Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Clinical Oncology volume 18, pages 473–487 (2021)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Glimelius, B. et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann. Oncol. 8, 163–168 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Thuss-Patience, P. C. et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer–a randomised phase III study of the arbeitsgemeinschaft internistische onkologie (AIO). Eur. J. Cancer 47, 2306–2314 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Kang, J. H. et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J. Clin. Oncol. 30, 1513–1518 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Ford, H. E. et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 15, 78–86 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Fuchs, C. S. et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 4, e180013 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kang, Y.-K. et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390, 2461–2471 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Moehler, M. et al. LBA6_PR. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann. Oncol. 31, S1191 (2020).

    Article  Google Scholar 

  9. El-Deiry, W. S. et al. The current state of molecular testing in the treatment of patients with solid tumors, 2019. CA Cancer J. Clin. 69, 305–343 (2019).

    PubMed  PubMed Central  Google Scholar 

  10. Lauren, P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand. 64, 31–49 (1965).

    Article  CAS  PubMed  Google Scholar 

  11. Lee, J. et al. Tumor genomic profiling guides patients with metastatic gastric cancer to targeted treatment: the VIKTORY umbrella trial. Cancer Discov. 9, 1388–1405 (2019).

    CAS  PubMed  Google Scholar 

  12. Nakamura, Y. & Shitara, K. Development of circulating tumour DNA analysis for gastrointestinal cancers. ESMO Open 5, e000600 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hutter, C. & Zenklusen, J. C. The Cancer Genome Atlas: creating lasting value beyond its data. Cell 173, 283–285 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

    Article  CAS  Google Scholar 

  15. Yanai, H. et al. Endoscopic and pathologic features of Epstein-Barr virus-associated gastric carcinoma. Gastrointest. Endosc. 45, 236–242 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. van Beek, J. et al. EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J. Clin. Oncol. 22, 664–670 (2004).

    Article  PubMed  Google Scholar 

  17. Camargo, M. C. et al. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut 63, 236–243 (2014).

    Article  PubMed  Google Scholar 

  18. Koh, J. et al. Clinicopathologic implications of immune classification by PD-L1 expression and CD8-positive tumor-infiltrating lymphocytes in stage II and III gastric cancer patients. Oncotarget 8, 26356–26367 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kawazoe, A. et al. Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer 20, 407–415 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Kang, G. H. et al. Epstein-Barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am. J. Pathol. 160, 787–794 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kaneda, A., Matsusaka, K., Aburatani, H. & Fukayama, M. Epstein-Barr virus infection as an epigenetic driver of tumorigenesis. Cancer Res. 72, 3445–3450 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Oki, E., Oda, S., Maehara, Y. & Sugimachi, K. Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair. Oncogene 18, 2143–2147 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Vilar, E. & Gruber, S. B. Microsatellite instability in colorectal cancer-the stable evidence. Nat. Rev. Clin. Oncol. 7, 153–162 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Latham, A. et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J. Clin. Oncol. 37, 286–295 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Gylling, A. et al. Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study. Gut 56, 926 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ma, C. et al. Programmed death-ligand 1 expression is common in gastric cancer associated with Epstein-Barr virus or microsatellite instability. Am. J. Surg. Pathol. 40, 1496–1506 (2016).

