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Targeted Therapy in Advanced Gastric Cancer

  • Li Xie
  • Jia Wei
  • Lijing Zhu
  • Wenjing Hu
Chapter

Abstract

Though molecular targeted therapy is one of the important parts of treatment for cancers that developed from lung, breast, colon and others, gastric cancer treatment still need great improvement in this area with only limited molecular targeted drugs approved up to now. Effort to reveal the mechanism of carcinogenesis helps to accelerate the development of new molecular targeted drugs. With the development of high throughput sequencing, new targets have been evaluated. HER-2 and VEGF pathway for angiogenesis are the two accepted molecular targets with corresponding drugs to inhibit their activity. In the future molecular targeted therapeutics for the treatment of gastric cancer could enable a mechanism to not only to block activated signaling pathways of tumour cells, but also to modulate the tumour microenvironment.

Keywords

Gastric Cancer Overall Survival Epidermal Growth Factor Receptor Gastric Cancer Patient Median Overall Survival 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Vogelstein B, Kinzler KW. The path to cancer–three strikes and you’re out. New Engl J Med. 2015;373(20):1895–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Hainaut P, Plymoth A. Targeting the hallmarks of cancer: towards a rational approach to next-generation cancer therapy. Curr Opin Oncol. 2013;25(1):50–1.CrossRefPubMedGoogle Scholar
  3. 3.
    Polkowski W, van Sandick JW, Offerhaus GJ, ten Kate FJ, Mulder J, Obertop H, et al. Prognostic value of Lauren classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol. 1999;6(3):290–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg. 2005;241(1):27–39.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefPubMedGoogle Scholar
  6. 6.
    Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, 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(5):673–84.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRefGoogle Scholar
  8. 8.
    Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56.CrossRefPubMedGoogle Scholar
  9. 9.
    Corso S, Giordano S. How can gastric cancer molecular profiling guide future therapies? Trends Mol Med. 2016;22(7):534–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13(3):143–58.CrossRefPubMedGoogle Scholar
  11. 11.
    Allgayer H, Babic R, Gruetzner KU, Tarabichi A, Schildberg FW, Heiss MM. c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J Clin Oncol Off J Am Soc Clin Oncol. 2000;18(11):2201–9.CrossRefGoogle Scholar
  12. 12.
    Hsu JT, Chen TC, Tseng JH, Chiu CT, Liu KH, Yeh CN, et al. Impact of HER-2 overexpression/amplification on the prognosis of gastric cancer patients undergoing resection: a single-center study of 1,036 patients. Oncologist. 2011;16(12):1706–13.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Janbabai G, Oladi Z, Farazmandfar T, Taghvaei T, Naghshvar F. The prognostic impact of EGFR, ErbB2 and MET gene amplification in human gastric carcinomas as measured by quantitative Real-Time PCR. J Cancer Res Clin Oncol. 2015;141(11):1945–52.CrossRefPubMedGoogle Scholar
  14. 14.
    Kim SY, Kim HP, Kim YJ, Oh DY, Im SA, Lee D, et al. Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. Int J Oncol. 2008;32(1):89–95.PubMedGoogle Scholar
  15. 15.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki 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(9742):687–97.CrossRefPubMedGoogle Scholar
  16. 16.
    Iqbal S, Goldman B, Fenoglio-Preiser CM, Lenz HJ, Zhang W, Danenberg KD, et al. Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann Oncol. 2011;22(12):2610–5.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, 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 Off J Am Soc Clin Oncol. 2016;34(5):443–51.CrossRefGoogle Scholar
  18. 18.
    Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, 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 Off J Am Soc Clin Oncol. 2014;32(19):2039–49.CrossRefGoogle Scholar
  19. 19.
    Gomez-Martin C, Plaza JC, Pazo-Cid R, Salud A, Pons F, Fonseca P, et al. Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(35):4445–52.CrossRefGoogle Scholar
  20. 20.
    Oh DY, Bang YJ. Pertuzumab in gastrointestinal cancer. Expert Opin Biol Ther. 2016;16(2):243–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Kang Y SMA, Ohtsu A, Van Cutsem E, Ajani J A, van der Horst T, Harle-Yge M, Piao Y, Althaus B, Thuss-Patience P C. 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). J Clin Oncol Off J Am Soc Clin Oncol. 2016;34S(4):5.Google Scholar
  22. 22.
    Birkman EM, Algars A, Lintunen M, Ristamaki R, Sundstrom J, Carpen O. EGFR gene amplification is relatively common and associates with outcome in intestinal adenocarcinoma of the stomach, gastro-oesophageal junction and distal oesophagus. BMC Cancer. 2016;16:406.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, 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(6):490–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Okines AF, Ashley SE, Cunningham D, Oates J, Turner A, Webb J, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(25):3945–50.CrossRefGoogle Scholar
  25. 25.
    Dragovich T, McCoy S, Fenoglio-Preiser CM, Wang J, Benedetti JK, Baker AF, et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(30):4922–7.CrossRefGoogle Scholar
  26. 26.
    Doshi S, Gisleskog PO, Zhang Y, Zhu M, Oliner KS, Loh E, et al. Rilotumumab exposure-response relationship in patients with advanced or metastatic gastric cancer. Clin Cancer Res. 2015;21(11):2453–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Cunningham D N C Tebbutt, Davidenko I, Murad A M, Al-Batran S, Ilson D H, 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 Off J Am Soc Clin Oncol. 2015; 33S(15):4000.Google Scholar
  28. 28.
