Abstract 5129: Clinical implication of plasma ctDNA features in HER2-positive gastric cancer treated with combinations of trastuzumab & anti-PD-1 agents
Authors: Chong Xiaoyi , Yan Zhengqing , Liu Hua , Cong Lin , Jiang Fangli , Xu Chenhui , Li Yan , Chen Hui , Li Yanyan , Ji Congcong , Chen Shiqing , Zhao Xiaochen , Zhang Xiaotian 
Published: June 2022

Abstract
PURPOSE:Previous studies supported combining PD-1 inhibitors with trastuzumab to treat HER2-positive cancers. Yet proper biomarkers for response/resistance prediction remain unveiled.
METHODS: Eligible patients were 18 years of age or older and had histologically confirmed gastric cancer (GC) or gastro-esophageal junction cancer (GEJ). The HER2 status was evaluated with tissue assay, including IHC and FISH. Paired plasma-white blood cell samples were collected prior treatment and assessed with targeted next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Different therapeutic regimens and ctDNA biomarkers were explored in HER2-positive patients, who received combining therapeutics containing trastuzumab and anti-PD-1 agents. The HER2-positive status was defined as IHC 3+ or IHC 2+/FISH-positive.
RESULTS: A total of 49 patients were included. Four patients were excluded due to fail in the quality control for NGS. The HER2 status of tumor tissue and matched plasma ctDNA at baseline display a high concordance of 84.4% (38/45). NGS ctDNA method demonstrated an 84.2% (33/40) sensitivity and a 100% (5/5) specificity to detect HER2 amplification. Among HER2-positive patients, nineteen and eighteen patients were administrated trastuzumab+anti-PD-1±anti-vascular (chemo-free) and trastuzumab+anti-PD-1+chemotherapy (chemo-containing) respectively. Compared to Chemo-free subgroup, the chemo-containing subgroup had numerically higher ORR (61.11% vs 31.58%, p = 0.10) and longer median PFS (8.98 vs 5.43 months, p = 0.54, HR 0.78, 95%CI: 0.35-1.73). Patients with HER2 amplification in ctDNA had higher ORR than those without amplification (56.67% vs 0%, p = 0.009). Besides, an immune-related negative gene set (PTEN mutations, MDM2 amplification and FGF3/4/19 amplification) was also explored. The patients carrying immune-related negative gene alterations achieved decreased ORR (0% vs 54.8%, p = 0.02) and shorter PFS (2.1 vs 6.9 months, p&lt;0.0001, HR 8.21, 95%CI: 2.76-24.48), compared to that of wild type.
CONCLUSIONS: The ctDNA display a high consistency with tumor tissue for HER2 status. Compared to chemo-free regimens, chemo-containing regimens trend to demonstrate improved PFS and ORR in HER2-postive GC/GEJ, though no statistically significant. The HER2 amplification and immune-related negative gene alterations in ctDNA might be used as alternative biomarkers for predicting the efficacy of combining therapeutics containing trastuzumab and anti-PD-1 agents. Further studies are warranted to confirm our observation for better management of HER2-positive GC/GEJ.
Citation Format: Xiaoyi Chong, Zhengqing Yan, Hua Liu, Lin Cong, Fangli Jiang, Chenhui Xu, Yan Li, Hui Chen, Yanyan Li, Congcong Ji, Shiqing Chen, Xiaochen Zhao, Xiaotian Zhang. Clinical implication of plasma ctDNA features in HER2-positive gastric cancer treated with combinations of trastuzumab & anti-PD-1 agents [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 5129.