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Biomarkers to predict response to epidermal growth factor receptor inhibitors.

机译：预测对表皮生长因子受体抑制剂反应的生物标志物。

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Epidermal growth factor receptors (EGFRs) are amplified and overexpressed in many different human cancers, a phenomenon generally associated with poor prognosis. Inhibitors of the tyrosine kinase activity associated with this receptor have been approved for the treatment of chemotherapy-refractory nonsmall cell lung cancer, and are in clinical trials for additional tumor types. While these inhibitors, gefitinib and erlotinib, display limited response rates when assessed in cohorts that include all patients, there are subgroups, defined by patient and tumor characteristics, that preferentially respond to these agents. We recently performed an analysis of tumors obtained from a Phase I trial of erlotinib in patients with glioblastoma multiforme (GBM), the most common malignant brain tumor in adults. We showed that patients whose tumors exhibited overexpression and amplification of EGFR responded better than patients who had normal levels of this gene and protein. We also demonstrated that the phosphorylation state of PKB/Akt was an important determinant for response, with low phospho-PKB/Akt levels predicting good response to erlotinib. We discuss these findings in the context of recent molecular analyses of the placebo-controlled Phase III trials that led to approval of EGFR inhibitors. These data underscore the importance of placebo-controlled trials to distinguish between prognostic indicators of disease progression more generally and predictive markers of response to therapy. Ultimately the goal of these studies is to allow selection of patients who will preferentially respond to EGFR inhibitors.
机译：表皮生长因子受体（EGFR）在许多不同的人类癌症中被扩增和过表达，这种现象通常与预后不良有关。与该受体相关的酪氨酸激酶活性的抑制剂已被批准用于治疗难治性化学疗法的非小细胞肺癌，并且正在针对其他肿瘤类型进行临床试验。尽管这些抑制剂吉非替尼和厄洛替尼在包括所有患者的队列中评估显示出有限的缓解率，但依患者和肿瘤特征定义的亚组优先对这些药物产生应答。我们最近对多形性胶质母细胞瘤（GBM）患者中厄洛替尼（Irlotinib）I期试验获得的肿瘤进行了分析，该胶质母细胞瘤是成人中最常见的恶性脑肿瘤。我们发现，肿瘤表现出EGFR过度表达和扩增的患者比具有正常水平的该基因和蛋白质的患者反应更好。我们还证明了PKB / Akt的磷酸化状态是反应的重要决定因素，低的PKB / Akt磷酸水平预示了对厄洛替尼的良好反应。我们在对安慰剂对照的III期临床试验进行近期分子分析的背景下讨论了这些发现，这些试验导致了EGFR抑制剂的批准。这些数据强调了安慰剂对照试验对区分疾病进展的预后指标和对治疗反应的预测指标的重要性。最终，这些研究的目的是允许选择将优先响应EGFR抑制剂的患者。

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