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Personalised Treatment in Gastric Cancer: Myth or Reality?

  • Translational Oncology (L Vecchione, Section Editor)
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Abstract

Despite recent diagnostic and therapeutic advances, the survival of patients with gastric cancer is still poor. The majority of patients are diagnosed with advanced disease and chemotherapy represents the only possible therapeutic approach. However, chemotherapy seems to have reached an efficacy plateau in this setting. Gastric cancer is a complex and heterogeneous disease because it emerges from multiple interactions of genetic, environmental and host factors. A better understanding of its molecular characteristics may lead to an improvement of outcomes. The recent molecular classification by The Cancer Genome Atlas project divides gastric cancer into four subtypes that could be taken into consideration in future clinical trials with targeted agents. So far trastuzumab, a monoclonal antibody addressing the HER2 receptor, is the only targeted agent approved in the first-line setting, but only in patients overexpressing HER2. Negative data have been obtained in first-line therapy when antiangiogenics, anti-EGFR or anti-MET monoclonal antibodies have been studied in randomised controlled trials. Ramucirumab, a monoclonal antibody binding to VEGFR2, is the only antiangiogenic agent currently recommended in patients progressing after first-line treatment. In this review, we discuss whether personalised therapy may have a role in gastric cancer.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Rahman R, Asombang AW, Ibdah JA. Characteristics of gastric cancer in Asia. World J Gastroenterol. 2014;20:4483–90.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of US gastric carcinoma patients treated with gastrectomy: fifth edition American Joint Committee on Cancer staging, proximal disease, and the ‘different disease’ hypothesis. Cancer. 2000;88:921–32.

    Article  CAS  PubMed  Google Scholar 

  4. MacDonald J, Smalley S, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–9.

    Article  CAS  PubMed  Google Scholar 

  5. Glimelius B, Ekström K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997;8:163–8.

    Article  CAS  PubMed  Google Scholar 

  6. 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. Trastuzumab represents the first example of personalized medicine for advanced gastric cancer patients, improving PFS and OS.

    Article  CAS  PubMed  Google Scholar 

  7. Wilke H, Muro K, Van Cutsem E, 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. 2014;15:1224–35. Ramucirumab represents the first antiangiogenic agent which led to clinical benefit in gastric cancer when used as single agent or in combination.

    Article  CAS  PubMed  Google Scholar 

  8. Siewert JR, Bottcher K, Stein HJ, et al. Relevant prognostic factors in gastric cancer. Ten-year results of the German Gastric Cancer Study. Ann Surg. 1998;228:449–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2010;24769(3):CD004064.

    Google Scholar 

  10. Garrido M, Fonseca PJ, Vieitez JM, et al. Challenges in first line chemotherapy and targeted therapy in advanced gastric cancer. Expert Rev Anticancer Ther. 2014;14:887–900.

    Article  CAS  PubMed  Google Scholar 

  11. Kang Y, Kang W, Shin D, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20:666–73.

    Article  PubMed  Google Scholar 

  12. Koizumi W, Narahara H, Hara T, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–21.

    Article  CAS  PubMed  Google Scholar 

  13. Yamada Y, Higuchi K, Nishikawa K, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer. Ann Oncol. 2015;26:141–8.

    Article  CAS  PubMed  Google Scholar 

  14. Al-Batran SE, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26:1435–42.

    Article  CAS  PubMed  Google Scholar 

  15. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.

    Article  CAS  PubMed  Google Scholar 

  16. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.

    Article  CAS  PubMed  Google Scholar 

  17. Ford HE, Marshall A, Bridgewater JA, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014;15:78–86.

    Article  CAS  PubMed  Google Scholar 

  18. Thuss-Patience PC, Kretzschmar A, Bichev D, 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. 2011;47:2306–14.

    Article  CAS  PubMed  Google Scholar 

  19. Hironaka S, Ueda S, Yasui H, 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. 2013;31:4438–44.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Lauwers GY, Carneiro F, Graham DY. Gastric carcinoma. In: Bowman FT, Carneiro F, Hruban RH, editors. Classification of tumours of the digestive system. Lyon: IARC; 2010.

    Google Scholar 

  22. Deng N, Goh LK, Wang H, 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. 2012;61:673–84. This analysis represents one of the most relevant studies of molecular target in gastric cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. The Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9. Molecular classification could improve the knowledge of gastric cancer leading to personalized medicine.