    Doi T K Y, Muro K, Jiang Y, Jain R K, Lizambri R. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The RILOMET-2 trial. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33S(3):226.Google Scholar
  29. 29.
    Shah MA, Cho JY, Tan IB, Tebbutt NC, Yen CJ, Kang A, 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(9):1085–90.CrossRefPubMedGoogle Scholar
  30. 30.
    Shah MA, Bang YJ, Lordick F, Alsina M, Chen M, Hack SP, 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. 2016. Epub ahead press.Google Scholar
  31. 31.
    Ahn S, Lee J, Hong M, Kim ST, Park SH, Choi MG, et al. FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod Pathol. 2016;29(9):1095–103.CrossRefPubMedGoogle Scholar
  32. 32.
    Su X, Zhan P, Gavine PR, Morgan S, Womack C, Ni X, et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer. 2014;110(4):967–75.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yu G, Wang J, Chen Y, Wang X, Pan J, Li G, et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 2009;15(5):1821–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Doi T, Muro K, Boku N, Yamada Y, Nishina T, Takiuchi H, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(11):1904–10.CrossRefGoogle Scholar
  35. 35.
    Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(31):3935–43.CrossRefGoogle Scholar
  36. 36.
    Holkova B, Supko JG, Ames MM, Reid JM, Shapiro GI, Perkins EB, et al. A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Clin Cancer Res. 2013;19(7):1873–83.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Schwartz GK, Ilson D, Saltz L, O'Reilly E, Tong W, Maslak P, et al. Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19(7):1985–92.CrossRefGoogle Scholar
  38. 38.
    Ciliberto D, Staropoli N, Caglioti F, Gualtieri S, Fiorillo L, Chiellino S, et al. A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: evidence does not translate? Cancer Biol Ther. 2015;16(8):1148–59.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, 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 Off J Am Soc Clin Oncol. 2011;29(30):3968–76.CrossRefGoogle Scholar
  40. 40.
    Hacker UT, Escalona-Espinosa L, Consalvo N, Goede V, Schiffmann L, Scherer SJ, et al. Evaluation of Angiopoietin-2 as a biomarker in gastric cancer: results from the randomised phase III AVAGAST trial. Br J Cancer. 2016;114(8):855–62.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, 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 Off J Am Soc Clin Oncol. 2012;30(17):2119–27.CrossRefGoogle Scholar
  42. 42.
    Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, 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(9911):31–9.CrossRefPubMedGoogle Scholar
  43. 43.
    S Qin. Phase III study of apatinib in advanced gastric cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32S(15):4003.Google Scholar
  44. 44.
    Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, 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 Off J Am Soc Clin Oncol. 2016;34(13):1448.CrossRefGoogle Scholar
  45. 45.
    Yi JH, Lee J, Lee J, Park SH, Park JO, Yim DS, 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(9):1469–74.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH, Benson 3rd AB. 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 Off J Am Soc Clin Oncol. 2010;28(18):2947–51.CrossRefGoogle Scholar
  47. 47.
    Martin-Richard M, Gallego R, Pericay C, Garcia Foncillas J, Queralt B, Casado E, et al. Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. Invest New Drugs. 2013;31(6):1573–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55.CrossRefPubMedGoogle Scholar
  49. 49.
    Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): a multinational placebo-controlled phase II trial. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(23):2728–35.CrossRefGoogle Scholar
  50. 50.
    Kataoka Y, Mukohara T, Tomioka H, Funakoshi Y, Kiyota N, Fujiwara Y, et al. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs. 2012;30(4):1352–60.CrossRefPubMedGoogle Scholar
  51. 51.
    Shah MA, Wainberg ZA, Catenacci DV, Hochster HS, Ford J, Kunz P, et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS One. 2013;8(3):e54014.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Desrichard A, Snyder A, Chan TA. Cancer neoantigens and applications for immunotherapy. Clin Cancer Res. 2016;22(4):807–12.CrossRefPubMedGoogle Scholar
  53. 53.
    Cohen JI, Fauci AS, Varmus H, Nabel GJ. Epstein-Barr virus: an important vaccine target for cancer prevention. Sci Transl Med. 2011;3(107):107fs7.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717–26.CrossRefPubMedGoogle Scholar
  55. 55.
    Chung H C, Arkenau H Wyrwicz L, Oh D, Lee K, Infante J R, Chin K M, von Heydebreck A, Kang Y, Safran H. Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34S(4):168.Google Scholar
  56. 56.
    Bramhall SR, Hallissey MT, Whiting J, Scholefield J, Tierney G, Stuart RC, et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer. 2002;86(12):1864–70.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Catenacci DV. Next-generation clinical trials: novel strategies to address the challenge of tumor molecular heterogeneity. Mol Oncol. 2015;9(5):967–96.CrossRefPubMedGoogle Scholar
  58. 58.
    Kim HS, Shin SJ, Beom SH, Jung M, Choi YY, Son T, et al. Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy. Oncotarget. 2016;7(28):44608–20.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81.CrossRefPubMedGoogle Scholar
  60. 60.
    Meador CB, Lovly CM. Liquid biopsies reveal the dynamic nature of resistance mechanisms in solid tumors. Nat Med. 2015;21(7):663–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Li Xie
    • 1
  • Jia Wei
    • 1
  • Lijing Zhu
    • 1
  • Wenjing Hu
    • 1
  1. 1.The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina

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