PT  - JOURNAL ARTICLE
AU  - De-Shen Wang
AU  - Ze-Xian Liu
AU  - Yun-Xin Lu
AU  - Hua Bao
AU  - Xue Wu
AU  - Zhao-Lei Zeng
AU  - Zekun Liu
AU  - Qi Zhao
AU  - Cai-Yun He
AU  - Jia-Huan Lu
AU  - Zhi-Qiang Wang
AU  - Miao-Zhen Qiu
AU  - Feng Wang
AU  - Feng-Hua Wang
AU  - Yu-Hong Li
AU  - Xiao-Nan Wang
AU  - Dan Xie
AU  - Wei-Hua Jia
AU  - Yang W Shao
AU  - Rui-Hua Xu
TI  - Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer
AID  - 10.1136/gutjnl-2018-316522
DP  - 2019 Jul 01
TA  - Gut
PG  - 1152--1161
VI  - 68
IP  - 7
4099  - http://gut.bmj.com/content/68/7/1152.short
4100  - http://gut.bmj.com/content/68/7/1152.full
SO  - Gut2019 Jul 01; 68
AB  - Objective 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).Design 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.Results The results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 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 PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 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.Conclusion Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.