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Gut. 2018 Sep 29. pii: gutjnl-2018-316522. doi: 10.1136/gutjnl-2018-316522. [Epub ahead of print]

Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer.

Wang DS#1,2, Liu ZX#1, Lu YX#1,2, Bao H3, Wu X3, Zeng ZL1, Liu Z1, Zhao Q1, He CY1,4, Lu JH1,2, Wang ZQ1,2, Qiu MZ1,2, Wang F1,2, Wang FH1,2, Li YH1,2, Wang XN5, Xie D1, Jia WH1, Shao YW3,6, Xu RH1,2.

Author information

1
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
2
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
3
Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada.
4
Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China.
5
Nanjing Geneseeq Technology Inc., Nanjing, China.
6
School of Public Health, Nanjing Medical University, Nanjing, China.
#
Contributed equally

Abstract

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.

KEYWORDS:

HER2; NF1; ctDNA; gastric cancer; next-generation sequencing; trastuzumab resistance

PMID:
30269082
DOI:
10.1136/gutjnl-2018-316522

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