    Article  PubMed  Google Scholar 

  27. Liu, Y. et al. Comparative molecular analysis of gastrointestinal adenocarcinomas. Cancer Cell 33, 721–735 e728 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ridley, A. J. et al. Cell migration: integrating signals from front to back. Science 302, 1704–1709 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Thumkeo, D., Watanabe, S. & Narumiya, S. Physiological roles of Rho and Rho effectors in mammals. Eur. J. Cell Biol. 92, 303–315 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Yao, F. et al. Recurrent fusion genes in gastric cancer: CLDN18-ARHGAP26 induces loss of epithelial integrity. Cell Rep. 12, 272–285 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Cho, S. Y. et al. Sporadic early-onset diffuse gastric cancers have high frequency of somatic CDH1 alterations, but low frequency of somatic RHOA mutations compared with late-onset cancers. Gastroenterology 153, 536–549 e526 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Bajrami, I. et al. E-cadherin/ROS1 inhibitor synthetic lethality in breast cancer. Cancer Discov. 8, 498–515 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, H. et al. Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer. Cancer Discov. 10, 288–305 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Sohn, B. H. et al. Clinical significance of four molecular subtypes of gastric cancer identified by the cancer genome atlas project. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-16-2211 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Janjigian, Y. Y. et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 8, 49–58 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Kubota, Y. et al. The impact of molecular subtype on efficacy of chemotherapy and checkpoint inhibition in advanced gastric cancer. Clin. Cancer Res. 26, 3784–3790 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Cristescu, R. et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat. Med. 21, 449–456 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Kim, S. T. et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat. Med. 24, 1449–1458 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Sathe, A. et al. Single-cell genomic characterization reveals the cellular reprogramming of the gastric tumor microenvironment. Clin. Cancer Res. 26, 2640–2653 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mun, D. G. et al. Proteogenomic characterization of human early-onset gastric cancer. Cancer Cell 35, 111–124 e110 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Hecht, J. R. et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC–a randomized phase III trial. J. Clin. Oncol. 34, 443–451 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Tabernero, J. et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 19, 1372–1384 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Satoh, T. et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN–a randomized, phase III study. J. Clin. Oncol. 32, 2039–2049 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Thuss-Patience, P. C. et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 18, 640–653 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Van Cutsem, E. et al. A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification. Ann. Oncol. 28, 1316–1324 (2017).

    Article  PubMed  Google Scholar 

  46. Waddell, T. et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 14, 481–489 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lordick, F. et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 14, 490–499 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Dutton, S. J. et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 15, 894–904 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Catenacci, D. V. T. et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1467–1482 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Shah, M. A. et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol. 3, 620–627 (2017).

    Article  PubMed  Google Scholar 

  51. Hofmann, M. et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52, 797–805 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Kurokawa, Y. et al. Multicenter large-scale study of prognostic impact of HER2 expression in patients with resectable gastric cancer. Gastric Cancer 18, 691–697 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. Lee, S., de Boer, W. B., Fermoyle, S., Platten, M. & Kumarasinghe, M. P. Human epidermal growth factor receptor 2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections. Histopathology 59, 832–840 (2011).

    Article  PubMed  Google Scholar 

  54. Lee, H. E. et al. Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur. J. Cancer 49, 1448–1457 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Wang, T. et al. Matched biopsy and resection specimens of gastric and gastroesophageal adenocarcinoma show high concordance in HER2 status. Hum. Pathol. 45, 970–975 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Ahn, S. et al. Ideal number of biopsy tumor fragments for predicting HER2 status in gastric carcinoma resection specimens. Oncotarget 6, 38372–38380 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Van Cutsem, E. et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18, 476–484 (2015).

    Article  PubMed  CAS  Google Scholar 

  58. Yagi, S. et al. Clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens in patients with advanced HER2 positive gastric cancer. Gastric Cancer 22, 518–525 (2019).

    Article  CAS  PubMed  Google Scholar 

  59. Kaito, A. et al. HER2 heterogeneity is a poor prognosticator for HER2-positive gastric cancer. World J. Clin. Cases 7, 1964–1977 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Albarello, L., Pecciarini, L. & Doglioni, C. HER2 testing in gastric cancer. Adv. Anat. Pathol. 18, 53–59 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Pirrelli, M., Caruso, M. L., Di Maggio, M., Armentano, R. & Valentini, A. M. Are biopsy specimens predictive of HER2 status in gastric cancer patients? Dig. Dis. Sci. 58, 397–404 (2013).

