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Introduction: The effect of trastuzumab in targeted therapy for HER2-positive gastric cancer (GC) is limited by the eventual development of resistance within patients. Although numerous studies have been published on this topic, both the mechanism of innate and acquired trastuzumab resistance are still not fully understood. In this study, we compare the mutational landscape of paired solid tumor samples before and after treatment in an effort to identify acquired events associated with resistance. Methods: We performed whole-exome sequencing on 46 tumor and 23 whole blood samples from patients with stage IV gastric cancer were obtained from before treatment (n = 23) and at disease progression (PD) (n = 23). HER2 status was checked using immunohistochemistry and validated with florescence in situ hybridization (FISH). Correlation analysis was then conducted between the mutational profile and clinical data of patients. Results: Comparisons between innate resistance samples and acquired resistance samples at baseline revealed three copy number variation events (CDK12 amplification, ERBB2 amplification, MECOM amplification) that occurs in significantly different proportions (p < 0.05). In addition, for baseline samples, MECOM was shown to be associated with poor progression-free survival (PFS) (Hazard Ratio (HR), 12; 95% CI, 1.6 - 85; p = 0.027). Commonly acquired events (i.e., lacking in before treatment samples and present at PD) within patients include TP53 mutation, MYC amplification, MCL1 amplification, CDKN2A/2B deletion, and CCNE1 amplification. Of these, patients with MCL1 gene amplification had worse survival (HR, 4.8; 95% CI, 1.2 - 20; p = 0.050) than patients with wild-type MCL1. In addition, the NOTCH pathway acquired mutations in 4 of 23 patients and was found to be correlated with a worse PFS (HR, 5.1; 95% CI, 1.4 - 19; p = 0.023), indicating that this pathway is possibly involved with trastuzumab resistance to some degree. Conclusion: Overall, our results show that comparisons of samples obtained before treatment and at PD can give insight about innate and acquired resistance mechanisms to trastuzumab in stage IV, HER2-positive GC patients. Citation Format: Qi Xu, Jingjing Li, Haimeng Tang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Jianying Jin, Cong Luo, Haimin Weng, Jieer Ying. Dissecting the molecular mechanism of trastuzumab resistance in stage IV HER2-positive gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5336. |
