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.
- gastric cancer
- trastuzumab resistance
- next-generation sequencing
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D-SW, Z-XL and Y-XL contributed equally.
Contributors Conception and design: D-SW, R-HX. Provision of study materials or patients: D-SW, Z-QW, M-ZQ, FW, F-HW, Y-HL, DX, W-HJ, R-HX. Collection and assembly of data: D-SW, Z-XL, Y-XL, HB, XW, Z-LZ, ZL, QZ, C-YH, J-HL, Z-QW, M-ZQ, FW, F-HW, Y-HL, X-NW, DX, W-HJ, YWS. In vitro and in vivo study: Y-XL, Z-LZ, C-YH, J-HL. Data analysis and interpretation: D-SW, Z-XL, HB, XW, ZL, QZ, X-NW, DX, W-HJ, YWS and R-HX. Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.
Funding (1) The National High Technology Research and Development Program of China (863 Program) (No. 2015AA020103); (2) The Natural Science Foundation of Guangdong Province (No. 2014A030312015), Science and Technology Program of Guangdong (No. 2015B020232008) and the Science and Technology Program of Guangzhou (Nos. 201508020250 and 201604020003); (3) The National Natural Science Foundation of China (Nos. 81602070 and 31501069); (4) The Major Special Project from Guangzhou Health and Medical Collaborative Innovation (No. 15570006); (5) Fundamental Research Funds for the Central Universities (SYSU: 16ykzd06) and (6) The National Key Research and Development Program of China (No. 2017YFC1308900).
Competing interests None declared.
Patient consent Obtained.
Ethics approval The human research ethics committees at Sun Yat-sen University Cancer Center.
Provenance and peer review Not commissioned; externally peer reviewed.
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