In patients with metastatic gastric cancer, median overall survival remains under 1 year and standard chemotherapy regimens are not able to substantially improve the prognosis of the patients. Amplification and over-expression of HER2 is reported in approximately 20% of gastric tumours, challenging the use of targeted therapies. There are several targeted therapies in different stages of clinical development with trastuzumab being the first overcoming the regulatory hurdle and getting European Medicines Agency approval. In patients with advanced gastric or gastro-oesophageal junction cancer, addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone. Addition of trastuzumab to chemotherapy did not increase the incidence of adverse events. Other agents targeting the HER2 pathway (lapatinib) or other domains of epidermal growth factor receptor family (cetuximab) are currently being investigated for the treatment of an advanced gastric cancer.
FerlayJShinHRBrayF. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer2010; 127(12): 2893–2917.
2.
OkinesAVerheijMAllumW. Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol2010; 21: Suppl. 5v50–v54.
3.
KamangarFDoresGMAndersonWF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol2006; 24(14): 2137–2150.
GravalosCJimenoA. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol2008; 19(9): 1523–1529.
6.
TannerMHollmenMJunttilaTT. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol2005; 16(2): 273–278.
MacdonaldJSSmalleySRBenedettiJ. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med2001; 345(10): 725–730.
9.
CunninghamDAllumWHStenningSP. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med2006; 355(1): 11–20.
10.
AlbertsSRCervantesAvan de VeldeCJ. Gastric cancer: epidemiology, pathology and treatment. Ann Oncol2003; 14: Suppl 2ii31–ii36.
11.
WatersJSNormanACunninghamD. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer1999; 80(1–2): 269–272.
12.
IcliFCelikIAykanF. A randomized phase III trial of etoposide, epirubicin, and cisplatin versus 5-fluorouracil, epirubicin, and cisplatin in the treatment of patients with advanced gastric carcinoma. Turkish Oncology Group. Cancer1998; 83(12): 2475–2480.
13.
VanhoeferURougierPWilkeH. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol2000; 18(14): 2648–2657.
14.
KangGHKimGSLeeHR. A phase II trial of paclitaxel, 5-fluorouracil (5-FU) and cisplatin in patients with metastatic or recurrent gastric cancer. Cancer Res Treat2008; 40(3): 106–110.
15.
KimJGSohnSKChaeYS. Multicenter phase II study of docetaxel plus oxaliplatin combination chemotherapy in patients with advanced gastric cancer: Daegu Gyeongbuk Oncology Group. Br J Cancer2008; 98(3): 542–546.
16.
Al-BatranSEHartmannJTProbstS. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol2008; 26(9): 1435–1442.
17.
GubanskiMJohnssonAFernebroE. Gastric Cancer Taxotere vs. Campto Trial (GATAC) Study Group. Randomized phase II study of sequential docetaxel and irinotecan with 5-fluorouracil/folinic acid (leucovorin) in patients with advanced gastric cancer: the GATAC trial. Gastric Cancer2010; 13(3): 155–161.
18.
DankMZaluskiJBaroneC. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol2008; 19(8): 1450–1457.
19.
WagnerADUnverzagtSGrotheW. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev2010(3CD004064–CD004064.
20.
SlamonDJGodolphinEJonesLA. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science1989; 244(4905): 707–712.
21.
MorrisMJReuterVEKellyWK. HER-2 prolining and targeting in prostate carcinoma. Cancer2002; 94(4): 980–986.
22.
SafranHSteinhoffMMangrayS. Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma. Am J Clin Oncol2001; 24(5): 496–499.
23.
RossJSSlodkowskaEASymmansWF. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist2009; 14(4): 320–368.
24.
HudisCA. Trastuzumab: mechanism of action and use in clinical practice. N Engl J Med2007; 357(1): 39–51.
BangYJVan CutsemEFeyereislovaA. 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. Lancet2010; 376(9742): 687–697.
27.
