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  • Review Article
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Early stage gastric adenocarcinoma: clinical and molecular landscapes

Nature Reviews Clinical Oncology volume 20, pages 453–469 (2023)Cite this article

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Abstract

Gastric adenocarcinoma, even when diagnosed at an early (localized) disease stage, poses a major health-care burden with cure rates that remain unsatisfactorily low, particularly in Western countries. This lack of progress reflects, among other aspects, the impracticality of early diagnosis, considerable variations in therapeutic approaches that is partly based on regional preferences, and the ingrained heterogeneity of gastric adenocarcinoma cells and their associated tumour microenvironment (TME). Clinical trials have long applied empirical interventions with the assumption that all early stage gastric adenocarcinomas are alike. Despite certain successes, the shortcomings of these approaches can potentially be overcome by targeting the specific molecular subsets of gastric adenocarcinomas identified by genomic and/or multi-omics analyses, including microsatellite instability-high, Epstein–Barr virus-induced, DNA damage repair-deficient, HER2-positive and PD-L1-high subtypes. Future approaches, including the availability of sophisticated vaccines, novel antibody technologies, agents targeting TME components (including fibroblasts, macrophages, cytokines or chemokines, and T cells) and novel immune checkpoint inhibitors, supported by improved tissue-based and blood-based diagnostic assays, seem promising. In this Review, we highlight current knowledge of the molecular and cellular biology of gastric adenocarcinomas, summarize the current approaches to clinical management of the disease, and consider the role of novel management and/or treatment strategies.

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Fig. 1: Alterations and potential targets involving the RAS and/or PI3K–AKT–mTOR signalling pathways in localized gastric adenocarcinomas.
Fig. 2: Deregulated cancer stemness pathways and putative targeted therapy strategies in patients with localized gastric adenocarcinoma.
Fig. 3: The interplay of tumour cells, cancer-associated fibroblasts and macrophages in the gastric adenocarcinoma TME.
Fig. 4: Western and Asian treatment algorithms.
Fig. 5: Surgical procedures for gastric cancer.

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Acknowledgements

We gratefully acknowledge A. Chaudry, Royal Marsden Hospital, London, UK for providing the video of a robotic gastrectomy. We gratefully acknowledge Y. Maeda, Maeda Hospital, Tokyo, Japan, for providing the video of endoscopic submucosal dissection.

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Authors and Affiliations

  1. Department of Surgery, Keio University School of Medicine, Tokyo, Japan

    Yuki Hirata

  2. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yuki Hirata

  3. Cancer Ageing and Somatic Mutation Group, Wellcome Sanger Institute, Hinxton, UK

    Ayesha Noorani

  4. Cambridge Oesophago-gastric Centre, Addenbrooke’s Hospital, Cambridge, UK

    Ayesha Noorani

  5. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shumei Song & Jaffer A. Ajani

  6. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Linghua Wang

  7. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA

    Linghua Wang

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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Jaffer A. Ajani.

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J.A.A. has acted as an adviser to Aadi, Arcus, Amgen, Astellas, AZ, BMS, BeiGene, Daiichi, Gilead, Grail, Merck, Novartis, Servier and Zymeworks, and has received institutional research funding from Astellas, BMS, Daiichi, Delta Fly, Gilead, LaNova, Leap, Merck, Prolinx, Taiho, Turning Point and Zymeworks. The other authors declare no competing interests.

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Supplementary information

Supplementary Video S1.

Robot-assisted total gastrectomy. Selected clip focusing on dissection and ligation of the left gastric artery and associated lymphadenectomy (stations 7, 8, 9 and 11) in a patient undergoing robot-assisted total gastrectomy for gastric adenocarcinoma.

Supplementary Video S2.

Selected clip showing an endoscopic submucosal dissection procedure in a patient with early stage gastric adenocarcinoma located at the greater curvature of middle gastric body.

Supplementary Fig. 1 and Table 1

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Hirata, Y., Noorani, A., Song, S. et al. Early stage gastric adenocarcinoma: clinical and molecular landscapes. Nat Rev Clin Oncol 20, 453–469 (2023). https://doi.org/10.1038/s41571-023-00767-w

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