    CAS  PubMed  Google Scholar 

  62. Wakatsuki, T. et al. Clinical impact of intratumoral HER2 heterogeneity on trastuzumab efficacy in patients with HER2-positive gastric cancer. J. Gastroenterol. 53, 1186–1195 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Marx, A. H. et al. HER-2 amplification is highly homogenous in gastric cancer. Hum. Pathol. 40, 769–777 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Kim, M. A., Lee, H. J., Yang, H. K., Bang, Y. J. & Kim, W. H. Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma. Histopathology 59, 822–831 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Bozzetti, C. et al. Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma. Br. J. Cancer 104, 1372–1376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fassan, M. et al. Human epithelial growth factor receptor 2 (HER2) status in primary and metastatic esophagogastric junction adenocarcinomas. Hum. Pathol. 43, 1206–1212 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Fusco, N. et al. HER2 in gastric cancer: a digital image analysis in pre-neoplastic, primary and metastatic lesions. Mod. Pathol. 26, 816–824 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Cho, E. Y. et al. Heterogeneity of ERBB2 in gastric carcinomas: a study of tissue microarray and matched primary and metastatic carcinomas. Mod. Pathol. 26, 677–684 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Cappellesso, R. et al. HER2 status in gastroesophageal cancer: a tissue microarray study of 1040 cases. Hum. Pathol. 46, 665–672 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Park, S. R. et al. Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: results of GASTric cancer HER2 reassessment study 1 (GASTHER1). Eur. J. Cancer 53, 42–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Pietrantonio, F. et al. HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: implication for further clinical research. Int. J. Cancer 139, 2859–2864 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Seo, S. et al. Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric Cancer 22, 527–535 (2019).

    Article  CAS  PubMed  Google Scholar 

  73. Kurokawa, Y. et al. Prognostic impact of major receptor tyrosine kinase expression in gastric cancer. Ann. Surg. Oncol. 21 (Suppl. 4), S584–S590 (2014).

    Article  PubMed  Google Scholar 

  74. Nagatsuma, A. K. et al. Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer 18, 227–238 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Kim, J. et al. Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma. J. Clin. Invest. 124, 5145–5158 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Lee, J. Y. et al. The impact of concomitant genomic alterations on treatment outcome for trastuzumab therapy in HER2-positive gastric cancer. Sci. Rep. 5, 9289 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nakamura, Y. & Yoshino, T. Clinical utility of analyzing circulating tumor DNA in patients with metastatic colorectal cancer. Oncologist 23, 1310–1318 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wang, D. S. et al. Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer. Gut 68, 1152–1161 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. Sanchez-Vega, F. et al. EGFR and MET amplifications determine response to HER2 inhibition in ERBB2-amplified esophagogastric cancer. Cancer Discov. 9, 199–209 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Pectasides, E. et al. Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma. Cancer Discov. 8, 37–48 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Maron, S. B. et al. Targeted therapies for targeted populations: anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma. Cancer Discov. 8, 696–713 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nakamura, Y. et al. Emergence of concurrent multiple EGFR mutations and MET amplification in a patient with EGFR-amplified advanced gastric cancer treated with cetuximab. JCO Precis. Oncol. 4, PO.20.00263 (2020).

    PubMed  PubMed Central  Google Scholar 

  83. Parikh, A. R. et al. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat. Med. 25, 1415–1421 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kwak, E. L. et al. Molecular heterogeneity and receptor coamplification drive resistance to targeted therapy in MET-amplified esophagogastric cancer. Cancer Discov. 5, 1271–1281 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wainberg, Z. A. et al. Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT). J Clin Oncol 39:3_suppl, 160-160 (2021).

  86. Strickler, J. H. et al. MOUNTAINEER-02: Phase II/III study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma — Trial in Progress. J Clin Oncol 39:3_suppl, TPS252-TPS252 (2021).

  87. Derks, S. et al. Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas. Ann. Oncol. 31, 1011–1020 (2020).

    Article  CAS  PubMed  Google Scholar 

  88. Lin, S. J. et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut 64, 1721–1731 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Yano, T. et al. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol. Rep. 15, 65–71 (2006).

    PubMed  Google Scholar 

  90. Park, D. I. et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig. Dis. Sci. 51, 1371–1379 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Giuffre, G., Ieni, A., Barresi, V., Caruso, R. A. & Tuccari, G. HER2 status in unusual histological variants of gastric adenocarcinomas. J. Clin. Pathol. 65, 237–241 (2012).

    Article  PubMed  Google Scholar 

  92. Muro, K. et al. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann. Oncol. 30, 19–33 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. NCCN. NCCN guidelines Version 2. 2021 Gastric Cancer https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf (2021).