TannerMHollménMJunttilaTT. Amplification of HER-2 in gastric carcinoma: association with topoisomerase II alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol2005; 16(2): 273–278.
28.
CidonEUCentenoRGLagartoEG. HER-2 Evaluation in a Specific Gastric Cancer Population with the Highest Rate of Mortality in Spain. J Oncol2011; 2011: 391564–391564. Epub 27 October 2011.
29.
LiuWZhongSChenJ. HER-2/neu overexpression is an independent prognostic factor for intestinal-type and early-stage gastric cancer patients. J Clin Gastroenterol. Epub ahead of print 4 November 2011.
30.
KasprzykPGSongSUDi FiorePP. Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. Cancer Res1992; 52(10): 2771–2776.
31.
Fujimoto-OuchiKSekiguchiFYasunoH. Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol2007; 59(6): 795–805.
32.
KimSYKimHPKimYJ. Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. Int J Oncol2008; 32(1): 89–95.
33.
GeyerCEForsterJLindquistD. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med2006; 355(26): 2733–2743.
34.
LordickFLuberBLorenzenS. Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br J Cancer2010; 102(3): 500–505.
35.
KangYOhtsuAVan CutsemE. AVAGAST: A randomized, double-blind, placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC) [abstract no. LBA4007]. J Clin Oncol2010; 28: Suppl18s–18s.
36.
HudisCA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med2007; 357(1): 39–51.
37.
Piccart-GebhartMJProcterMLeyland-JonesB. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med2005; 353(16): 1659–1672.
38.
Fujimoto-OuchiKSekiguchiFYasunoH. Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol2007; 59(6): 795–805.
39.
RomondEHPerezEABryantJ. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med2005; 353(16): 1673–1684.
40.
SmithIProcterMGelberRD. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet2007; 369(9555): 29–36.
41.
SlamonDJLeyland-JonesBShakS. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med2001; 344(11): 783–792.
42.
VogelCLCobleighMATripathyD. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol2002; 20(3): 719–726.
43.
GrávalosCGómez-MartínCRiveraF. Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer. Clin Transl Oncol2011; 13(3): 179–184.
44.
KimJWKimHPImSA. The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett2008; 272(2): 296–306.
45.
TanizakiJOkamotoITakezawaK. Synergistic antitumor effect of S-1 and HER2-targeting agents in gastric cancer with HER2 amplification. Mol Cancer Ther2010; 9(5): 1198–1207.
46.
WainbergZAAnghelADesaiAJ. 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 Res2010; 16(5): 1509–1519.
47.
WongSF. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther2005; 27(6): 684–694.
48.
RiveraFVega-VillegasMELopez-BreaMF. Cetuximab, its clinical use and future perspectives. Anticancer Drugs2008; 19(2): 99–113.
49.
YasuiWHataJYokozakiH. Interaction between epidermal growth factor and its receptor in progression of human gastric carcinoma. Int J Cancer1988; 41(2): 211–217.
50.
SafranHSuntharalingamMDipetrilloT. Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity. Int J Radiat Oncol Biol Phys2008; 70(2): 391–395.
51.
KimCLeeJLRyuMH. 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 Drugs2011; 29(2): 366–373.
52.
PintoCDi FabioFBaroneC. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastrooesophageal junction adenocarcinoma (DOCETUX study). Br J Cancer2009; 101(8): 1261–1268.
53.
MoehlerMMuellerATrarbachT. Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study. Ann Oncol2011; 22(6): 1358–1366.
54.
ChanJABlaszkowskyLSEnzingerPC. A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma. Ann Oncol2011; 22(6): 1367–1373.
55.
OhtsuAShahMAVan CutsemE. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol2011; 29(30): 3968–3976.
56.
El-RayesBFZalupskiMBekai-SaabT. A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers. Ann Oncol2010; 21(10): 1999–2004.
57.
WainbergZALinLSDiCarloB. Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. Br J Cancer2011; 105(6): 760–765.
58.
SunWPowellMO’DwyerPJ. 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 Oncol2010; 28(18): 2947–2951.
