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Molecular characterization of ctDNA from Chinese patients with advanced gastric adenocarcinoma reveals actionable alterations for targeted and immune therapy

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Abstract

Circulating tumor DNA (ctDNA) is considered an ideal sample type for genotyping patients with advanced unresectable cancer to inform treatment decision. It may better capture tumor heterogeneity, especially in gastric adenocarcinoma (GAC). However, there exists little evidence regarding genomic profiling of Chinese advanced GAC patients from ctDNA. Blood samples were obtained from 200 advanced GAC patients. Next-generation sequencing (NGS) was performed on ctDNA using a validated 150-gene panel. Blood tumor mutation burden (bTMB) was calculated according to the NGS results. Blood microsatellite instability (bMSI) status was determined by targeted sequencing of 100 microsatellite loci. One hundred sixty-nine (84.5%) patients carried at least one genomic alteration and 138 (69%) patients had at least one deleterious or likely deleterious alteration (del-alteration). The clonal fraction of del-alterations was higher than that of non-del-alterations (80.1% vs 54.5%, P < 0.0001). The most frequently altered genes were TP53 (38%), LRP1B (20%), MYC (13.5%), ERBB2 (12.5%), and KRAS (11.5%). The alterations were most enriched in the TP53/cell cycle (52%) and the RTK-Ras-MAPK pathway (51.5%). The median bTMB was two (range 0 to 42). Eight patients were identified to be high bMSI, with higher median bTMB than the blood microsatellite stable (bMSS) patients (15 vs 2, P = 0.0062). Patients harboring del-alterations of the DDR pathway had significantly higher percentages of high bTMB and bMSI-H patients than the wild-type subgroup (61.1% vs 6.5%, P < 0.0001; 33.3% vs 1.7%, P = 0.0002). A total of 45.5% cases harbored at least one potentially actionable alteration and one patient achieved complete response after receiving matched targeted therapy. Our study uncovered the molecular characterization of Chinese patients with advanced GAC from ctDNA, including genomic alteration, bTMB, and bMSI status. The findings suggested that targeted NGS-based ctDNA analysis may help inform the clinical decision in advanced GAC.

Key Messages

  • We report the molecular profiling of the largest Chinese advance stage GACs cohort using a CLIA-certified ctDNA assay.

  • Potentially actionable genomic alterations were identified in 45.5% of patients, suggesting clinical utility for ctDNA NGS in advance stage GACs.

  • There was evidence of clinical benefit in one GAC patient with MET amplification treated with MET inhibitor.

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Acknowledgements

The authors thank the patients who participate in this study and the members who involved in the data collection and analysis.

Funding

This study was financially supported by the Capital Health Research and Development of Special (grant number 2018-2-1023) and the Pilot Project (3rd Round) to Reform Public Development of Beijing Municipal Medical Research Institutes (grant number 2019-1).

Author information

Author notes

  1. Meng Zhang and Changsong Qi contributed equally and they are co-authors.

Authors and Affiliations

  1. Department of Molecular Diagnostics, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, China

    Meng Zhang & Shuqin Jia

  2. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China

    Changsong Qi & Zhenghang Wang

  3. The Medical Department, 3D Medicines Inc., Shanghai, China

    Hui Chen, Xiaochen Zhao, Xueming Zhang, Yifan Zhou, Chan Gao & Yuezong Bai

  4. Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China

    Jiafu Ji

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  1. Meng Zhang
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Contributions

Meng Zhang, Hui Chen, Xiaochen Zhao, Yuezong Bai, Shuqin Jia, and Jiafu Ji conceived and designed the study. Changsong Qi, Zhenghang Wang, and Hui Chen performed the research. Meng Zhang, Hui Chen, Xueming Zhang, Yifan Zhou, Chan Gao, and Xiaochen Zhao wrote the paper. Changsong Qi and Hui Chen analyzed the data. All authors contributed to manuscript revision, read, and approved the final manuscript.

Corresponding author

Correspondence to Shuqin Jia.

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Ethics approval

This study was conducted according to the Declaration of Helsinki and was approved by the Institutional Ethical Standards Committee of Peking University Cancer Hospital and Institute (NO.2016XJS01).

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Written informed consent was obtained from each patient.

Conflict of interest

The authors declare no competing interests.

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Supplementary information

Figure S1

Comparison of alteration frequencies between 3DMed cohort and MSK-UC cohort (A) and MSK-SMC cohort (B). (PNG 44 kb)

High Resolution Image (TIF 223 kb)

Figure S2

Correlation between SNV/indels number and MSI status. (PNG 17 kb)

High Resolution Image (TIFF 8.95 mb)

Figure S3

Number of deleterious DDR alterations (PNG 22 kb)

High Resolution Image (TIF 151 kb)

Table S1

Panel gene list (XLSX 10 kb)

Table S2

Case presentation of patient with target therapy based on ctDNA (XLSX 9 kb)

Table. S3

anti-ERBB2 resistance related alterations in ERBB2+ GACs (XLSX 9 kb)

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Zhang, M., Qi, C., Wang, Z. et al. Molecular characterization of ctDNA from Chinese patients with advanced gastric adenocarcinoma reveals actionable alterations for targeted and immune therapy. J Mol Med 99, 1311–1321 (2021). https://doi.org/10.1007/s00109-021-02093-z

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  • DOI: https://doi.org/10.1007/s00109-021-02093-z

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