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Trastuzumab cardiotoxicity: biological hypotheses and clinical open issues.

机译：曲妥珠单抗心脏毒性：生物学假设和临床开放问题。

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BACKGROUND: Trastuzumab has significantly improved the prognosis of breast cancer patients overexpressing the human epidermal growth factor receptor 2 (HER2). This result has been achieved in all disease settings, by increasing overall survival in early stage and advanced disease and by increasing pathological complete responses in neoadjuvant disease. OBJECTIVE: Although the greatest impact of this monoclonal antibody has been seen in the adjuvant setting, by increasing disease-free survival and overall survival rates an increased rate of both symptomatic and non-symptomatic cardiac toxicity has also been observed. METHODS: In the following review, the different mechanisms of trastuzumab cardiac toxicity are described and, in addition, the clinical data coming from both trials and meta-analyses is discussed. RESULTS: While there is strong evidence for the incidence of trastuzumab-related cardiac toxicity, there is still little known on the exact pathogenesis of this toxicity. Interestingly, both experimental and clinical data suggest that trastuzumab may sensitize cardiomyocytes to injuries and stress from administration of anthracyclines. This has led to a proposed novel mechanism of cardiotoxicity that appears to be quite different from the anthracycline-associated cardiotoxicity. Trastuzumab does not seem to cause any overt ultrastructural abnormality; it does, however, lead to myocardial dysfunction. CONCLUSION: Most of the proposed hypotheses seems to be related to the activity of trastuzumab in interfering with the ERBB-2 receptor. Indeed, data from clinical trials in the adjuvant setting report increased cardiac toxicity in those patients who previously received anthracyclines.
机译：背景：曲妥珠单抗显着改善了过度表达人表皮生长因子受体2（HER2）的乳腺癌患者的预后。通过增加早期和晚期疾病的总体存活率以及增加新辅助疾病的病理完全反应，已经在所有疾病中实现了这一结果。目的：尽管这种单克隆抗体在佐剂环境中具有最大的影响，但通过增加无病生存期和总体生存率，还可以观察到有症状和无症状心脏毒性的发生率增加。方法：在下面的综述中，描述了曲妥珠单抗心脏毒性的不同机制，此外，还讨论了来自试验和荟萃分析的临床数据。结果：尽管有强有力的证据表明曲妥珠单抗相关的心脏毒性发生率，但对这种毒性的确切发病机理仍知之甚少。有趣的是，实验和临床数据均表明曲妥珠单抗可能使蒽环类药物引起的心肌细胞对伤害和压力敏感。这导致了拟议的心脏毒性新机制，似乎与蒽环类药物相关的心脏毒性完全不同。曲妥珠单抗似乎并未引起任何明显的超微结构异常;但是，它确实会导致心肌功能障碍。结论：大多数提出的假设似乎与曲妥珠单抗干扰ERBB-2受体的活性有关。确实，佐剂临床试验的数据报告了先前接受蒽环类药物的患者的心脏毒性增加。

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