Lenneman Carrie G, Abdallah Wissam M, Smith Holly M, Abramson Vandana, Mayer Ingrid A, Silverstein Cheri, Silverstein Cheri, Means-Powell Julie, Paranjape Sachin Y, Lenihan Daniel, Sawyer Douglas B, Raj Satish R
Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA ; Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
Ecancermedicalscience. 2014 Jul 17;8:446. doi: 10.3332/ecancer.2014.446. eCollection 2014.
HER2 antagonists (anti-HER2; e.g., trastuzumab and lapatinib) are effective in treating an aggressive form of breast cancer (BC), but can cause cardiotoxicity due to the disruption in neuregulin (NRG)/HER2+ ligand receptor signalling. The recent data show that NRG-HER2 receptors located in the medulla oblongata are important regulators of vasomotor tone. Disrupting the NRG-HER2 signalling in mouse medulla results in increased sympathetic nerve output and blood pressure. We hypothesized that anti-HER2 agents would cause increased sympathetic tone with changes in plasma catecholamines and NRG.
In 15 newly diagnosed HER2+ BC patients receiving anti-HER2 agents, vital signs were measured along with supine plasma epinephrine (EPI), norepinephrine (NE), and NRG at baseline and three months. Serial echocardiography was performed.
With three months of anti-HER2 treatment, NE increased (2.334 ± 1.294 nmol/L vs. 3.262 ± 2.103 nmol/L; p = 0.004) and NRG decreased (12.7±15.7 ng/ml vs. 10.9 ± 13.3 ng/ml; p = 0.036) with a corresponding increase in systolic blood pressure (110 ± 10 mmHg vs. 120 ± 16 mmHg, p = 0.049) and diastolic blood pressure (67 ± 14 vs. 77 ± 10, p = 0.009). There was no change, however, in EPI (0.183 ± 0.151 nmol/L vs. 0.159 ± 0.174 nmol/L; p = 0.519) or heart rate (73 ± 12 bpm vs. 77 ± 10 bpm, p = 0.146). Left ventricular ejection function declined over the follow-up period (baseline 63 ± 6% vs. follow-up 56 ± 5%).
Anti-HER2 treatment results in increased NE, blood pressure, and decreased NRG; this suggests that the inhibition of NRGHER2 signalling leads to increased sympathoneural tone. Larger studies are needed to determine if these observations have prognostic value and may be offset with medical interventions, such as beta-blockers.
The study was registered with www.clinicaltrials.gov (NCT00875238).
HER2拮抗剂（抗HER2；如曲妥珠单抗和拉帕替尼）在治疗侵袭性乳腺癌（BC）方面有效，但由于神经调节蛋白（NRG）/HER2+配体受体信号传导中断，可导致心脏毒性。最近的数据表明，位于延髓的NRG-HER2受体是血管运动张力的重要调节因子。破坏小鼠延髓中的NRG-HER2信号传导会导致交感神经输出增加和血压升高。我们假设抗HER2药物会导致交感神经张力增加，同时血浆儿茶酚胺和NRG发生变化。
在15例新诊断的接受抗HER2药物治疗的HER2+ BC患者中，在基线和三个月时测量生命体征以及仰卧位血浆肾上腺素（EPI）、去甲肾上腺素（NE）和NRG。进行系列超声心动图检查。
经过三个月的抗HER2治疗，NE升高（2.334±1.294 nmol/L对3.262±2.103 nmol/L；p = 0.004），NRG降低（12.7±15.7 ng/ml对10.9±13.3 ng/ml；p = 0.036），同时收缩压相应升高（110±10 mmHg对120±16 mmHg，p = 0.049），舒张压升高（67±14对77±10，p = 0.009）。然而，EPI（0.183±0.151 nmol/L对0.159±0.174 nmol/L；p = 0.519）或心率（73±12次/分钟对77±10次/分钟，p = 0.146）没有变化。在随访期间左心室射血功能下降（基线63±6%对随访56±5%）。
抗HER2治疗导致NE升高、血压升高和NRG降低；这表明抑制NRG-HER2信号传导会导致交感神经张力增加。需要进行更大规模的研究来确定这些观察结果是否具有预后价值，以及是否可以通过β受体阻滞剂等医学干预措施来抵消。
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