Predictive Markers and Targeted Therapies in Gastroesophageal Cancer (GEC)

  • Josef RüschoffEmail author


For more than 15 years, several combination therapies have been used in the treatment of advanced gastroesophageal cancer (GEC) raising the median survival rate from about 3 to 4 months (best supportive care) to about 8–11 months. The most important achievement was the introduction of trastuzumab in combination with 5-FU/cisplatin or capecitabine/cisplatin as first-line therapy in HER2-positive advanced GEC. Recent ASCO/CAP guidelines recommend immunohistochemical assessment as the first diagnostic step with ISH confirmation only in IHC2+ equivocal cases. Another agent (ramucirumab) has been approved for second-line therapy directed against VEGFR2 but without any biomarker. A number of other drugs targeting transmembranous growth factor receptors and downstream signaling pathways have been evaluated but so far without final results or approvals. Most promising data have recently been shown for checkpoint inhibitors using anti PD1/PD-L1 therapies where a demonstration of mismatch repair deficiency (MMRd) or immunohistochemical demonstration of PD-L1 expression seems to be of predictive value.


Gastric cancer Biomarkers Targeted therapy HER2 ToGA trial PD-L1 


  1. 1.
    World Cancer Research Fund International. Stomach cancer statistics. Retrieved from:
  2. 2.
    Bang YJ, Van Cutsem E, Feyereislova A, 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. 2010;376:687–97.CrossRefGoogle Scholar
  3. 3.
    Lorenzen S, Riera Knorrenschild J, Haag GM, et al. Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: a randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Eur J Cancer. 2015;51:569–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Tabernero J, Hoff P, Shen L, et al. Pertuzumab (P) + trastuzumab (H) + chemotherapy (CT) for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (mGC/GEJC): final analysis of a phase III study (JACOB). Ann Oncol. 2017;28(suppl_5):v209–68.Google Scholar
  5. 5.
    Thuss-Patience PC, Shah MA, Ohtsu A, 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. 2017;18:640–53.CrossRefPubMedGoogle Scholar
  6. 6.
    Bartley AN, Washington MK, Colasacco C, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35:446–64.CrossRefPubMedGoogle Scholar
  7. 7.
    Doucet L, Terris B, Chenard MP, et al. Concordance of HER2 status between local and Central Review in Gastric (GC) and gastroesophageal Junction Cancers (GEJC): a French observational study of 394 specimens: HERable study. Mod Pathol. 2016;29:170A. (Abstract 671).Google Scholar
  8. 8.
    Rüschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299–307.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRefGoogle Scholar
  10. 10.
    Cetin B, Gumusay O, Cengiz M, Ozet A. Advances of molecular targeted therapy in gastric cancer. J Gastrointest Cancer. 2016;47:125–34.CrossRefPubMedGoogle Scholar
  11. 11.
    Shah MA, Cho JY, Tan IB, et al. A randomized phase II study of FOLFOX with or without the MET inhibitor onartuzumab in advanced adenocarcinoma of the stomach and gastroesophageal junction. Oncologist. 2016;21:1085–90.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Marx AH, Zielinski M, Kowitz CM, et al. Homogeneous EGFR amplification defines a subset of aggressive Barrett’s adenocarcinomas with poor prognosis. Histopathology. 2010;57:418–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Han SW, Oh DY, Im SA, et al. Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. Br J Cancer. 2009;100:298–304.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Fuchs CS, Doi T, Woo-Jun Jang R, et al. KEYNOTE-059 cohort 1: efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. JCO. 2017;35(suppl):4003. (Abstract 4003).CrossRefGoogle Scholar
  15. 15.
    Kang YK, Boku N, Satoh T, 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. 2017;390:2461–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Setia N, Agoston AT, Han HS, et al. A protein and mRNA expression-based classification of gastric cancer. Mod Pathol. 2016;29:772–84.CrossRefPubMedGoogle Scholar
  18. 18.
    Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Targos Molecular Pathology GmbHKasselGermany

Personalised recommendations