Breast cancer therapy and cardiovascular risk: focus on trastuzumab

Abstract

Breast cancer is the most common cancer in the UK. Advances in the methods of early diagnosis as well as newer and more effective treatments have led to improvements of disease-free and overall survival over the last decade. Almost one-third of breast cancers present with an aggressive form characterized by increased expression of human epidermal growth receptor 2 (HER2) proteins. A targeted treatment using monoclonal antibodies against HER2 expression such as trastuzumab has been shown to improve survival. Unfortunately, there is a degree of cardiotoxicity associated with these agents, as inhibition of HER2 pathways can also impair cardioprotective pathways. In the present review, we discuss the mechanisms by which trastuzumab might affect vascular homeostasis leading to endothelial dysfunction. We also provide suggestions for future research examining the effects of trastuzumab on the vasculature in breast cancer.

Keywords: congestive heart failure; endothelial dysfunction; macrovasculature; microvasculature.

Figure 1

The generation of reactive oxygen species following inhibition of the neuregulin/HER2 pathway. Abbreviations: HER, human epidermal growth receptor; ANG II, angiotensin II; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; PGDF, platelet-derived growth factor; TGF-α, tumor growth factor-alpha.

Figure 2

The effects of trastuzumab on the vasculature and its subsequent contribution to congestive heart failure. Notes: Administration of trastuzumab inhibits HER2 receptors, which prevents dimerization with the neuregulin–HER4 complex. This subsequently causes a reduction in eNOS expression and NO bioavailability, along with a concomitant increase in ANG II and ROS. These processes culminate in endothelial dysfunction which is characterized by reduced vasodilatory capacity, enhanced vasoconstrictor tone, and endothelial injury. Endothelial dysfunction is a well-established causal factor for congestive heart failure because it increases systemic vascular resistance, afterload, and myocardial workload, but reduces coronary microvascular blood flow. Abbreviations: ANG II, angiotensin II; eNOS, endothelial nitric oxide synthase; HER, human epidermal growth receptor; NO, nitric oxide; ROS, reactive oxygen species.