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  • Review Article
  • Published:

Clinical impact of tumour biology in the management of gastroesophageal cancer

Nature Reviews Clinical Oncology volume 13, pages 348–360 (2016)Cite this article

Subjects

Key Points

  • Oesophageal and gastric cancers are aggressive tumours that result in more than 1 million deaths annually worldwide

  • Oesophageal and gastric cancers harbour a high number of genetic and molecular alterations, some of which contribute to an aggressiveness phenotype resulting in early development of drug resistance

  • A new molecular classification of gastric cancer into four subtypes on the basis of genotypic, epigenetic and proteomic characteristics has been developed

  • HER2-targeting with trastuzumab remains an important strategy in patients with HER2-positive, advanced-stage gastric cancer; however, novel anti-HER2 targeted drugs are being explored in the advanced-stage and perioperative treatment settings

  • Antiangiogenic treatment with ramucirumab has proved effective in a biologically unselected patient population with disease progression after first-line therapy

  • Treatments that target cancer stemness and immune-based therapies are two evolving concepts in the management of advanced-stage gastroesophageal cancer

Abstract

The characterization of oesophageal and gastric cancer into subtypes based on genotype has evolved in the past decade. Insights into the molecular landscapes of gastroesophageal cancer provide a roadmap to assist the development of new drugs and their use in combinations, for patient stratification, and for trials of targeted therapies. Trastuzumab is the only approved treatment for gastroesophageal cancers that overexpress HER2. Acquired resistance usually limits the duration of response to this treatment, although a number of new agents directed against HER2 have the potential to overcome or prolong the time until resistance occurs. Beyond that, anti-VEGFR2 therapy with ramucirumab was the first biological treatment strategy to produce a survival benefit in an unselected population of patients with chemotherapy-refractory gastroesophageal cancer. Large initiatives are starting to address the role of biomarker-driven targeted therapy in the metastatic and in the perioperative setting for patients with this disease. Immunotherapy also holds promise, and our understanding of subsets of gastroesophageal cancer based on patterns of immune response continues to evolve. Efforts are underway to identify more relevant genomic subsets through genomic screening, functional studies, and molecular characterization. Herein, we provide an overview of the key developments in the treatment of gastroesophageal cancer, and discuss potential strategies to further optimize therapy by targeting disease subtypes.

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Figure 1: Proposed treatment algorithm for advanced gastroesophageal cancer based on publish recommendations7,13.
Figure 2: Key features of gastric cancer subtypes according to The Cancer Genome Atlas (TCGA)37.
Figure 3: Biopsy of a gastric cancer.
Figure 4: Angiogenic signalling network and inhibition by antiangiogenic drugs.
Figure 5: Mutational heterogeneity in oesophageal and gastric cancer.

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References

  1. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

    CAS  PubMed  Google Scholar 

  2. de Martel, C. et al. Gastric cancer: epidemiology and risk factors. Gastroenterol. Clin. North Am. 42, 219–240 (2013).

    Article  PubMed  Google Scholar 

  3. Colquhoun, A. et al. Global patterns of cardia and non-cardia gastric cancer incidence in 2012. Gut 64, 1881–1888 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Kim, J. Y. et al. Lymph node metastasis in early gastric cancer: evaluation of a novel method for measuring submucosal invasion and development of a nodal predicting index. Hum. Pathol. 44, 2829–2836 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Gockel, I. et al. Risk of lymph node metastasis in submucosal esophageal cancer: a review of surgically resected patients. Expert Rev. Gastroenterol. Hepatol. 5, 371–384 (2011).

    Article  PubMed  Google Scholar 

  6. Wagner, A. D. et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 3, CD004064 (2010).

    Google Scholar 

  7. Lordick, F. et al. Optimal chemotherapy for advanced gastric cancer: is there a global consensus? Gastric Cancer 17, 213–225 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Van Cutsem, E. et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J. Clin. Oncol. 24, 4991–4997 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Van Cutsem, E. et al. Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: a randomized phase II study. Ann. Oncol. 26, 149–156 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. 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 

  12. 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 

  13. Lordick, F. Gastrointestinal cancer: over the RAINBOW — renaissance in antiangiogenesis. Nat. Rev. Clin. Oncol. 12, 7–8 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Moehler, M. et al. International comparison of the German evidence-based S3-guidelines on the diagnosis and multimodal treatment of early and locally advanced gastric cancer, including adenocarcinoma of the lower esophagus. Gastric Cancer 18, 550–563 (2015).

