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EGFR in Early Non-Small Cell Lung Cancer: Tyrosine Kinase Inhibition in a Neoadjuvant Trial.

机译：早期非小细胞肺癌中的EGFR：新辅助试验中酪氨酸激酶抑制作用。

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摘要

EGFR TKIs are standard therapy for advanced NSCLC. In order to define their role in early disease, we implemented a phase II trial of neoadjuvant gefitinib in clinical stage I NSCLC. Tumour shrinkage was seen in 43% of patients, with 11% achieving RECIST partial response (PR). Analysis of molecular markers showed EGFR TKD mutations in 17% of cases, being the only associated with PR. For the first time we defined the histopathological response of NSCLC to these agents, characterized by reduction in tumour cellularity and proliferative index as well as presence of non-mucinous BAC histology. Clinical PR tumours also presented large areas of stromal fibrosis with presence of focal residual tumour. In a characterization of intracellular signalling response, EGFR dephosphorylation in the residues Y1068 and Y1173 was not concordant and only the former was significantly reduced. pAkt Ser473/Akt and Thr308/Akt ratios were significantly reduced but observed among both, clinical responders and resistant patients. Interestingly, reduction in pEGFR Y1068 was significantly associated with increase in tumour cellularity (p=0.047), Ki-67 index (p=0.018) and tumour growth (p=0.019) with a residual perinuclear localization been detected, suggesting a novel mechanism of resistance involving receptor internalization. Finally, we determined that the EGFR protein remains stable up to one hour of post resection ischemia but two to three tumour samples are necessary for an adequate tumour representation. Furthermore, EGFR cytoplasmic compartment presented the best association with clinical response in our cohort. Taking all together, we were able to generate the first clinical trial exploring the use of an EGFR TKI in early NSCLC, characterizing for the first time the histopathological and signalling responses to these agents with an evidence of a potential novel mechanism of resistance. Finally, we observed that multiple samples collection for an adequate tumour representation, and assessment of the cytoplasmic compartment, are warrant.
机译：EGFR TKIs是晚期NSCLC的标准疗法。为了确定它们在早期疾病中的作用，我们在临床I期NSCLC中实施了新辅助吉非替尼的II期试验。 43％的患者可见肿瘤缩小，其中11％达到RECIST部分缓解（PR）。分子标记物分析显示，EGFR TKD突变在17％的病例中是唯一与PR相关的疾病。我们首次定义了NSCLC对这些药物的组织病理学反应，其特征是肿瘤细胞数量和增殖指数降低，以及非粘液性BAC组织学的存在。临床PR肿瘤还表现出大面积的间质纤维化，并伴有局灶性残余肿瘤。在细胞内信号传导反应的表征中，残基Y1068和Y1173中的EGFR去磷酸化不一致，只有前者显着减少。 pAkt Ser473 / Akt和Thr308 / Akt比率明显降低，但在临床应答者和耐药患者中均观察到。有趣的是，pEGFR Y1068的减少与肿瘤细胞增多（p = 0.047），Ki-67指数（p = 0.018）和肿瘤生长（p = 0.019）以及剩余的核周定位显着相关，提示了一种新的机制。涉及受体内在化的抗性。最后，我们确定EGFR蛋白在切除缺血后的一小时内保持稳定，但是要获得足够的肿瘤代表性，则需要两到三个肿瘤样品。此外，在我们的队列研究中，EGFR细胞质区室与临床反应之间存在最佳关联。综上所述，我们能够产生第一个探索在早期NSCLC中使用EGFR TKI的临床试验，首次表征了对这些药物的组织病理学和信号传导反应，并证明了潜在的新型耐药机制。最后，我们观察到有足够的肿瘤代表性的多个样品收集以及对细胞质区室的评估是必要的。

著录项

  • 作者

    Lara-Guerra, Humberto.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 246 p.
  • 总页数 246
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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