Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer
Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer
复制标题
液体活检追踪转移性 HER2 阳性胃癌的曲妥珠单抗耐药性
DOI：
10.1136/gutjnl-2018-316522
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发表时间：
2019-07-01
期刊：
影响因子：
24.5
通讯作者：
Xu, Rui-Hua
中科院分区：
文献类型：
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作者：
Wang, De-Shen;Liu, Ze-Xian;Xu, Rui-Hua
目的监测曲妥珠单抗（trastuzumab）耐药情况，探讨HER 2+转移性胃癌（mGC）疗效有限和耐药迅速出现的机制。然后，我们进行了纵向分析，收集了97个系列血浆样品从24例患者谁是HER 2+跟踪在曲妥珠单抗治疗期间的耐药性和验证的候选resistance.ResultsThe结果从靶向测序为基础的检测体细胞拷贝数改变（SCNA）ofHER 2基因是高度一致的荧光原位杂交数据，检测到的HER 2SCNA在预测肿瘤缩小和进展方面优于血浆癌胚抗原水平。与基线相比，大多数先天性曲妥珠单抗耐药患者在进展期的HER 2SCNA升高，而获得性耐药患者的HER 2SCNA降低; PIK 3CA突变在先天性耐药患者中显著富集，ERBB 2/4基因是突变最多的基因，分别占基线和进展血浆中曲妥珠单抗耐药患者的6例（35.3%）和5例（29.4%）。基线血浆中有PIK 3CA/R1/C3或ERBB 2/4突变的患者无进展生存期显著更差。此外，突变在NF 1有助于曲妥珠单抗耐药，这是进一步证实，通过在体外和体内研究，而结合HER 2和MEK/ERK封锁克服trastuzumab resistance.ConclusionLongitudinal循环肿瘤DNA测序提供了新的见解基因改变的基础曲妥珠单抗耐药HER 2+胃癌。
ObjectiveTo monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC).DesignTargeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes.ResultsThe results from targeted sequencing-based detection of somatic copy number alterations (SCNA) ofHER2gene were highly consistent with fluorescence in situ hybridisation data, and the detectedHER2SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented highHER2SCNA during progression compared with baseline, whileHER2SCNA decreased in patients with acquired resistance.PIK3CAmutations were significantly enriched in patients with innate resistance, andERBB2/4genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients withPIK3CA/R1/C3orERBB2/4mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations inNF1contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance.ConclusionLongitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.