    Article  PubMed  Google Scholar 

  15. National Comprehensive Cancer Network GuidelinesVersion 3.2015 Gastric Cancer. [online],

  16. Lauren, P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol. Microbiol. Scand. 64, 31–49 (1965).

    Article  CAS  PubMed  Google Scholar 

  17. Marrelli, D. et al. Different patterns of recurrence in gastric cancer depending on Lauren's histologic type: longitudinal study. World J. Surg. 26, 1160–1165 (2002).

    Article  PubMed  Google Scholar 

  18. Carneiro, F. et al. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and it's implications for patient screening. J. Pathol. 203, 681–687 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Yuo, W. C. et al. Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res. 53, 1317–1321 (1993).

    Google Scholar 

  20. Correa, P. et al. Gastric precancerous process in a high risk population: cross-sectional studies. Cancer Res. 50, 4731–4736 (1990).

    CAS  PubMed  Google Scholar 

  21. Anderson, W. F. et al. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 303, 1723–1728 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Blot, W. J. et al. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265, 1287–1289 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Crew, K. D. & Neugut, A. I. Epidemiology of gastric cancer. World J. Gastroenterol. 12, 354–362 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sakaguchi, T. et al. Characteristics and clinical outcome of proximal-third gastric cancer. J. Am. Coll. Surg. 187, 352–357 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Tafe, L. J. et al. Human epidermal growth factor receptor 2 testing in gastroesophageal cancer: correlation between immunohistochemistry and fluorescence in situ hybridization. Arch. Pathol. Lab. Med. 135, 1460–1465 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Steevens, J. et al. Trends in incidence of oesophageal and stomach cancer subtypes in Europe. Eur. J. Gastroenterol. Hepatol. 22, 669–678 (2010).

    PubMed  Google Scholar 

  28. Marshall, B. J. & Warren, J. R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 1311–1314 (1984).

    Article  CAS  PubMed  Google Scholar 

  29. Correa, P. Helicobacter pylori and gastric carcinogenesis. Am. J. Surg. Pathol. 19, S37–S43 (1995).

    Article  PubMed  Google Scholar 

  30. Figueiredo, C. et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J. Natl Cancer Inst. 94, 1680–1687 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Yang, P. et al. Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur. J. Cancer 45, 2867–2873 (2009).

    Article  PubMed  Google Scholar 

  32. Tsugane, S. & Sasazuki, S. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer 10, 75–83 (2007).

    Article  PubMed  Google Scholar 

  33. Mendez, M. A. et al. Cereal fiber intake may reduce risk of gastric adenocarcinomas: the EPIC-EURGAST study. Int. J. Cancer 121, 1618–1623 (2007).

    Article  CAS  Google Scholar 

  34. Lunet, N. et al. Fruit and vegetables consumption and gastric cancer: a systematic review and meta-analysis of cohort studies. Nutr. Cancer 53, 1–10 (2005).

    Article  PubMed  Google Scholar 

  35. Shibata, D. et al. Association of Epstein−Barr virus with undifferentiated gastric carcinomas with intense lymphoid infiltration. Lymphoepithelioma-like carcinoma. Am. J. Pathol. 139, 469–474 (1991).

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Kusano, M. et al. Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein–Barr virus. Cancer 106, 1467–1479 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Bass, A. J. et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

    Article  CAS  Google Scholar 

  38. Cheng, D. T. et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J. Mol. Diagn. 17, 251–264 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Memorial Sloan Kettering Cancer Center. cBioPortal for Cancer Genomics http://www.cbioportal.org/study.do?cancer_study_id=egc_tmucih_2015#summary

  40. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Riches, J. C. et al. Genomic profiling of esophagogastric (EG) tumors in clinical practice [abstract]. J. Clin. Oncol. 33 (Suppl. 3), 57 (2015).

    Article  Google Scholar 

  42. 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 

  43. Janjigian, Y. Y. et al. Patient-derived xenografts as models for the identification of predictive biomarkers in esophagogastric cancer [abstract]. J. Clin. Oncol. 32 (Suppl. 5), 4059 (2014).

