title: Current status of novel agents in advanced gastroesophageal adenocarcinoma.
abstract: Gastroesophageal (GE) adenocarcinomas are highly lethal malignancies and despite multiple chemotherapy options, 5-year survival rates remain dismal. Chemotherapy is the mainstay of treatment but patients are often limited by toxicity and poor performance status. Because of molecular heterogeneity, it is essential to classify tumors based on the underlying oncogenic pathways and develop targeted therapies that act on individual tumors. Trastuzumab, a human epidermal growth factor receptor type 2 (HER2) monoclonal antibody, was the first such agent shown to improve response rate, progression free survival (PFS), and overall survival (OS) when added to cisplatin based chemotherapy in patients with HER2 over-expressing GE junction (GEJ) and gastric adenocarcinomas. However, HER2 over expressing GE tumors are in the minority and the need for additional targeted agents is urgent. Though many agents are in development, incorporating targeted therapy in the treatment of GE cancers comes with a unique set of challenges. In this review, we outline oncogenic pathways relevant to GE adenocarcinomas, including HER2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and c-Met, and discuss recent trials with agents targeting these pathways.
authors: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Nishi
authors: N
authors: Kothari
authors: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Khaldoun
authors: K
authors: Almhanna
keywords: Gastric and esophageal adenocarcinoma; targeted therapy
references: Cancer Res. 1998 Jan 15;58(2):204-9
references: 9443392
references: Int J Radiat Oncol Biol Phys. 2004;59(2 Suppl):21-6
references: 15142631
references: Ann Oncol. 2014 May;25(5):1039-44
references: 24562448
references: Ann Oncol. 2011 Feb;22(2):268-79
references: 20643861
references: Int J Cancer. 2008 Jan 15;122(2):433-43
references: 17935137
references: Hum Pathol. 2010 Feb;41(2):304-5; author reply 305-6
references: 19914678
references: Science. 1985 Sep 6;229(4717):974-6
references: 2992089
references: Lancet. 2010 Aug 28;376(9742):687-97
references: 20728210
references: J Clin Oncol. 2016 Feb 10;34(5):443-51
references: 26628478
references: Clin Cancer Res. 1996 Aug;2(8):1373-81
references: 9816310
references: Oncogene. 2000 Oct 12;19(43):4947-53
references: 11042681
references: N Engl J Med. 2008 Jul 24;359(4):378-90
references: 18650514
references: J Clin Oncol. 2010 Feb 20;28(6):1061-8
references: 20100962
references: N Engl J Med. 2012 Jun 28;366(26):2455-65
references: 22658128
references: Lancet. 2007 Dec 22;370(9605):2103-11
references: 18156031
references: N Engl J Med. 2006 Dec 14;355(24):2542-50
references: 17167137
references: N Engl J Med. 2004 Jun 3;350(23):2335-42
references: 15175435
references: J Clin Oncol. 2015 Nov 20;33(33):3858-65
references: 26282658
references: Br J Cancer. 2007 Sep 3;97(5):678-85
references: 17700571
references: Br J Cancer. 2012 Apr 24;106(9):1469-74
references: 22460270
references: J Clin Oncol. 2006 Oct 20;24(30):4922-7
references: 17050876
references: Invest New Drugs. 2013 Dec;31(6):1573-9
references: 24077981
references: Invest New Drugs. 2011 Dec;29(6):1449-58
references: 20461441
references: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references: 19474385
references: Nat Rev Cancer. 2002 Jul;2(7):489-501
references: 12094235
references: Jpn J Clin Oncol. 2010 Jan;40(1):17-23
references: 19783551
references: Br J Cancer. 2011 Apr 26;104(9):1372-6
references: 21487407
references: Lancet. 2014 Jan 4;383(9911):31-39
references: 24094768
references: BMC Cancer. 2011 Dec 07;11:509
references: 22152101
references: Adv Cancer Res. 2005;94:29-86
references: 16095999
references: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references: 21296855
