Perspectives of the Stomach Cancer Treatment: The Introduction of Molecular Targeted Therapy and the Hope for Cure

Dae Young Cheung; Jae Kwang Kim

doi:10.4166/kjg.2013.61.3.117

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Cheung and Kim: Perspectives of the Stomach Cancer Treatment: The Introduction of Molecular Targeted Therapy and the Hope for Cure

Review Article

Korean J Gastroenterol 2013;61(3):117-127.

Published online: 4 October 2013

DOI: https://doi.org/10.4166/kjg.2013.61.3.117

Perspectives of the Stomach Cancer Treatment: The Introduction of Molecular Targeted Therapy and the Hope for Cure

Dae Young Cheung, Jae Kwang Kim

Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea

Correspondence to: Jae Kwang Kim, Department of Internal Medicine, The Catholic University of Korea, Yeouido St. Mary's Hospital, 10 63-ro, Yeongdeungpo-gu, Seoul 150-713, Korea. Tel: +82-2-3779-1328, Fax: +82-2-3779-1331, E-mail: jkkim@catholic.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The overall survival of patients with gastric cancer has increased markedly in Korea, even higher than those of developed nations in Western world. It is due to the virtue of Korean National Cancer Screening Program and nowadays more than half of patients are diagnosed at the early stage of gastric cancer. However, for patients with unresectable gastric cancer, the outcomes of traditional cytotoxic chemotherapy regimens stay at a median survival of 9–11 months. The knowledge of cancer biology and the data from gene expression profiling has explosively expanded. Alternations in the expression of receptor tyrosine kinases pathways including Human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), phosphatydyl inositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) were proved to be critical in cancer cell survival and biological agents targeting those altered receptor tyrosine kinases, their ligands and downstream effector molecules are developed for anti-cancer purpose. Until now, only trastuzumab succeeded to significantly increase overall survival of patients with HER2 overexpressing gastric cancer. Other agents including bevacizumab, gefitinib, erlotinib, and lapatinib failed to achieve the efficacy in survival gain over standard chemotherapy. Insights about the variations between regions, races, and individuals call for the effort to find reliable predictive biomarkers for drug efficacy and to design finely stratified clinical trials. Compared to current treatment paradigms, it is hoped that molecularly targeted treatment along with conventional cytotoxic chemotherapy will lead to significant gains in survival.

Keywords: Gastric neoplasms, Molecular targeted therapy, Biological agents, Receptor tyrosine kinase

References

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010; 127:2893–2917.

2. Kim TH, Park SR, Ryu KW, et al. Phase 3 trial of postoperative chemotherapy alone versus chemoradiation therapy in stage III-IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. Int J Radiat Oncol Biol Phys. 2012; 84:e585–e592.

3. 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.

4. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001; 345:725–730.

5. Cunningham D, Starling N, Rao S, et al. Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008; 358:36–46.

6. Tan IB, Ivanova T, Lim KH, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011; 141:476–485. 485.e1–11.

7. Shah MA, Khanin R, Tang L, et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res. 2011; 17:2693–2701.

8. Oh SC, Park YY, Park ES, et al. Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer. Gut. 2012; 61:1291–1298.

9. 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; 61:673–684.

10. Corso G, Velho S, Paredes J, et al. Oncogenic mutations in gastric cancer with microsatellite instability. Eur J Cancer. 2011; 47:443–451.

11. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002; 418:934.

12. Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008; 455:1069–1075.

13. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A. 2007; 104:20932–20937.

14. Tomioka H, Mukohara T, Kataoka Y, et al. Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification. Int J Oncol. 2012; 41:551–558.

15. Chen CT, Kim H, Liska D, Gao S, Christensen JG, Weiser MR. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther. 2012; 11:660–669.

16. Bang YJ, Van Cutsem E, Feyereislova A, et al. ToGA Trial Investigators. 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; 376:687–697.

17. Baselga J, Cortés J, Kim SB, et al. CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366:109–119.

18. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011; 29:398–405.

19. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006; 355:2733–2743.

20. Iqbal S, Goldman B, Fenoglio-Preiser CM, 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; 22:2610–2615.

21. Shitara K, Mizota A, Yatabe Y, et al. Lapatinib plus trastuzumab for a patient with heavily pre-treated gastric cancer that progressed after trastuzumab. Jpn J Clin Oncol. 2011; 41:663–665.

22. LaBonte MJ, Manegold PC, Wilson PM, et al. The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. Int J Cancer. 2009; 125:2957–2969.

23. Tabernero J, Van Cutsem E, Díaz-Rubio E, et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2007; 25:5225–5232.

24. Pishvaian M, Sakaeva D, Hsieh RK, et al. A global, multicenter phase II trial of lapatinib plus capecitabine in gastric cancer. J Clin Oncol. 2011; 29(Suppl 4):abstr 88.

25. Kim MA, Lee HS, Lee HE, Jeon YK, Yang HK, Kim WH. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology. 2008; 52:738–746.

26. Chan JA, Blaszkowsky LS, Enzinger PC, et al. A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma. Ann Oncol. 2011; 22:1367–1373.

27. Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol. 2007; 18:510–517.

28. Pinto C, Di Fabio F, Barone C, et al. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br J Cancer. 2009; 101:1261–1268.

29. Kim C, Lee JL, Ryu MH, et al. A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Invest New Drugs. 2011; 29:366–373.

30. 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.

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

32. Enzinger P, Burtness B, Hollis D, et al. CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer. J Clin Oncol. 2010; 28(15 Suppl):abstr 4006.

