Abstract 2277: HER2 copy number variation detected by next-generation sequencing reveals HER2 expression heterogeneity in gastric cancer

Abstract

Abstract Purpose: Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in gastric cancer (GC). Both HER2-positive and HER2-low GC could benefit from HER2 inhibitors including trastuzumab and trastuzumab deruxtecan. However, it is difficult to accurately evaluate HER2 status by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), owing to intra-tumor heterogeneity and the experience of the pathologist. Herein, we investigated whether HER2 copy number variation (CNV) detected by next-generation sequencing (NGS) could assist in accurately determining the HER2 status. Methods: We analyzed HER2 CNV on tumor specimens from 212 GC patients using NGS in a CLIA-certified laboratory. The log ratio of HER2 >0.7 was defined as amplification and log ratio of 0.4 to 0.7 was defined as low amplification. HER2 expression was examined in all 212 GC patients by IHC and HER2 amplification was assessed in 22 patients by FISH. Results: Of 212 patients, three had HER2 amplification and three had low HER2 amplification. Among three patients with HER2 amplification, all were found to have strong positive HER2 expression (IHC 3+). Among three patients with HER2 low amplification, two patients had HER2 IHC 2+ (including one HER2 FISH-negative and one HER2 FISH-unknown) and one patient had HER2 IHC 1+. Moreover, two patients were found HER2 IHC 3+ in whom without HER2 amplification. Of the two, one was most HER2 IHC 2+ with focal tumor IHC 3+, and the HER2 CNV was close to the threshold (log ratio of HER2: 0.2882). The reason for the discordance may be related to intra-tumor heterogeneity. HER2 copy number will be diluted in samples with focal 3+ and NGS reflects the relative global nature of the tumor specimens. No HER2 IHC-negative cases (N=99) showed HER2 CNV, suggesting that HER2 CNV detected by NGS has specificity of 100%. Conclusions: HER2 CNV detected by NGS could predicts HER2 status in GC and more accurately stratified GC patients with either HER2-positive or HER2-low. Thus, we can screen out those who can truly benefit from trastuzumab and trastuzumab deruxtecan (eg. DS-8201). Prospective cohorts are needed to validate HER2 CNV detected by NGS for predicting response to anti-HER2 therapy. Citation Format: Xiaotian Zhang, Hui Chen, Xiaochen Zhao, Jie Wang, Yuezong Bai. HER2 copy number variation detected by next-generation sequencing reveals HER2 expression heterogeneity in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2277.