    Article  Google Scholar 

  44. Fitzgerald, R. C. et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J. Med. Genet. 47, 436–444 (2010).

    Article  PubMed  CAS  Google Scholar 

  45. Guilford, P. et al. E-cadherin germline mutations in familial gastric cancer. Nature 392, 402–405 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Huntsman, D. G. et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N. Engl. J. Med. 344, 1904–1909 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Pharoah, P. D. et al. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121, 1348–1353 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Benusiglio, P. R. et al. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J. Med. Genet. 50, 486–489 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. van der Post, R. S. et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J. Med. Genet. 52, 361–374 (2015).

    Article  PubMed  CAS  Google Scholar 

  50. Moran, A. et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Familial Cancer 11, 235–242 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Watanabe, H. et al. Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. Hum. Pathol. 9, 269–283 (1978).

    Article  CAS  PubMed  Google Scholar 

  52. Lynch, H. T. et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104, 1535–1549 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Jakubowska, A. et al. BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br. J. Cancer 87, 888–891 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Oliveira, C. et al. Genetic screening for hereditary diffuse gastric cancer. Expert Rev. Mol. Diagn. 3, 201–215 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Worthley, D. L. et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut 61, 774–779 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Oliveira, C. et al. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol. 16, e60–e70 (2015).

    Article  PubMed  Google Scholar 

  57. Hansford, S. et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 1, 23–32 (2015).

    Article  PubMed  Google Scholar 

  58. Hoskins, L. C. et al. Distribution of ABO blood groups in patients with pernicious anemia, gastric carcinoma and gastric carcinoma associated with pernicious anemia. N. Engl. J. Med. 273, 633–637 (1965).

    Article  CAS  PubMed  Google Scholar 

  59. Edgren, G. et al. Risk of gastric cancer and peptic ulcers in relation to ABO blood type: a cohort study. Am. J. Epidemiol. 172, 1280–1285 (2010).

    Article  PubMed  Google Scholar 

  60. Won, E. et al. HER2 directed therapy for gastric/esophageal cancers. Curr. Treat. Opt. Oncol. 15, 395–404 (2014).

    Article  Google Scholar 

  61. Zhang, X. L. et al. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J. Surg. 33, 2112–2118 (2009).

    Article  PubMed  Google Scholar 

  62. Begnami, M. D. et al. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J. Clin. Oncol. 29, 3030–3036 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Warneke, V. S. et al. Her2/neu testing in gastric cancer: evaluating the risk of sampling errors. Ann. Oncol. 24, 725–733 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Katai, H. et al. HER2 expression in carcinomas of the true cardia (Siewert type II esophagogastric junction carcinoma). World J. Surg. 38, 426–430 (2014).

    Article  PubMed  Google Scholar 

  65. 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 

  66. Tanner, M. et al. Amplification of HER-2 in gastric carcinoma: association with topoisomerase IIα gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann. Oncol. 16, 273–278 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Janjigian, Y. Y. et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann. Oncol. 23, 2656–2662 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Terashima, M. et al. Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin. Cancer Res. 18, 5992–6000 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Aizawa, M. et al. Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population. Gastric Cancer 17, 34–42 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Okines, A. F. et al. Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial. Ann. Oncol. 24, 1253–1261 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. 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 

  72. Gómez-Martín, C. et al. Consensus of the Spanish Society of Medical Oncology (SEOM) and Spanish Society of Pathology (SEAP) for HER2 testing in gastric carcinoma. Clin. Transl. Oncol. 13, 636–651 (2011).

    Article  PubMed  Google Scholar 

  73. Lordick, F. HER2 in gastric cancer: a biomarker with clinical impact, but not without translational challenges. Clin. Transl. Oncol. 13, 597–598 (2011).

    Article  PubMed  Google Scholar 

  74. Gullo, I. et al. Minimum biopsy set for HER2 evaluation in gastric and gastro-esophageal junction cancer. Endosc. Int. Open 3, E165–E170 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Tominaga, N. et al. Five biopsy specimens from the proximal part of the tumor reliably determine HER2 protein expression status in gastric cancer. Gastric Cancer http://dx.doi.org/10.1007/s10120-015-0502-3 (2015).

