Abstract 14138: Changes in Sympathetic Tone With Her2+ Antagonists: An Early Marker of Cardiotoxicity in a Breast Cancer Cohort?
Background: HER2 antagonists (anti-HER2) are effective in treating an aggressive form of breast cancer (BC) but causes cardiotoxicity in select patients. Cardiotoxicity observed with anti-HER2 therapy is linked to the disruption in neuregulin (NRG) / HER2 receptor signaling. Recent data shows that NRG-HER2 receptors are also located in the medulla and are important regulators of vasomotor tone. Disrupting the NRG-HER2 signaling in the medulla resulted in increased hypertension and a shift toward increased sympathetic nerve output. Therefore we hypothesized that women treated with an anti-HER2 agent would exhibit increased sympathetic tone with changes in plasma catecholamines, heart rate (HR) variability (HRV), and circulating NRG, which may be an early sign of cardiotoxicity.
Methods: In a pilot study, 17 newly diagnosed female HER2+ BC patients receiving an anti-HER2 agent were enrolled. Supine plasma epinephrine (EPI), norepinephrine (NE), NRG levels were drawn (n=17), and 10-minute continuous ECG recordings were obtained at baseline, and 3 months into anti-HER2 therapy (n=13). HRV was measured using a Fourier transform and low frequency (LF; 0.04-0.15Hz) and high frequency (HF; 0.15-0.4Hz) power were normalized to total power (no units). Parasympathetic cardiac modulation was estimated by HF, and LF/HF ratio was a marker of relative sympathoneural cardiac modulation. Paired analyses were performed with Wilcoxon-Rank Sum tests and P<0.05 was significant.
Results: Compared to baseline, 3-months of anti-HER2 treatment significantly increased plasma NE (382 ±210 pg/ml vs. 528±340 pg/ml; p=0.004), significantly decreased plasma NRG (12.7±15.7 ng/ml vs. 10.9±13.3 ng/ml; p=0.04), but did not change plasma EPI (31.5±27.0 pg/ml vs. 28.6±30.6 pg/ml; p=0.47). Anti-HER2 treatment resulted in a trend to lower LF/HF.
Conclusions: Anti-HER2 treatment results in increased circulating NE levels and decreased circulating NRG, suggesting that inhibition of NRG-HER2+ signaling leads to increased sympathoneural tone. Larger studies are needed to determine if plasma NE and NRG are prognostic markers of early cardiotoxicity and if beta-blockers offer cardioprotection by suppressing the shift in sympathetic tone.
- © 2013 by American Heart Association, Inc.