State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Gut. 2019 Jul;68(7):1152-1161. doi: 10.1136/gutjnl-2018-316522. Epub 2018 Sep 29.
To monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC).
Targeted 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.
The results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of gene were highly consistent with fluorescence in situ hybridisation data, and the detected SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high SCNA during progression compared with baseline, while SCNA decreased in patients with acquired resistance. mutations were significantly enriched in patients with innate resistance, and genes 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 with or mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance.
Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.
监测曲妥珠单抗耐药性，并确定 HER2+转移性胃癌（mGC）应答率有限和耐药迅速出现的潜在机制。
对 78 对血浆和组织活检样本中的 416 个临床相关基因进行靶向测序，以确定血浆-组织一致性。然后，我们对 24 名 HER2+患者的 97 个连续血浆样本进行了纵向分析，以跟踪曲妥珠单抗治疗期间的耐药情况，并验证了鉴定出的候选耐药基因。
基于靶向测序检测基因体细胞拷贝数改变（SCNA）的结果与荧光原位杂交数据高度一致，并且检测到的 SCNA在预测肿瘤缩小和进展方面优于血浆癌胚抗原水平。此外，大多数先天曲妥珠单抗耐药的患者在进展时比基线时表现出更高的 SCNA，而获得性耐药的患者 SCNA 降低。在先天耐药的患者中， 突变明显富集， 基因是突变最多的基因，分别占基线和进展血浆中 6 例（35.3%）和 5 例（29.4%）患者的曲妥珠单抗耐药。基线血浆中存在 或 突变的患者无进展生存期明显更差。此外， 基因中的突变导致曲妥珠单抗耐药，这通过体外和体内研究得到了进一步证实，而联合 HER2 和 MEK/ERK 阻断克服了曲妥珠单抗耐药性。
纵向循环肿瘤 DNA 测序为 HER2+mGC 中曲妥珠单抗耐药的基因改变提供了新的见解。
