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Current developments in gastric cancer: from molecular profiling to treatment strategy

Abstract

Gastric cancer and gastro-oesophageal junction cancer represent a global health-care challenge. Despite the efficacy of improved chemotherapy and surgical options, these patients still have a poor prognosis. In advanced disease, only trastuzumab and some immune checkpoint inhibitors, such as nivolumab and pembrolizumab in addition to chemotherapy, have demonstrated consistent and reliable efficacy in patients with HER2-positive and PDL1-positive tumours, respectively. In this Review, we discuss the intrinsic characteristics of gastric and gastro-oesophageal cancer from the molecular and clinical perspectives and provide a comprehensive review of previously reported and ongoing phase II and III clinical trials with targeted agents and immunotherapy in advanced and localized settings. Finally, we suggest alternative strategies to help overcome current challenges in precision medicine and to improve outcomes for these patients.

Key points

  • The spatial and temporal heterogeneity features of gastric and gastro-oesophageal tumours have jeopardized the success of most phase II and III clinical trials with targeted treatments.

  • Current biomarkers for treatment decisions in patients with gastric and gastro-oesophageal cancer include testing for HER2 overexpression and amplification, PDL1 combined positive score expression and microsatellite instability-high status.

  • Chemotherapy drugs of reduced toxicity, together with some molecularly driven targeted therapies, have been shown to be particularly valuable for sequential treatment strategies in optimizing the survival of patients with gastric and gastro-oesophageal cancer.

  • National strategies with massive molecular screening of patients with gastric and gastro-oesophageal cancer have emerged as promising approaches to detect those candidates who could benefit from targeted treatments.

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Fig. 1: Current algorithm for the treatment of gastric and gastro-oesophageal junction cancer.
Fig. 2: Gastric cancer particularities.
Fig. 3: Proposed algorithm for the treatment of patients with gastric and gastro-oesophageal junction cancer.

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M.A., V.A. and M.D. researched data for the article. M.A. and V.A. contributed substantially to discussion of the content. M.A., V.A. and M.D. wrote the article. M.A., V.A. and J.T. reviewed and/or edited the manuscript before submission.

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Correspondence to Josep Tabernero.

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M.A. declares consulting/advisory roles with BMS, Lilly, MSD and Servier; and honoraria for speaking from Amgen, BMS, Lilly, MSD and Servier. V.A. declares consulting/advisory roles with BMS and MSD; and honoraria for speaking from BMS and Lilly. M.D. reports a financial interest in the form of a scientific consultancy role for Lilly and travel expenses partially covered by Lilly. J.T. reports a personal financial interest in the form of a scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc; and also educational collaborations with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER); and declares institutional financial interests in the form of financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, BMS, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK.

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Alsina, M., Arrazubi, V., Diez, M. et al. Current developments in gastric cancer: from molecular profiling to treatment strategy. Nat Rev Gastroenterol Hepatol (2022). https://doi.org/10.1038/s41575-022-00703-w

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