  94. Shah, M. A. et al. Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer. Gastric Cancer 22, 803–816 (2019).

    Article  CAS  PubMed  Google Scholar 

  95. Kim, S. T. et al. Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients. Ann. Oncol. 29, 1037–1048 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Doi, T. et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 18, 1512–1522 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Shitara, K. et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 382, 2419–2430 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Yamaguchi, K. et al. 1422MO. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-low, advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Results of the exploratory cohorts in the phase II, multicenter, open-label DESTINY-Gastric01 study. Ann. Oncol. 31, S899–S900 (2020).

    Article  Google Scholar 

  99. Gall, V. A. et al. Trastuzumab increases HER2 uptake and cross-presentation by dendritic cells. Cancer Res. 77, 5374–5383 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Iwata, T. N., Sugihara, K., Wada, T. & Agatsuma, T. [Fam-]trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti-CTLA-4 antibody in a mouse model. PLoS ONE 14, e0222280 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Varadan, V. et al. Immune signatures following single dose trastuzumab predict pathologic response to preoperativetrastuzumab and chemotherapy in HER2-positive early breast cancer. Clin. Cancer Res. 22, 3249–3259 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chaganty, B. K. R. et al. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNgamma secretion. Cancer Lett. 430, 47–56 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Stagg, J. et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108, 7142–7147 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Janjigian, Y. Y. et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol. 21, 821–831 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Janjigian, Y. Y. et al. KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJC): a double-blind, randomized, placebo-controlled phase 3 study. J. Clin. Oncol. 37, TPS4146–TPS4146 (2019).

    Article  Google Scholar 

  106. Catenacci, D. V. T. et al. Antitumor activity of margetuximab (M) plus pembrolizumab (P) in patients (pts) with advanced HER2+ (IHC3+) gastric carcinoma (GC). J. Clin. Oncol. 37, 65–65 (2019).

    Article  Google Scholar 

  107. Catenacci, D. V. T. et al. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial. Lancet Oncol. 21, 1066–1076 (2020).

    Article  CAS  PubMed  Google Scholar 

  108. Kulukian, A. et al. Preclinical activity of HER2-selective tyrosine kinase inhibitor tucatinib as a single agent or in combination with trastuzumab or docetaxel in solid tumor models. Mol. Cancer Ther. 19, 976–987 (2020).

    Article  CAS  PubMed  Google Scholar 

  109. No authors listed. ZW25 effective in HER2-positive cancers. Cancer Discov. 9, 8 (2019).

    Google Scholar 

  110. Weisser, N., Wickman, G., Davies, R. & Rowse, G. Abstract 31. Preclinical development of a novel biparatopic HER2 antibody with activity in low to high HER2 expressing cancers. Cancer Res. 77, 31 (2017).

    Article  CAS  Google Scholar 

  111. Meric-Bernstam F, et al. Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): Results from a phase I study. DOI: 10.1200/JCO.2021.39.3_suppl.164 Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021) 164-164.

  112. Jung, E. J., Jung, E. J., Min, S. Y., Kim, M. A. & Kim, W. H. Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma. Hum. Pathol. 43, 1559–1566 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Helsten, T. et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin. Cancer Res. 22, 259–267 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Kuboki, Y. et al. In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients. Gastric Cancer 21, 401–412 (2018).

    Article  CAS  PubMed  Google Scholar 

  115. Pearson, A. et al. High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. Cancer Discov. 6, 838–851 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jang, J. et al. Antitumor effect of AZD4547 in a fibroblast growth factor receptor 2-amplified gastric cancer patient-derived cell model. Transl. Oncol. 10, 469–475 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Cha, Y. et al. FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro. Mol. Oncol. 12, 993–1003 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Goyal, L. et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 9, 1064–1079 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bahleda, R. et al. Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors. Ann. Oncol. 31, 1405–1412 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Hollebecque, A. et al. A phase II study of futibatinib (TAS-120) in patients (pts) with advanced (adv) solid tumors harboring fibroblast growth factor receptor (FGFR) genomic aberrations. J. Clin. Oncol. 38, TPS470–TPS470 (2020).

