Cardiotoxicity of breast cancer drug treatments

Abstract

Breast cancer (BC) is a leading cause of cancer-related mortality among women worldwide. BC is regarded as a systemic disease. Consequently, the majority of BC patients undergo systemic therapy to reduce the risk of distant metastasis (DM) and associated mortality. Although systemic therapies improve patients' outcome, they are associated with significant side effects, particularly cardiotoxicity and cardiovascular complications. Such side effects vary significantly in severity and duration. Cardiotoxicity may remain undetected for years post-treatment until the symptoms of heart failure (HF) present in the patient, which can reduce life expectancy, quality of life, and even lead to death. Therefore, it is vital to investigate the cardiotoxic and cardiovascular risks of BC treatment regimens to identify patients who would benefit most from cardiac monitoring. As it stands, cardiotoxicity is reported from individual studies or for selected drug therapies only. This review fulfils a gap in the literature by combining clinical studies of cardiotoxicity together from clinical trial data published on clinicaltrials.gov.uk.

Keywords: Breast cancer; Cardiotoxicity; Chemotherapy; HER2 targeted therapy.

Graphical abstract

Fig. 1

An overview of breast cancer treatment by subtype. HR+ (ER+/PR+) = hormone positive breast cancers; HER2+ (human epidermal growth factor receptor 2 positive breast cancer); TNBC = triple negative breast cancer; ET= endocrine therapy; ChT = chemotherapy; RT = radiotherapy; OFS = ovarian function suppression. Treatment shown for early and metastatic breast cancer with fundamental differences explained in terms of goals of treatment and use of the different therapies involved. T1 (T1a, T1b, and T1c): tumour is 2 cm or less. T2: tumour is more than 2cm but less than 5cm. N0: cancer not spread to nearby lymph nodes. N+: cancer spread to the nearby lymph nodes. Image created in CorelDRAW.

Fig. 2

PRISMA flowchart showing the study selection process to identify relevant clinical trials reporting on the cardiac safety of breast cancer treatments. Image created in CorelDRAW.

Fig. 3

An overview of the mechanisms underlying treatment-related cardiotoxicity. Anthracyclines can induce cardiotoxicity by upregulation of death receptors in cardiomyocytes. Alkylating agents directly bind to DNA and cause DNA strand breaks. Taxanes can stimulate histamine receptors in cardiac cells causing damage. HER2 targeted therapy e.g. Trastuzumab can cause cardiac cell disruption by interfering with the ErbB/NRG-1 signalling pathway and affect myocyte development. Endocrine therapy such as Aromatase Inhibitors can cause cardiotoxicity by reducing the amount of endogenous oestrogen which increases the risk of CVD (cardiovascular disease). Image created using Inkscape.

Fig. 4

Mechanism of action of Trastuzumab Deruxtecan on breast cancer cells. Trastuzumab (a monoclonal antibody) is covalently linked to Deruxtecan. Trastuzumab attaches to the HER2 protein and delivers the cytotoxic drug directly to the cancerous cell. The cell internalises the cytotoxic compound, killing the cell and releases it to neighbouring cells in a phenomenon called the bystander effect. Image created using Inkscape.