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Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm

Abstract

Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.

Key points

  • Molecular subtypes, such as those provided by The Cancer Genome Atlas (TCGA), based on molecular profiling of gastric and gastro-oesophageal junction (G/GEJ) cancers are associated with distinct molecular and clinical characteristics.

  • Molecular heterogeneity is a major reason for the frequent failure of biomarker-based clinical trials in patients with G/GEJ cancers and can be assessed by analysis of circulating tumour DNA (ctDNA).

  • Novel agents, including receptor tyrosine kinase inhibitors, monoclonal antibodies and antibody–drug conjugates, are currently being tested in ongoing biomarker-guided trials.

  • Sequencing of both tumour tissue DNA and ctDNA can be used for the identification of targetable alterations, including rare alterations, thus enabling precision medicine approaches for patients with G/GEJ cancers.

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Fig. 1: Molecular and clinical characteristics of TCGA subtypes of G/GEJ cancer by anatomical distribution.
Fig. 2: Molecular heterogeneity of HER2-positive G/GEJ cancer.
Fig. 3: Biomarker-based selection of targeted therapies in G/GEJ cancer.

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Acknowledgements

The work of Y.N. is supported by SCRUM-Japan Funds and a grant from the Japan Agency for Medical Research and Development (no. 19ck0106445h0002).

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Y.N. has received research funding from Chugai Pharmaceutical, Genomedia, Guardant Health and Taiho Pharmaceutical. A.K. has received research funding from MSD, Ono, Sumitomo Dainippon and Taiho, and honoraria from Ono and Taiho. F.L. has received research funding from BMS, Iomedico and Zymeworks, and honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, BioNTech, BMS, Eli Lilly, Elsevier, Excerpta Medica, Imedex, Infomedica, Iomedico, Medscape, MedUpdate, Merck Serono, MSD, Oncovis, Promedicis, Roche, SpringerNature, StreamedUp! and Zymeworks. Y.Y.J. has received institutional research funding from Bayer, Boehringer Ingelheim, BMS, Eli Lilly, Genentech/Roche, Merck and Roche, has acted as an advisor for AstraZeneca, Basilea Pharmaceutica, Bayer, BMS, Daiichi-Sankyo, Eli Lilly, Imugene, Merck, Merck Serono, Pfizer, Rgenix and Zymeworks, and holds stock options in Rgenix. K.S. has received research funding from Astellas, Chugai, Daiichi Sankyo, Eli Lilly, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Taiho, Medi Science and MSD, has acted as a consultant or advisor for AbbVie, Astellas, BMS, Eli Lilly, GSK, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho and Takeda, and has received honoraria from AbbVie, Novartis and Yakult.

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Nature Reviews Clinical Oncology thanks L.-T. Chen, Y.-J. Bang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Nakamura, Y., Kawazoe, A., Lordick, F. et al. Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol (2021). https://doi.org/10.1038/s41571-021-00492-2

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