  76. Kushima, R. et al. Interpretation of HER2 tests in gastric cancer: confirmation of interobserver differences and validation of a QA/QC educational program. Virchows Arch. 464, 539–545 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Gomez-Martin, C. et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J. Clin. Oncol. 31, 4445–4452 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Rüschoff, J. et al. HER2 testing in gastric cancer: a practical approach. Mod. Pathol. 25, 637–650 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Wainberg, Z. A. et al. Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin. Cancer Res. 16, 1509–1519 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. 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 

  81. 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. http://dx.doi.org/10.1200/JCO.2015.62.6598 (2015).

  82. Lorenzen, S. 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 51, 569–576 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. Blackwell, K. L. et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J. Clin. Oncol. 30, 2585–2592 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Yamashita-Kashima, Y. et al. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin. Cancer Res. 17, 5060–5070 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Kang, Y. K. et al. A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Br. J. Cancer 111, 660–666 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Tabernero, J. et al. Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: an international phase III study (JACOB) [abstract]. J. Clin. Oncol. 31 (Suppl.), TPS4150 (2013).

    Google Scholar 

  87. Kang, Y. K. et al. A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC) [abstract]. J. Clin. Oncol. 34 (Suppl. 4s), 5 (2016).

    Article  Google Scholar 

  88. Rivera, F. et al. NeoHx study: perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma — R0 resection, pCR, and toxicity analysis [abstract]. J. Clin. Oncol. 31 (Suppl.), 4098, (2013).

    Google Scholar 

  89. Hofheinz, R. D. et al. HER-FLOT: trastuzumab in combination with FLOT as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: a phase II trial of the AIO Gastric Cancer Study Group [abstract]. J. Clin. Oncol. 32 (Suppl.), 4073 (2014).

    Article  Google Scholar 

  90. U.S. National Library of Science. ClinicalTrials.gov [online], (2015).

  91. U.S. National Library of Science. ClinicalTrials.gov [online], (2015).

  92. Japan Clinical Oncology Group. A randomized phase II study of sysemic chemotherapy with and without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis (Trastuzumab In Gastric or Esophagogastric junction Adenocarcinoma): trigger study. [online],

  93. GBG GERMAN BREAST GROUP et al. Trastuzumab improves the efficacy of chemotherapy in breast cancer treatment beyond progression. Breast Care (Basel) 3, 364–365 (2008).

  94. Jackisch, C. et al. Impact of trastuzumab treatment beyond disease progression for advanced/metastatic breast cancer on survival — results from a prospective, observational study in Germany. Breast 23, 603–608 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Arteaga, C. L. & Engelman, J. A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25, 282–303 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Janjigian, Y. Y. et al. Loss of human epidermal growth factor receptor 2 (HER2) expression in HER2-overexpressing esophagogastric (EG) tumors treated with trastuzumab. J. Clin. Oncol. 33 (Suppl. 3), 63 (2015).

    Article  Google Scholar 

  97. Leyland-Jones, B. et al. Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated. J. Clin. Oncol. 28, 960–966 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Oude Munnink, T. H. et al. Trastuzumab pharmacokinetics influenced by extent human epidermal growth factor receptor 2-positive tumor load. J. Clin. Oncol. 28, e355–e356; author reply e357 (2010).

    Article  PubMed  Google Scholar 

  99. Dijkers, E. C. et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin. Pharmacol. Ther. 87, 586–592 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Oude Munnink, T. H. et al. Trastuzumab pharmacokinetics influenced by extent human epidermal growth factor receptor 2-positive tumor load. J. Clin. Oncol. 28, e355–e356 (2010).

    Article  PubMed  Google Scholar 

  101. Janjigian, Y. Y. et al. Monitoring afatinib treatment in HER2-positive gastric cancer with 18F-FDG and 89Zr-trastuzumab PET. J. Nucl. Med. 54, 936–943 (2013).

    Article  PubMed  CAS  Google Scholar 

  102. Lordick, F. et al. Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br. J. Cancer 102, 500–505 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Luber, B. et al. Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). BMC Cancer 11, 509 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. 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 

  105. 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  PubMed  PubMed Central  CAS  Google Scholar 

  106. Dragovich, T. et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J. Clin. Oncol. 24, 4922–4927 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. 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 

  108. Petty, R. D. et al. Epidermal growth factor receptor copy number gain (EGFR CNG) and response to gefitinib in esophageal cancer (EC): results of a biomarker analysis of a phase III trial of gefitinib versus placebo (TRANS-COG) [abstract]. J. Clin. Oncol. 32 (Suppl.), 4016 (2014).

