Advances in molecular, genetic and immune signatures of gastric cancer: Are we ready to apply them in our patients’ decision making?

Table 1 Molecular subtypes of gastric cancer according to the Cancer Genome Atlas and Asian Cancer Research Group

Molecular subtypes of gastric cancer
TCGA	ACRG
CIN (50%)	MSS/TP53− (35.7%)
MSI-Η (21%)	MSS/TP53+ (26.3%)
GS (20%)	MSI-H (22.7%)
EBV + (9%)	MSS-EMT (15.3%)

TCGA: Cancer Genome Atlas; ACRG: Asian Cancer Research Group; CIN: Chrosomal instability; MSI-Η: Microsatellite-high; GS: Genomically stable; EBV: Epstein-Barr virus; MSS: Microsatellite stable; TP53: Tumor protein p53; EMT: Epithelial-mesenchymal transition.

Table 2 Main targeted agents evaluated in metastatic gastric cancer

Biologic target	Targeted agent	Name/type of trial	Line of therapy	Study arms	Results	Ref.
c-MET	Rilutumumab	RILOMET-1 Phase III	1st	ECX + Ril	Negative effect	[58]
EGFR	Cetuximab	EXPAND Phase III	1st	XP ± Cet	No benefit	[48]
		AIO Phase II	1st	FOLFOX + Cet	> 4 EGFR gene copies: Increased OS (log-rank P = 0.011; HR = 0.2, 95%CI: 0-0.8; P = 0.022)	[50]
	Panitumumab	REAL-3 Phase III	1st	EOX ± Pani	No benefit	[49]
HER-2	Trastuzumab	ToGA Phase III	1st	XP/FP ± H	OS: 13.8 vs 11.1, P = 0.0046 OS (IHC+3, IHC+2/FISH+): 16 mo vs 11.8 mo, P = 0.0036	[18]
	Pertuzumab	JACOB Phase III	1st	FP + H ± Pert	No benefit	[19]
	Lapatinib	Tytan Phase III	2nd	Pac w ± Lap	No benefit (unselected population) OS (IHC: 3+): 14 mo vs 7.6 mo, P = 0.0176	[21]
	Trastuzumab emtansine	GATSBY Phase II-III	2nd	TDM-1 vs taxane	No superiority	[22]
mTOR	Everolimus	GRANITE-1 Phase III	2nd, 3rd	Everolimus vs placebo	No benefit	[55]
VEGF, VEGFR	Bevacizumab	AVAGAST Phase III	1st	XP ± Bev	Primary endpoint (OS) was not met PFS: 6.7 mo vs 5.3 mo, P = 0.0037 ORR: 46% vs 37.4%, P = 0.0315	[25]
	Ramucirumab	REGARD Phase III	2nd	Ram vs placebo	OS: 5.2 mo vs 3.8 mo, P = 0.047	[26]
		RAINBOW Phase III	2nd	Pac w ± Ram	OS: 9.6 mo vs 7.4 mo, P = 0.017	[27]
		Phase II	1st	FOLFOX ± Ram	No benefit	[28]
	Apatinib	Phase III	beyond 2nd line	Apa vs placebo	OS: 6.5 mo vs 4.7 mo, P = 0.0149 PFS: 2.6 mo vs 1.8, mo, P < 0.001	[30]

ECX: Epirubicin-Cisplatin-Capecitabine; Ril: Rilutumumab; XP: Cisplatin-Capecitabine; Cet: Cetuximab; EOX: Epirubicin - Oxaliplatin - Capecitabine; Pani: Panitumumab; FP: Cisplatin - 5Fu; H: Herceptin; Pert: Pertuzumab; Pac w: Paclitaxel weekly; Lap: Lapatinib; TDM-1: Trastuzumab emtansine; Bev: Bevacizumab; Ram: Ramucirumab; Apa: Apatinib; OS: Overall survival; PFS: Progression free survival; ORR: Overall response rate.