Negative effects of trastuzumab adjuvant chemotherapy on cardiac mechanics. role of specific myocardial layers

Abstract

Background: Trastuzumab (TZB), an anti HER-2 receptor monoclonal antibody, has been shown to be very effective in patients with breast cancer overexpressing HER-2. It has a mild cardiac toxicity, which may increase when administered in combination with anthracyclines. Anthracycline treatment showed to induce a myocardial overexpression of HER-2 receptors. Myocardial deformation indexes associated with Speckle Tracking (ST) myocardial imaging have shown to be very sensitive identifying left ventricular (LV) dysfunction in this setting. The aim of the study is to assess the effect of TZB therapy on specific myocardial layers after anthracycline treatment. Patients and methods: The study was designed to assess TZB-induced cardiac damage by ST technique in patients with HER-2 positive breast cancer treated with TZB sequentially after Epirubicin treatment. Inclusion criteria: 18–70 yo, histologically confirmed HER-2 positive breast cancer, candidates for TZB-based regimen; LVEF ≥55%; ECOG PS score 0-2, no history of cardiac disease. The following assessments were carried out at baseline, after Epirubucin treatment, at each TZB treatment and every 3 months during 1 year follow-up: ECOG PS score, conventional echocardiography and 2D/3D ST parameters (circumferential and longitudinal S and SR, LV torsion) Results: At Dec 2012, 38 patients (mean ± SD age 51±10 yo) have been enrolled. A significant reduction of the longitudinal peak of SR (0.71±0.16 s-1 vs 0.81±0.14 s-1; p<0.05) was found after Epi treatment, while a significant increase of circumferential function (1.03±0.31 s-1 vs 0.71±0.13 s-1; p<0.01) was evidenced. From the third dose of TZB a maked reduction of the circumferential function (0.69±0.18 s-1 vs 1.03±0.31 s-1; p<0.01) and of LV rotation (15.26±5.38 vs 22.88±6.41; p<0.001) was found, while no further reduction in the longitudinal function was determined. Conclusions: The aim of the study was that to ascertain the amount, timing and type of the pre-clinical cardiac dysfunction induced by TZB when administered after anthracyclines. We evidenced that after anthracyclines longitudinal function is impaired while a compensatory increase of LV circumferential function and of LV torsion is present. After TZB we showed mostly a toxicity of mid and sub epicardial fibres, responsible mainly for the circumferential function and of the torsion of the left ventricle. These effects could be related to the higher toxicity of TZB on the hyperactive myocardial fibres after Epi treatment. Follow up data will show if this mid and sub epicardial myocardial impairment will persist over time.