Cardiac toxicity of trastuzumab in elderly patients with breast cancer

Abstract

Breast cancer (BC) is diagnosed in ≥ 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unfortunately, administration of trastuzumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure (CHF), possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%-15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in > 60-65 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques (three-dimension, tissue Doppler echocardiography, magnetic resonance imaging) is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart.

Keywords: Cardiotoxicity; Elderly; HER-2; Heart failure; Trastuzumab.

Figure 1.. Schematic representation of the NRG-1/HER-2 paradigm for trastuzumab cardiotoxicity.

In oncology, trastuzumab is used to treat breast cancer in which HER-2 is overexpressed and spontaneously homodimerizes or forms heterodimers with other HER receptors, especially HER-3. As this ligand-independent activation of HER-2 sustains tumor growth and survival, trastuzumab halts the proliferation and causes the death of tumor cells (left side). In the heart, HER-2 functions as a dimerization partner of HER-4 after this latter is recruited by NRG-1 and regulates homeostatic cell responses. Off-target inhibition of cardiac HER-2 results in the disruption of part of NRG-1 dependent signaling and, eventually, in alterations of structure and function that may be lethal to cardiomyocytes (right side). HER: human epidermal growth factor receptor; NRG-1: neuregulin.