    Article  Google Scholar 

  109. Deng, N. et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61, 673–684 (2012).

    Article  PubMed  CAS  Google Scholar 

  110. Lennerz, J. K. et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J. Clin. Oncol. 29, 4803–4810 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Iveson, T. et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 15, 1007–1018 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Lordick, F. Targeting the HGF/MET pathway in gastric cancer. Lancet Oncol. 15, 914–916 (2014).

    Article  PubMed  Google Scholar 

  113. Cunningham, D. et al. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced MET-positive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study [abstract]. J. Clin. Oncol. 33 (Suppl.), 4000 (2015).

    Article  Google Scholar 

  114. Shah, M. et al. METGastric: a phase III study of onartuzumab plus mFOLFOX6 in patients with metastatic HER2-negative (HER2-) and MET-positive (MET+) adenocarcinoma of the stomach or gastroesophageal junction (GEC) [abstract]. J. Clin. Oncol. 33 (Suppl.), 4012 (2015).

    Article  Google Scholar 

  115. Kawakami, H. et al. MET amplification as a potential therapeutic target in gastric cancer. Oncotarget 4, 9–17 (2013).

    Article  PubMed  Google Scholar 

  116. Kwak, E. L. et al. Clinical activity of AMG 337, an oral MET kinase inhibitor, in adult patients (pts) with MET-amplified gastroesophageal junction (GEJ), gastric (G), or esophageal (E) cancer [abstract]. J. Clin. Oncol. 33 (Suppl. 3), 01 (2015).

    Article  Google Scholar 

  117. Xie, L. et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin. Cancer Res. 19, 2572–2583 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Bang, J. Y. et al. A randomized, open-label phase II study of AZD4547 (AZD) versus paclitaxel (P) in previously treated patients with advanced gastric cancer (AGC) with fibroblast growth factor receptor 2 (FGFR2) polysomy or gene amplification (amp): SHINE study [abstract]. J. Clin. Oncol. 33 (Suppl.), 4014 (2015).

    Article  Google Scholar 

  119. Smyth, E. C. et al. Phase II multicenter proof of concept study of AZD4547 in FGFR amplified tumours [abstract]. J. Clin. Oncol. 33 (Suppl.), 2508 (2015).

    Article  Google Scholar 

  120. Ohtsu, A. et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J. Clin. Oncol. 31, 3935–3943 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  PubMed  Google Scholar 

  122. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Clarke, J. M. & Hurwitz, H. I. Targeted inhibition of VEGF receptor 2: an update on ramucirumab. Expert Opin. Biol. Ther. 13, 1187–1196 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. 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 

  125. 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 

  126. 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 

  127. Hironaka, S. et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J. Clin. Oncol. 31, 4438–4444 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Li, J. et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J. Clin. Oncol. 31, 3219–3225 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Anastassiadis, T. et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol. 29, 1039–1045 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov. 5, 835–844 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Janjigian, Y. Y. et al. Phase II trial of sorafenib in patients with chemotherapy refractory metastatic esophageal and gastroesophageal (GE) junction cancer. PLoS ONE 10, e0134731 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Pavlakis, N. et al. INTEGRATE: a randomized, phase II, double-blind, placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC): a study by the Australasian Gastrointestinal Trials Group (AGITG) — final overall and subgroup results [abstract]. J. Clin. Oncol. 33 (Suppl.), 4003 (2015).

    Article  Google Scholar 

  133. 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 

  134. 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 

  135. Yoon, H. H. et al. Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): randomized, double-blind, multicenter phase 2 trial [abstract]. J. Clin. Oncol. 32 (Suppl.), 4004 (2014).

    Article  Google Scholar 

  136. Erber, R. et al. Combined inhibition of VEGF- and PDGF-signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 18, 338–340 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Fischer, C. et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131, 463–475 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Fuchs, C. S. et al. A randomized, double-blind, placebo-controlled phase III study of cisplatin plus a fluoropyrimidine with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophogeal junction (GEJ) adenocarcinoma (RAINFALL, NCT02314117) [abstract]. J. Clin. Oncol. 33 (Suppl.), TPS4131 (2015).