references: N Engl J Med. 2007 Dec 27;357(26):2666-76
references: 18160686
references: N Engl J Med. 2008 Sep 11;359(11):1116-27
references: 18784101
references: Ann Oncol. 2005 Feb;16(2):273-8
references: 15668283
references: Gan To Kagaku Ryoho. 1994 Jul;21(8):1283-5
references: 7518222
references: Ann Oncol. 2011 Jun;22(6):1358-1366
references: 21119032
references: J Clin Oncol. 2007 Oct 10;25(29):4557-61
references: 17876013
references: Ann Oncol. 2007 Mar;18(3):510-7
references: 17164226
references: Ann Surg Oncol. 2008 Jan;15(1):69-79
references: 17896140
references: Int J Cancer. 2005 Nov 10;117(3):376-80
references: 15900596
references: J Clin Oncol. 2006 Sep 10;24(26):4309-16
references: 16963731
references: Science. 2004 Apr 23;304(5670):554
references: 15016963
references: Cell Cycle. 2014;13(13):2129-37
references: 24841718
references: Biochem Soc Trans. 2004 Apr;32(Pt 2):350-4
references: 15046607
references: Lancet. 2012 May 19;379(9829):1879-86
references: 22595799
references: J Clin Oncol. 2007 Aug 1;25(22):3205-9
references: 17664467
references: N Engl J Med. 2012 Jan 12;366(2):109-19
references: 22149875
references: Oncology. 2008;74(1-2):76-83
references: 18544998
references: J Clin Oncol. 2010 Jun 20;28(18):2947-51
references: 20458043
references: Cancer Chemother Pharmacol. 2010 Feb;65(3):579-87
references: 19629485
references: Lancet Oncol. 2014 Aug;15(9):1007-18
references: 24965569
references: J Clin Oncol. 2007 Nov 20;25(33):5180-6
references: 18024865
references: Breast Cancer Res Treat. 2008 Dec;112(3):533-43
references: 18188694
references: Curr Opin Pharmacol. 2008 Aug;8(4):393-412
references: 18721898
references: N Engl J Med. 2006 Dec 28;355(26):2733-43
references: 17192538
references: Hum Pathol. 2009 Jun;40(6):769-77
references: 19269014
references: Nat Med. 2003 Jun;9(6):669-76
references: 12778165
references: Cytokine Growth Factor Rev. 2005 Apr;16(2):179-86
references: 15863033
references: Gastroenterology. 2006 Nov;131(5):1530-41
references: 17101326
references: Clin Cancer Res. 2007 May 15;13(10):3051-7
references: 17505008
references: Science. 1985 Dec 6;230(4730):1132-9
references: 2999974
references: J Clin Oncol. 2010 Apr 10;28(11):1904-10
references: 20231677
references: Lancet Oncol. 2010 Oct;11(10):962-72
references: 20851682
references: Nat Genet. 2014 Jun;46(6):573-82
references: 24816253
references: J Clin Oncol. 2014 Jul 1;32(19):2039-49
references: 24868024
references: Int J Oncol. 2005 Sep;27(3):681-5
references: 16077916
references: Mol Syst Biol. 2005;1:2005.0010
references: 16729045
references: J Clin Oncol. 2006 Nov 20;24(33):5201-6
references: 17114652
references: N Engl J Med. 2007 Jan 11;356(2):125-34
references: 17215530
references: Lancet Oncol. 2013 May;14(6):490-9
references: 23594786
references: Lancet Oncol. 2013 May;14(6):481-9
references: 23594787
references: Cancer Lett. 2003 May 8;194(1):119-24
references: 12706865
references: Clin Exp Immunol. 2009 Oct;158(1):1-9
references: 19737224
references: J Clin Oncol. 2011 Oct 20;29(30):3968-76
references: 21844504
references: World J Surg. 2007 Jul;31(7):1458-68
references: 17516110
references: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references: 24399786
references: Mol Cancer Ther. 2009 Sep;8(9):2537-45
references: 19723882
references: Br J Cancer. 2010 Feb 2;102(3):500-5
references: 20068568
references: J Pathol. 2005 Jan;205(2):145-53
references: 15641016
references: Cancer. 2007 Feb 15;109(4):658-67
references: 17211865
references: Mol Cancer Res. 2004 Nov;2(11):643-52
references: 15561780
references: N Engl J Med. 2013 Jul 11;369(2):134-44
references: 23724846
references: Int J Cancer. 2003 Dec 20;107(6):873-7
references: 14601044
references: Cancer. 1999 May 1;85(9):1894-902
references: 10223227
references: Nat Med. 2003 Jun;9(6):653-60
references: 12778163