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

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 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.

CONCLUSION

Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.