a link between mechanisms and subsequent risk. Here, this link is exploited to learn about the underlying mechanisms from the observed age-time patterns of ACE risk. A process-oriented model of atherosclerosis and subsequent ACEs was applied to a contemporary breast cancer cohort of 810 patients with measurements of coronary artery calcification. Patients with prior ischemic heart disease were excluded. The process-oriented model describes disease development as a series of different stages. Different variants of the model were fitted to the data. In each variant, one stage was assumed to be accelerated in relation to mean heart dose. During a mean follow-up of 9.1 years, 25 ACEs occurred. The model reproduced the prevalence and associated risk of coronary calcifications. Mean heart dose significantly improved the fit only when implemented as affecting a late stage of atherosclerosis on already-existing complicated lesions (achieving P=.007). This can be understood by atherosclerosis being a slowly progressing disease. Therefore, an increase in ACEs a few years after RT requires advanced atherosclerosis at the time of RT. Risk of ACE increases within a few years in patients with advanced atherosclerosis at RT. Therefore, patients should be assessed for cardiovascular risk, and older patients need to be considered for heart-sparing techniques.