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Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib.
Lung Cancer ( IF 5.3 ) Pub Date : 2019-11-25 , DOI: 10.1016/j.lungcan.2019.10.021
Jun Zhao 1 , Gen Lin 2 , Minglei Zhuo 1 , Zaiwen Fan 3 , Liyun Miao 4 , Likun Chen 5 , Aiping Zeng 6 , Rong Yin 7 , Yangming Ou 8 , Zhihui Shi 9 , Jie Yin 10 , Wen Gao 11 , Jianhua Chen 12 , Xiangdong Zhou 13 , Yong Zeng 14 , Xiang Liu 15 , Huamin Xu 16 , Rongrong Chen 16 , Xuefeng Xia 16 , David P Carbone 17
Affiliation  

OBJECTIVES The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. MATERIALS AND METHODS We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes. RESULTS AND CONCLUSION Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

中文翻译:

基于下一代测序的突变分析揭示了临床反应的异质性和对奥西替尼的耐药性。

目的第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKI)奥西替尼在已对第一代或第二代EGFR TKI产生耐药性的EGFR突变,T790M阳性非小细胞肺癌(NSCLC)患者中均显示出有希望的疗效EGFR致敏突变患者作为一线治疗药物。但是,对奥西替尼的反应程度和持续时间是异质的。我们假设这些肿瘤的并发基因组格局可能在临床结果和/或耐药机制中起作用。材料和方法我们对肺癌患者产生了对奥西替尼耐药的回顾性多中心研究。通过使用涵盖59-1021个癌症相关基因的靶向下一代测序,对所有患者进行了基因组图谱分析。结果与结论在所有异质性很大的患者中,有44%发现了已知的EGFR依赖性耐药突变和其他途径的激活。CTNNB1的功能获得性突变在我们的队列中高度丰富。还确定了其他对奥西替尼的耐药机制,例如复发性EGFR V834 L突变。此外,TP53的致病性突变与奥西替尼的疗效负相关。综上所述,对奥西替尼耐药的异质性不仅表现在个体间差异上,还体现在个体内多样性上。CTNNB1的功能获得性突变在我们的队列中高度丰富。还确定了其他对奥西替尼的耐药机制,例如复发性EGFR V834 L突变。此外,TP53的致病性突变与奥西替尼的疗效负相关。综上所述,对奥西替尼耐药的异质性不仅表现在个体间差异上,还体现在个体内多样性上。CTNNB1的功能获得性突变在我们的队列中高度丰富。还确定了其他对奥西替尼的耐药机制,例如复发性EGFR V834 L突变。此外,TP53的致病性突变与奥西替尼的疗效负相关。综上所述,对奥西替尼耐药的异质性不仅表现在个体间差异上,还体现在个体内多样性上。
更新日期:2019-11-26
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