    Article  Google Scholar 

  24. Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56. This article is very relevant representing a good example of correlation between molecular features and outcome.

    Article  CAS  PubMed  Google Scholar 

  25. Jacome AA, Wohnrath DR, Scapulatempo Neto C, et al. Prognostic value of epidermal growth factor receptors in gastric cancer: a survival analysis by Weibull model incorporating long-term survivors. Gastric Cancer. 2014;17:76–86.

    Article  CAS  PubMed  Google Scholar 

  26. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.

    Article  CAS  PubMed  Google Scholar 

  27. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab and docetaxel in HER-2 positive metastatic breast cancer. N Engl J Med. 2015;372:724–34.

    Article  CAS  PubMed  Google Scholar 

  28. Oh DY, Bang YJ. Pertuzumab in gastrointestinal cancer. Expert Opin Biol Ther. 2015;16:243–253.

  29. Hecht JR, Bang YJ, Qin S, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial. J Clin Oncol. 2016;34:443–51. This phase III trial does not show any improvement in survival by adding lapatinib to platinum-based I line chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  30. Satoh T, Xu RH, Chung HC, 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. 2014;32:2039–49. This phase III trial does not show any improvement in survival by adding lapatinib to paclitaxel-based II line chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  31. Lordick F, Kang YK, Chung HC, 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. 2013;14:490–9. This phase III trial does not show any improvement in survival by adding cetuximab to platinum-based I line chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  32. Waddell T, Chau I, Cunningham D, 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. 2013;14:481–9. This phase III trial does not show any improvement in survival by adding panitumumab to platinum-based I line chemotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Adelstein DJ, Rodriguez CP, Rybicki LA, Ives DI, Rice TW. A phase II trial of gefitinib for recurrent or metastatic cancer of the esophagus or gastroesophageal junction. Investig New Drugs. 2012;30:1684–9.

    Article  CAS  Google Scholar 

  34. Dragovich T, McCoy S, Fenoglio-Preiser CM, et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006;24:4922–7.

    Article  CAS  PubMed  Google Scholar 

  35. Grigore D, Simionescu CE, Stepan A, et al. Assessment of CD105, alpha-SMA and VEGF expression in gastric carcinomas. Romanian J Morphol Embryol. 2013;54:701–7.

    Google Scholar 

  36. Ohtsu A, Shah MA, Van Cutsem E, 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. 2011;29:3968–76.

    Article  CAS  PubMed  Google Scholar 

  37. Van Cutsem E, de Haas S, Kang YK, 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. 2012;30:2119–27. This phase III trial does not show any improvement in survival by adding bevacizumab to platinum-based I line chemotherapy.

    Article  PubMed  Google Scholar 

  38. Fuchs CS, Tomasek J, Yong CJ, 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. 2014;383:31–9. Ramucirumab as single agent was able to improve survival in pretreated patients.

    Article  CAS  PubMed  Google Scholar 

  39. Li J, Qin S, Xu J, Xiong J. 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. 2016. Apatinib showed efficacy in pretreated patients.

  40. Ilson DH. Targeting the vascular endothelial growth factor pathway in gastric cancer: a hit or a miss? J Clin Oncol 2016.

  41. Yi JH, Lee J, Lee J, Park SH, et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer. 2012;106:1469–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sun W, Powell M, O’Dwyer PJ, et al. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol. 2010;28:2947–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kawakami H, Okamoto I, Arao T, et al. MET amplification as a potential therapeutic target in gastric cancer. Oncotarget. 2013;4:9–17.

    PubMed  Google Scholar 

  44. Iveson T, Donehower RC, Davidenko I, 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. 2014;15:1007–18.

    Article  CAS  PubMed  Google Scholar 

  45. Cunningham D, Tebbutt NC, Davidenko I, 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. J Clin Oncol. 2015;33(Suppl):abstr 4000. This phase III trial does not underlie clinical benefit by adding a MET antibody to chemotherapy.

    Google Scholar 

  46. Salgia R, Patel P, Bothos J, et al. Phase I dose-escalation study of onartuzumab as a single agent and in combination with bevacizumab in patients with advanced solid malignancies. Clin Cancer Res. 2014;20:1666–75.