    Article  Google Scholar 

  121. Catenacci, D. V. T. et al. Phase I escalation and expansion study of bemarituzumab (FPA144) in patients with advanced solid tumors and FGFR2b-selected gastroesophageal adenocarcinoma. J. Clin. Oncol. 38, 2418–2426 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Catenacci, D. V. et al. Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT phase III study design. Future Oncol. 15, 2073–2082 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Liao, J. B., Lee, H. P., Fu, H. T. & Lee, H. S. Assessment of EGFR and ERBB2 (HER2) in gastric and gastroesophageal carcinomas: EGFR amplification is associated with a worse prognosis in early stage and well to moderately differentiated carcinoma. Appl. Immunohistochem. Mol. Morphol. 26, 374–382 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Lordick, F. et al. Clinical outcome according to tumor HER2 status and EGFR expression in advanced gastric cancer patients from the EXPAND study. J. Clin. Oncol. 31, 4021–4021 (2013).

    Article  Google Scholar 

  125. Petty, R. D. et al. Gefitinib and EGFR gene copy number aberrations in esophageal cancer. J. Clin. Oncol. 35, 2279–2287 (2017).

    Article  CAS  PubMed  Google Scholar 

  126. Montagut, C. et al. Efficacy of Sym004 in patients with metastatic colorectal cancer with acquired resistance to anti-EGFR therapy and molecularly selected by circulating tumor DNA analyses: a phase 2 randomized clinical trial. JAMA Oncol. 4, e175245 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kato, S. et al. Revisiting epidermal growth factor receptor (EGFR) amplification as a target for anti-EGFR therapy: analysis of cell-free circulating tumor DNA in patients with advanced malignancies. JCO Precis. Oncol. 3, PO.18.00180 (2019).

    PubMed Central  Google Scholar 

  128. Schmees, N. et al. Abstract 4454. Identification of BAY-218, a potent and selective small-molecule AhR inhibitor, as a new modality to counteract tumor immunosuppression. Cancer Res. 79, 4454 (2019).

    Google Scholar 

  129. Van Cutsem, E. et al. A multicenter phase II study of AMG 337 in patients with MET-amplified gastric/gastroesophageal junction/esophageal adenocarcinoma and other MET-amplified solid tumors. Clin. Cancer Res. 25, 2414–2423 (2019).

    Article  PubMed  Google Scholar 

  130. Lee, J. et al. Gastrointestinal malignancies harbor actionable MET exon 14 deletions. Oncotarget 6, 28211–28222 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Guo, R. et al. MET-dependent solid tumours - molecular diagnosis and targeted therapy. Nat. Rev. Clin. Oncol. 17, 569–587 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Frigault, M. M. et al. Mechanisms of acquired resistance to savolitinib, a selective MET inhibitor in MET-amplified gastric cancer. JCO Precis. Oncol. 4, PO.19.00386 (2020).

    PubMed  PubMed Central  Google Scholar 

  133. Yuan, F. et al. Capecitabine metronomic chemotherapy inhibits the proliferation of gastric cancer cells through anti-angiogenesis. Oncol. Rep. 33, 1753–1762 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Zhang, Y. et al. Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy. Proc. Natl Acad. Sci. USA 114, E5226–E5235 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Ohtsu, A. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J. Clin. Oncol. 29, 3968–3976 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Shen, L. et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer 18, 168–176 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Fuchs, C. S. et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383, 31–39 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Wilke, H. et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 15, 1224–1235 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. Li, J. et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J. Clin. Oncol. 34, 1448–1454 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Kang, Y. K. et al. Randomized phase III ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastatic gastric cancer who failed ≥2 prior chemotherapy regimens. Ann. Oncol. 30, v877–v878 (2019).

    Article  Google Scholar 

  141. Van Cutsem, E. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J. Clin. Oncol. 30, 2119–2127 (2012).

    Article  PubMed  CAS  Google Scholar 

  142. Van Cutsem, E. et al. Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study. Eur. J. Cancer 127, 150–157 (2020).