33. Richards DA, Kocs DM, Spira AI, et al. Results of docetaxel plus oxaliplatin (DOCOX) with or without cetuximab in patients with metastatic gastric and/or gastroesophagel junction adenocarcinoma: results of a randomized phase II study. J Clin Oncol. 2011; 29(Suppl):);abstr 4015.

34. Moehler M, Mueller A, Trarbach T, et al. German Arbeitsgemeinschaft Internistische Onkologie. Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multicenter biomarker-oriented phase II study. Ann Oncol. 2011; 22:1358–1366.

35. Han SW, Oh DY, Im SA, et al. Epidermal growth factor receptor in-tron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6. Cancer Sci. 2010; 101:793–799.

36. Okines AF, Ashley SE, Cunningham D, 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. 2010; 28:3945–3950.

37. Rao S, Starling N, Cunningham D, et al. Matuzumab plus epi-rubicin, cisplatin and capecitabine (ECX) compared with epi-rubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophagogastric cancer: a randomised, multicentre open-label phase II study. Ann Oncol. 2010; 21:2213–2219.

38. 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; 24:4922–4927.

39. Janmaat ML, Gallegos-Ruiz MI, Rodriguez JA, et al. Predictive factors for outcome in a phase II study of gefitinib in second-line treatment of advanced esophageal cancer patients. J Clin Oncol. 2006; 24:1612–1619.

40. 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. Invest New Drugs. 2012; 30:1684–1689.

41. Peng L, Zhan P, Zhou Y, et al. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: a metaanalysis. Mol Biol Rep. 2012; 39:9473–9484.

42. Chen J, Li T, Wu Y, et al. Prognostic significance of vascular endothelial growth factor expression in gastric carcinoma: a metaanalysis. J Cancer Res Clin Oncol. 2011; 137:1799–1812.

43. 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; 29:3968–3976.

44. 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; 30:2119–2127.

45. Okines AF, Langley R, Cafferty FH, et al. Preliminary safety data from a randomized trial of perioperative epirubicin, cisplatin plus capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with gastric or oesophagogastric junction (OGJ) adenocarcinoma. J Clin Oncol. 2010; 28(15 Suppl):abstr 4019.

46. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008; 7:3129–3140.

47. Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH, Benson AB 3rd. 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; 28:2947–2951.

48. Kim C, Lee JL, Choi YH, et al. Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer. Invest New Drugs. 2012; 30:306–315.

49. Lyros O, Mueller A, Heidel F, et al. Analysis of anti-proliferative and chemosensitizing effects of sunitinib on human esophagogastric cancer cells: Synergistic interaction with vandetanib via inhibition of multi-receptor tyrosine kinase pathways. Int J Cancer. 2010; 127:1197–1208.

50. Bang YJ, Kang YK, Kang WK, et al. Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest New Drugs. 2011; 29:1449–1458.

51. Yi JH, Lee J, Lee J, 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; 106:1469–1474.

52. Li J, Qin S, Xu J, et al. A randomized, double-blind, multicenter, phase II, three-arm, placebo control study of apatinib as third-line treatment in patients with metastatic gastric carcinoma. J Clin Oncol. 2011; 29(Suppl):abstr 4019.

53. Lindsay CR, MacPherson IR, Cassidy J. Current status of cediranib: the rapid development of a novel anti-angiogenic therapy. Future Oncol. 2009; 5:421–432.

54. Satoh T, Yamada Y, Muro K, et al. Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer. Cancer Chemother Pharmacol. 2012; 69:439–446.

55. An JY, Kim KM, Choi MG, et al. Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer. Int J Cancer. 2010; 126:2904–2913.

56. Cejka D, Preusser M, Woehrer A, et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol Ther. 2008; 7:1377–1385.

57. Doi T, Muro K, Boku N, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol. 2010; 28:1904–1910.

58. Lim T, Lee J, Lee DJ, et al. Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer. Cancer Chemother Pharmacol. 2011; 68:255–262.

59. Nishi T, Iwasaki K, Ohashi N, et al. Phosphorylation of 4E-BP1 predicts sensitivity to everolimus in gastric cancer cells. Cancer Lett. 2013. [Epub ahead of print].

60. Cutsem EV, Yeh K, Bang YJ, et al. Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1. J Clin Oncol. 2012; 30(Suppl 4):abstr LBA3.

61. Lee KH, Oh HA, Lee G, et al. Overexpression of c-met protein in gastric cancer and role of uPAR as a therapeutic target. Proc Am Soc Clin Oncol. 2002; 21:abstr 3016.

62. Graziano F, Galluccio N, Lorenzini P, et al. Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer. J Clin Oncol. 2011; 29:4789–4795.

63. Lennerz JK, Kwak EL, Ackerman A, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 2011; 29:4803–4810.

64. Catenacci DV, Henderson L, Xiao SY, et al. Durable complete response of metastatic gastric cancer with anti-Met therapy followed by resistance at recurrence. Cancer Discov. 2011; 1:573–579.

65. Kataoka Y, Mukohara T, Tomioka H, et al. Foretinib (GSK1363089), a multikinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs. 2012; 30:1352–1360.

66. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010; 10:116–129.

67. Takeda M, Arao T, Yokote H, et al. AZD2171 shows potent anti-tumor activity against gastric cancer overexpressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin Cancer Res. 2007; 13:3051–3057.

68. Chang H, Rha SY, Jeung HC, et al. Identification of genes related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells. J Cancer Res Clin Oncol. 2010; 136:1901–1913.

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