    Article  CAS  PubMed  Google Scholar 

  47. Cunningham D, Bang YJ, Tabernero J, et al. MetGastric: A randomized phase III study of onartuzumab (MetMAb) in combination with mFOLFOX6 in patients with metastatic HER2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 2013: 31(suppl; abstr TPS4155).

  48. Kwak F. Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor. J Clin Oncol. 2009;27 Suppl:abstr 15.

    Google Scholar 

  49. Kwak E L, LoRusso P, Hamid O 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. Clin Oncol 2015: 33(suppl 3; abstr 1).

  50. Gavine PR, Mooney L, Kilgour E, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72:2045–56.

    Article  CAS  PubMed  Google Scholar 

  51. Smyth EC, Turner NC, Peckitt C, et al. Phase II multicenter proof of concept study of AZD4547 in FGFR amplified tumours. J Clin Oncol. 2015;33:abstr 2508.

    Article  Google Scholar 

  52. Bang YJ, Van Cutsem E, Mansoor W, 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. J Clin Oncol. 2015;33:abstr 4014.

    Article  Google Scholar 

  53. Tapia O, Riquelme I, Leal P, et al. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch. 2014;465:25–33.

    Article  CAS  PubMed  Google Scholar 

  54. Ohtsu A, Ajani JA, Bai YX, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31:3935–43. This phase III trial does not show clinical benefit by adding everolimus to chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  55. Wu T, Li Y, Lu J, et al. Increased MMP-21 expression is associated with poor overall survival of patients with gastric cancer. Med Oncol. 2013;30:323.

    Article  PubMed  Google Scholar 

  56. Bramhall SR, Hallissey MT, Whiting J, et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer. 2002;86:1864–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Alexandrov LB, Nik-Zainal S, Siu HC, et al. A mutational signature in gastric cancer suggests therapeutic strategies. Nat Commun. 2015;6:8683. This article suggests the possibility of use new treatment based on genetical study in GC.

    Article  CAS  PubMed  Google Scholar 

  59. Bang YJ, Im SA, Lee KE, et al. Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol. 2015;33:3858–65. This trial demonstrates the possible benefit deriving from using olaparib in selected patients diagnosed with gastric cancer.

    Article  PubMed  Google Scholar 

  60. Burtness B. Complexity in the gastric cancer genome and a biomarker-driven trial of poly (ADP-Ribose) polymerase inhibition in gastric cancer. J Clin Oncol. 2015;33:3845–6.

    Article  CAS  PubMed  Google Scholar 

  61. Cervantes A, Roda D, Tarazona N, et al. Current questions for the treatment of advanced gastric cancer. Cancer Treat Rev. 2013;39:60–7.

    Article  CAS  PubMed  Google Scholar 

  62. Lordick F, Allum W, Carneiro F, et al. Unmet needs and challenges in gastric cancer: the way forward. Cancer Treat Rev. 2014;40:692–700.

    Article  PubMed  Google Scholar 

  63. Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011;12:642–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tabernero J, Cervantes A, Rivera F, et al. Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study JCO 2010:1181–1189.

  65. Brekken RA, Overholser JP, Stastny VA, et al. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Cancer Res. 2000;60:5117–24.

    CAS  PubMed  Google Scholar 

  66. Gandara DR, Kawaguchi T, Crowley J, et al. Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J Clin Oncol. 2009;27:3540–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Muro K, Bang YJ, Shankaran V, 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. J Clin Oncol. 2015;33 Suppl 3:abstr 03.

    Google Scholar 

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Acknowledgments

Valentina Gambardella holds a grant from the European Society for Medical Oncology. Noelia Tarazona holds a Rio Hortega Contract CM15/00246 from the Instituto de Salud Carlos III, Spain.

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Correspondence to Andrés Cervantes.

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Noelia Tarazona, Valentina Gambardella, Marisol Huerta, Susana Roselló and Andrés Cervantes declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Translational Oncology

Noelia Tarazona and Valentina Gambardella contributed equally to this work.

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Tarazona, N., Gambardella, V., Huerta, M. et al. Personalised Treatment in Gastric Cancer: Myth or Reality?. Curr Oncol Rep 18, 41 (2016). https://doi.org/10.1007/s11912-016-0525-x

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