    Article  Google Scholar 

  139. 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  CAS  PubMed  Google Scholar 

  140. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 17, 645–648 (1994).

    Article  Google Scholar 

  141. Kaiser, J. The cancer stem cell gamble. Science 347, 226–229 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Patrawala, L. et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res. 65, 6207–6219 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Patrawala, L. et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25, 1696–1708 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Vries, R. G. et al. Stem cells and cancer of the stomach and intestine. Mol. Oncol. 4, 373–384 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Marx, J. Cancer's perpetual source? Science 317, 1029–1031 (2007).

    Article  CAS  PubMed  Google Scholar 

  147. Scheitz, C. J. et al. Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J. 31, 4124–4139 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Yu, H. et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat. Rev. Cancer 14, 736–746 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Susman, S. et al. The Lauren classification highlights the role of epithelial-to-mesenchymal transition in gastric carcinogenesis: an immunohistochemistry study of the STAT3 and adhesion molecules expression. J. Gastrointestin. Liver Dis. 24, 77–83 (2015).

    PubMed  Google Scholar 

  150. Li, Y. et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc. Natl Acad. Sci. USA 112, 1839–1844 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Shah, M. A. et al. The BRIGHTER trial: a phase III randomized double-blind study of BBI608 + weekly paclitaxel versus placebo (PBO) + weekly paclitaxel in patients (pts) with pretreated advanced gastric and gastro-esophageal junction (GEJ) adenocarcinoma [abstract]. J. Clin. Oncol. 33 (Suppl.), PS4139 (2015).

    Article  Google Scholar 

  152. Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Lesokhin, A. M. et al. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci. Transl. Med. 7, 280sr1 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Doi, T. et al. Pembrolizumab (MK-3475) for patients (pts) with advanced esophageal carcinoma: preliminary results from KEYNOTE-028 [abstract]. J. Clin. Oncol. 33 (Suppl.), 4010 (2015).

    Article  Google Scholar 

  155. Muro, K. et al. Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012 [abstract]. J. Clin. Oncol. 33 (Suppl. 3), 03 (2015).

    Article  Google Scholar 

  156. Curran, M. A. et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Duraiswamy, J. et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 369, 122–133 (2013).

    Google Scholar 

  158. Callahan, M. et al. Phase I/II, open-label study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) as monotherapy or combined with ipilimumab advanced or metastatic solid tumor [abstract]. J. Clin. Oncol. 32 (Suppl.), TPS3114 (2014).

    Article  Google Scholar 

  159. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Papa, S. et al. Clinical evaluation of ErbB-targeted CAR T-cells, following intracavity delivery in patients with ErbB-expressing solid tumors. Methods Mol. Biol. 1317, 365–382 (2015).

    Article  PubMed  Google Scholar 

  161. Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2- positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. 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 

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Authors and Affiliations

  1. University Cancer Center Leipzig, University Medicine Leipzig, Liebigstraße 20 D, Leipzig, 04103, Germany

    Florian Lordick

  2. Division of Solid Tumor Oncology, Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, 1275 York Avenue, New York, 10065, New York, USA

    Yelena Y. Janjigian

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  1. Florian Lordick
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Both authors made substantial contributions to researching data for article, discussion of content, and review/editing of manuscript before submission.

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Correspondence to Florian Lordick.

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Competing interests

F.L. has lectured and chaired sponsored symposia for Amgen, Celgene, Eli Lilly, Elsevier, Roche and Taiho. He has received support for participation in scientific congresses from Amgen, Bayer, Eli Lilly, Merck-Serono, Roche and Taiho. He receives research support from Fresenius Biotech, GSK and Merck-Serono. He has also served on advisory boards for BMS, Eli Lilly, Nordic, Roche and Taiho. Y.J. has received research funding from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly, Genentech and Merck. She has also served on advisory boards for Eli Lilly and Pfizer.

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Lordick, F., Janjigian, Y. Clinical impact of tumour biology in the management of gastroesophageal cancer. Nat Rev Clin Oncol 13, 348–360 (2016). https://doi.org/10.1038/nrclinonc.2016.15

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