Trastuzumab cardiotoxicity: from clinical trials to experimental studies

Abstract

Epidermal growth factor receptor-2 (HER-2) is overexpressed in 20 to 25% of human breast cancers, which is associated with aggressive tumour growth and poor prognosis. Trastuzumab (Herceptin®) is a humanized monoclonal antibody directed against HER-2, the first highly selective form of therapy targeting HER-2 overexpressing tumours. Although initial trials indicated high efficacy and a favourable safety profile of the drug, the first large, randomized trial prompted a retrospective analysis of cardiac dysfunction in earlier trials utilizing trastuzumab. There has been ongoing debate on the cardiac safety of trastuzumab ever since, initiating numerous clinical and preclinical investigations to better understand the background of trastuzumab cardiotoxicity and evaluate its effects on patient morbidity. Here, we have given a comprehensive overview of our current knowledge on the cardiotoxicity of trastuzumab, primarily focusing on data from clinical trials and highlighting the main molecular mechanisms proposed.

Linked articles: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.

Figure 1

Cardiotoxicity of doxorubicin and anti‐HER‐2 treatment in breast cancer. Anti‐HER‐2 treatment results in diminished pro‐survival signalling in cardiomyocytes. Gene expression, ATP‐ and nitric oxide production favouring survival and proliferation are attenuated. In parallel, without appropriate counterbalancing, pro‐apoptotic and necrosis‐inducing processes such as cytochrome‐c release from mitochondria and an increase in intracellular calcium concentration can facilitate cell death. The addition of doxorubicin to the system boosts oxidative and nitrosative stress via increased mitochondrial and iron‐dependent generation of superoxide, which then is transformed into hydrogen peroxide and peroxynitrite. These reactive oxygen and nitrogen species are capable of inducing oxidative DNA damage, further aggravating the imbalance between pro‐survival and pro‐apoptotic/necrotic signalling. Green lines represent pro‐survival mechanisms, while red lines show pro‐apoptotic/necrotic processes. Dashed lines indicate an indirect connection. Akt – protein kinase B; Cyt‐C – cytochrome‐c; Dox – doxorubicin; MAPK – mitogen activated protein kinase; NO – nitric oxide; NOS3 – endothelial nitric oxide synthase; NRG‐1 – neuregulin‐1; ONOO⁻ – peroxynitrite; PI3K ‐ phosphatidylinositol‐3‐kinase; PKG – protein kinase G; Pln – phospholamban; SERCA2 – sarcoplasmic/endoplasmic reticulum Ca^{2 +}‐ATPase 2; SOD – superoxide dismutase.

Figure 2

Timeline of development of anti‐HER‐2 treatment. Discovered in 1985, HER‐2 rapidly emerged into the centre of focus after its linkage to poor clinical outcomes in breast cancer patients was shown. Proliferation of breast cancer cells was successfully decreased using mouse mAbs developed against HER‐2, and humanization of the most active 4D5 enabled it to enter the clinical stage. Despite the unexpected adverse cardiac effect of trastuzumab, the drug was approved by the FDA to treat metastatic breast cancer in 1998. Since then, anti‐HER‐2 treatment options have broadened with the approval of lapatinib and pertuzumab in 2007 and 2012 respectively. FDA – Food and Drug Administration; mAb – monoclonal antibody.