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

Abstract

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 <i>HER2</i> gene were highly consistent with fluorescence in situ hybridisation data, and the detected <i>HER2</i> SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high <i>HER2</i> SCNA during progression compared with baseline, while <i>HER2</i> SCNA decreased in patients with acquired resistance. <i>PIK3CA</i> mutations were significantly enriched in patients with innate resistance, and <i>ERBB2/4</i> 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 <i>PIK3CA/R1/C3</i> or <i>ERBB2/4</i> mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in <i>NF1</i> 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.