    Article  PubMed  CAS  Google Scholar 

  143. Fuchs, C. S. et al. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br. J. Cancer 115, 974–982 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Alexandrov, L. B., Nik-Zainal, S., Siu, H. C., Leung, S. Y. & Stratton, M. R. A mutational signature in gastric cancer suggests therapeutic strategies. Nat. Commun. 6, 8683 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sahasrabudhe, R. et al. Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer. Gastroenterology 152, 983–986 e986 (2017).

    Article  CAS  PubMed  Google Scholar 

  146. Smyth, E. C. et al. Genomic loss of heterozygosity and survival in the REAL3 trial. Oncotarget 9, 36654–36665 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Bang, Y. J. et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1637–1651 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. Liu, Y. Z. et al. Olaparib plus paclitaxel sensitivity in biomarker subgroups of gastric cancer. Ann. Oncol. 29, viii25–viii26 (2018).

    Article  Google Scholar 

  149. Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

    Article  CAS  PubMed  Google Scholar 

  150. Moore, K. et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379, 2495–2505 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Golan, T. et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381, 317–327 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. de Bono, J. et al. Olaparib for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 382, 2091–2102 (2020).

    Article  PubMed  Google Scholar 

  153. Penson, R. T. et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J. Clin. Oncol. 38, 1164–1174 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jiao, S. et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin. Cancer Res. 23, 3711–3720 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Sen, T. et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 9, 646–661 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Domchek, S. M. et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 21, 1155–1164 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Lampert, E. J. et al. Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase II study. Clin. Cancer Res. 26, 4268–4279 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Mathews, M. T. & Berk, B. C. PARP-1 inhibition prevents oxidative and nitrosative stress-induced endothelial cell death via transactivation of the VEGF receptor 2. Arterioscler. Thromb. Vasc. Biol. 28, 711–717 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Liu, J. F. et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 15, 1207–1214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Niimi, T. et al. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol. Cell Biol. 21, 7380–7390 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Sahin, U. et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin. Cancer Res. 14, 7624–7634 (2008).

    Article  CAS  PubMed  Google Scholar 

  162. Nakayama, I. et al. Enrichment of CLDN18-ARHGAP fusion gene in gastric cancers in young adults. Cancer Sci. 110, 1352–1363 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Singh, P., Toom, S. & Huang, Y. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J. Hematol. Oncol. 10, 105 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Tureci, O. et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann. Oncol. 30, 1487–1495 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sahin, U. et al. Zolbetuximab combined with EOX as first-line therapy in advanced CLDN18.2+ gastric (G) and gastroesophageal junction (GEJ) adenocarcinoma: updated results from the FAST trial. Ann. Oncol. https://doi.org/10.1016/j.annonc.2021.02.005 (2021).

    Article  PubMed  Google Scholar 

  166. Moran, D., Maurus, D., Rohde, C. & Arozullah, A. 103P. Prevalence of CLDN18.2, HER2 and PD-L1 in gastric cancer samples. Ann. Oncol. 29, viii32 (2018).

    Article  Google Scholar 

  167. Jiang, H. et al. Claudin18.2-specific chimeric antigen receptor engineered T cells for the treatment of gastric cancer. J. Natl Cancer Inst. 111, 409–418 (2019).

    Article  PubMed  CAS  Google Scholar 

  168. Zhan, X. et al. Phase I trial of claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma. J. Clin. Oncol. 37, 2509–2509 (2019).

    Article  Google Scholar 

  169. Shitara, K. et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 392, 123–133 (2018).

    Article  CAS  PubMed  Google Scholar 

  170. Shitara, K. et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 6, 1571–1580 (2020).

    Article  PubMed  Google Scholar 

  171. Shitara, K. et al. The association of tissue tumor mutational burden (tTMB) using the Foundation Medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (pts) with gastric cancer (GC) from KEYNOTE-061. J. Clin. Oncol. 38, 4537–4537 (2020).

    Article  Google Scholar 

  172. Fuchs, C. S. et al. The association of molecular biomarkers with efficacy of pembrolizumab versus paclitaxel in patients with gastric cancer (GC) from KEYNOTE-061. J. Clin. Oncol. 38, 4512–4512 (2020).

