Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab

Abstract

Background: Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a large group of patients treated with pertuzumab.

Patients and methods: A complete database of patients treated with full-dose pertuzumab was used to describe the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) and symptomatic heart failure (HF).

Results: Information for 598 unique patients was available for the current analysis. Of the patients treated with pertuzumab alone (n = 331) or pertuzumab in combination with a non-anthracycline-containing cytotoxic (n = 175) or trastuzumab (n = 93), 23 (6.9%), 6 (3.4%), and 6 (6.5%), respectively, developed asymptomatic LVSD and 1 (0.3%), 2 (1.1%), and 1 (1.1%), respectively, displayed symptomatic HF. None of the 15 patients receiving both pertuzumab and erlotinib demonstrated LVSD.

Conclusions: Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects when pertuzumab was given in combination with other anticancer agents.

Figure 1.

Human epidermal growth factor receptor (HER) 2 signaling pathways involved in tumorigenesis and cardiac survival. (A) In breast cancer cells, HER dimer formation results in cross-phosphorylation of the dimer tyrosine kinase domain and leads to the initiation of mitogenic cell signaling pathways, including activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways [2]. While the HER2 to HER3 heterodimer is considered the most potent HER dimer with respect to strength of interaction, ligand-induced tyrosine phosphorylation, and downstream signaling, other dimer pairs do show weak mitogenic activity [3]. Blocking HER2 signaling with trastuzumab [4] or HER2 dimerization with pertuzumab [1] prevents activation of the signaling pathways that mediate cell proliferation and survival. (B) In cardiac myocytes, activation of cardiac stress pathways results in release of neuregulin that stimulates the formation of HER2:HER4 and HER4:HER4 dimers. These activate downstream signaling pathways, resulting in the promotion of cardiomyocyte growth and cardiac repair mechanisms [–7]. However, under conditions of HER2 inhibition, the homeostatic cardioprotection afforded by the activation of these downstream pathways may be attenuated, resulting in vulnerability to cardiac stress. (C) Anthracycline exposure exerts direct cytotoxicity against cardiac myocytes, resulting in the cardiotoxic effects of these agents. Activation of the stress pathway described in panel B may afford some protection from the cytotoxic effects of anthracycline exposure. However, it is possible that HER2 inhibition in the presence of anthracycline stress may further attenuate the innate cardioprotective mechanisms by preventing the induction of HER2:HER4-mediated stimulation of cardiomyocyte growth and cardiac repair mechanisms, thus limiting the capacity for cardiac repair. Therefore, inhibition of HER2 dimerization in association with anthracycline therapy can exacerbate anthracycline-induced cardiac damage [8, 9].