Concomitant Taxane Administration Enhances Efficacy of Trastuzumab

SAN FRANCISCO, CA— Concomitant administration of taxanes and trastuzumab (TZM) enhances the efficacy of TZM but also induces subclinical early impairment of left ventricular function as presented by Christian Cadeddu, MD, PhD, from the University of Cagliari, Cagliari, Italy at ACC.13, the American College of Cardiology's 62nd Annual Scientific Session.

Trastuzumab, an anti HER-2 receptor monoclonal antibody, has been shown to be very effective in patients with breast cancer overexpressing HER-2 in the neoadjuvant, adjuvant, and metastatic setting. The efficacy of TZM is enhanced when administered concomitantly with taxanes, paclitaxel, and docetaxel. However the combination therapy results in an unexpected synergistic increase in cardiac dysfunction. Concomitant inhibition of HER-2 receptors and taxane therapy has an additive worsening effect on adult cardiomyocytes. Currently, there is very little data regarding the short and long term effects on the cardiac structure and function of TZM associated with taxane administration.

Dr. Cadeddu and colleagues investigated the correlation between biologic markers of chronic inflammation and oxidative stress and early cardiac dysfunction using an echocardiographic myocardial imaging technique called Speckle Tracking. This assessed cardiac mechanics such as circumferential, radial, and longitudinal strain (S) and strain rate (SR).

This prospective, non-randomized trial assessed TZM-induced cardiac damage in patients with HER-2+ breast cancer patients, concomitantly treated with TZM and taxanes (docetaxel/paclitaxel). As of December 2012, 36 patients were enrolled into the study. Patients were analyzed at baseline, after each TZM, and every three months during the 1-year follow up for ECOG PS score, conventional echocardiography, and ST parameters (global circumferential, radial and longitudinal S and SR), chronic inflammation (IL-6 and TNF-alpha) and oxidative stress (reactive oxygen species and glutathione peroxidase) markers.

Results demonstrated a significant progressive reduction of the peak of longitudinal SR during all TZM treatments starting at the 4th dose of TZM (0.80±0.15 s-1 vs. respectively 0.61±0.18 s-1, P<0.005; vs. 0.56±0.14 s-1, P<0.001; vs. 0.53±0.21 s-1, P<0.005) as signs of systolic dysfunction. A significant reduction of the circumferential SR (0.52±0.11 s-1 vs. 0.64±0.13 s-1; P<0.01) and of the rotation (1.48±0.43 vs. 2.31±0.68; P<0.001) was observed earlier at the 3rd dose. At the 3rd dose of TZM, there was a significant increase in TNF alpha (16.7±15.6pg/ml vs. 25±11.7; P=0.03).

Concomitant administration of taxanes and TZM improves the efficacy of TZM. However, a subclinical early impairment of left ventricular function may be related to trastuzumab's ability to induce pre-clinical or clinical cardiac dysfunction. Dr. Cadeddu stated, “It is critical to identify patients that would benefit most from an early suspension of the treatment.”