    Article  Google Scholar 

  173. Wyrwicz, L. S. et al. 1442P association of TMB using the foundation medicine companion diagnostic (F1CDx) with efficacy of first-line pembrolizumab (pembro) or pembro plus chemotherapy (pembro+chemo) versus chemo in patients with gastric cancer (gc) from KEYNOTE-062. Ann. Oncol. 31, S907–S908 (2020).

    Article  Google Scholar 

  174. Boku, N. et al. LBA7_PR Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Ann. Oncol. 31, S1192 (2020).

    Article  Google Scholar 

  175. Marabelle, A. et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21, 1353–1365 (2020).

    Article  CAS  PubMed  Google Scholar 

  176. Arlauckas, S. P. et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci. Transl. Med. 9, eaal3604 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Kamada, T. et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl Acad. Sci. USA 116, 9999–10008 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lo Russo, G. et al. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin. Cancer Res. 25, 989–999 (2019).

    Article  CAS  PubMed  Google Scholar 

  179. Kumagai, S. et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat. Immunol. 21, 1346–1358 (2020).

    Article  CAS  PubMed  Google Scholar 

  180. Hoff, S., Grünewald, S., Röse, L. & Zopf, D. 1198P. Immunomodulation by regorafenib alone and in combination with anti PD1 antibody on murine models of colorectal cancer. Ann. Oncol. https://doi.org/10.1093/annonc/mdx376.060 (2017).

    Article  Google Scholar 

  181. Chen, C.-W. et al. FRI-471-regorafenib may enhance efficacy of anti-program cell death-1 therapy in hepatocellular carcinoma through modulation of macrophage polarization. J. Hepatol. 70, e605–e606 (2019).

    Article  Google Scholar 

  182. Kato, Y. et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE 14, e0212513 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Fukuoka, S. et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J. Clin. Oncol. 38, 2053–2061 (2020).

    Article  CAS  PubMed  Google Scholar 

  184. Kawazoe, A. et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 21, 1057–1065 (2020).

    Article  CAS  PubMed  Google Scholar 

  185. Catenacci, D. V. T. et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): a phase II study evaluating an individualized treatment strategy for metastatic disease. Cancer Discov. 11, 308 (2021).

    Article  CAS  PubMed  Google Scholar 

  186. van Grieken, N. C. et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. Br. J. Cancer 108, 1495–1501 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Shinozaki-Ushiku, A. et al. The first case of gastric carcinoma with NTRK rearrangement: identification of a novel ATP1B-NTRK1 fusion. Gastric Cancer 23, 944–947 (2020).

    Article  CAS  PubMed  Google Scholar 

  188. Alese, O. B. et al. Anaplastic lymphoma kinase (ALK) gene alteration in signet ring cell carcinoma of the gastrointestinal tract. Ther. Adv. Med. Oncol. 7, 56–62 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Lee, J. et al. Identification of ROS1 rearrangement in gastric adenocarcinoma. Cancer 119, 1627–1635 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Yuki, S. et al. The nationwide cancer genome screening project in Japan SCRUM-Japan GI-SCREEN: efficient identification of cancer genome alterations in advanced gastric cancer (GC). J. Clin. Oncol. 36, 4050–4050 (2018).

    Article  Google Scholar 

  191. Nakamura, Y. et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat. Med. 26, 1859–1864 (2020).

    Article  PubMed  CAS  Google Scholar 

Download references

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).

Author information

Author notes

  1. These authors contributed equally: Yoshiaki Nakamura, Akihito Kawazoe.

Authors and Affiliations

  1. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura, Akihito Kawazoe & Kohei Shitara

  2. Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura

  3. Division of Oncology, Department of Medicine, University Cancer Center Leipzig, Leipzig University Medical Center, Leipzig, Germany

    Florian Lordick

  4. Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Yelena Y. Janjigian

  5. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Yelena Y. Janjigian

Authors
  1. Yoshiaki Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akihito Kawazoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florian Lordick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yelena Y. Janjigian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kohei Shitara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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

Corresponding author

Correspondence to Kohei Shitara.

Ethics declarations

Competing interests

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Reviewer information

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.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 18, 473–487 (2021). https://doi.org/10.1038/s41571-021-00492-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-021-00492-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer