Tracking of Trastuzumab Resistance in Patients with HER2-positive Metastatic Gastric Cancer by CTC Liquid Biopsy

This study aimed to utilize circulating tumor cell-DNA (CTC-DNA) from liquid biopsies to monitor trastu-zumab resistance in Gastric cancer (GC) and assess the limited response rate in HER2 metastatic gastric cancer. Given the heterogeneity of GC, we established a high-precision CTC detection system that effectively isolates tumor cells with high HER2 expression for downstream analysis. Targeted sequencing of 610 genes was conducted on 20 paired CTC and tissue samples to assess uniformity. A longitudinal analysis of CTC samples was then performed to monitor trastuzumab resistance throughout treatment. Targeted sequencing of the HER2 gene showed strong consistency with fluorescence in situ hybridization data. Detected HER2 Scna was superior in predicting tumor shrinkage and progression. Most patients with innate trastuzumab resistance exhibited elevated HER2 Scna levels during progression. PIK3CA mutations were significantly enriched, and ERBB2/4 gene mutations were predominant in patients with innate trastuzumab resistance. CTC-DNA sequencing provides new insights into gene alterations associated with trastuzumab resistance in HER2 mGC.