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

Abstract

ObjectiveTo monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC).DesignTargeted 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.ResultsThe 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.ConclusionLongitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.

Comparative analysis of HER2 copy number between plasma and tissue samples in gastric cancer using droplet digital PCR

“…Further prospective studies with larger cohorts will be needed. In addition, HER2 measurement in patients after www.nature.com/scientificreports www.nature.com/scientificreports/ gastrectomy and during the follow-up period will give more information about relapse or treatment effects of trastuzumab 23,31 . The other limitation is that there has been no consensus about setting cutoffs for HER2 amplification.…”

HER2 Heterogeneity in Personalized Therapy of Gastro-Oesophageal Malignancies: An Overview by Different Methodologies

“…In our opinion, to improve personalized management strategies in GC, HER2 status of CTCs might be assessed. It is well known that some patients with HER2-positive GEA, treated with trastuzumab, develop resistance, even if the precise mechanisms are still unexplained [109]. It has been reported that matching pre-treatment and post-progression samples from patients receiving chemotherapy and trastuzumab for advanced HER2-positive GEA, HER2 loss has been encountered in 32% of cases due to a mechanism of resistance [110,111].…”

Dissection of gastric cancer heterogeneity for precision oncology

“…For instance, an analysis of the PANGEA trial cohort by Pectasides et al found discordant genomic alterations between primary and metastatic tissue in 10 of 28 (36%) patients, of which 87.5% displayed concordance between ctDNA and metastatic tissue suggesting that ctDNA may better represent disease in the advanced setting. ctDNA could also be used to inform the clonality of targetable genomic alterations, capture co‐occurring alterations that may predict treatment failure, or longitudinally track a tumor as it undergoes temporal evolution as a result of therapeutic pressure . Nonetheless, it should be acknowledged that liquid biopsies are unlikely to be an exhaustive catalogue of tumor traits, as some genomic alterations identified in primary tumor tissue were not found in matched ctDNA .…”

“…ctDNA could also be used to inform the clonality of targetable genomic alterations, 66 capture co-occurring alterations that may predict treatment failure, 67 or longitudinally track a tumor as it undergoes temporal evolution as a result of therapeutic pressure. 70,71 Nonetheless, it should be acknowledged that liquid biopsies are unlikely to be an exhaustive catalogue of tumor traits, as some genomic alterations identified in primary tumor tissue were not found in matched ctDNA. 68 Whether this is a pitfall of ctDNA profiling, or an indication of the lack of clonality of the genomic alteration is still an open but crucial question.…”