Clinical significance of MET in gastric cancer

Table 1 MET protein expressions on immunohistochemistry and clinical outcomes in gastric cancer

	n	Definition of overexpression	%	Relation to clinicopathological factors	Relation to survival	Ref.
Usual IHC	495	2+/3+, > 10%	22	Intestinal type, recurrence	Worse3	[14]
	170	Cytoplasmic, 2+/3+	13	ND	ND	[38]
	121	≥ 5%	66	N, stage	Worse	[20]
	114	> 30%	74	NA	Worse3	[30]
	98	Intensity and extensity scoring system	59	N, M	Worse	[25]
	50		78	NA	NA	[28]
	38	2+/3+, ≥ 25%	63	Intestinal type	ND	[22]
	941	≥ 50%	50	NA	NA	[24]
	1212	Any staining	98	Liver metastasis	ND	[29]
TMA	438	Membranous, 2+/3+, > 10%	24	T, N, M, stage, intestinal type	Worse	[12]
	436	Intensity and extensity scoring system	44	T, N, M, diffuse type	Worse34	[13]
	215	Cytoplasmic, > 10%	69	NA	NA	[27]
	212	2+/3+	12	ND	Worse3	[32]
	182	Intensity and extensity scoring system	66	N, intestinal type, differentiated type	Worse	[19]
	163	Cytoplasmic 2+/3+ ≥ 10%, and positive > 75%	4	ND	Worse3	[31]
	124	Cytoplasmic, 3+	71	T, stage, intestinal type	ND	[23]
	114	Intensity and extensity scoring system	82	N, stage	Worse	[26]
	35		43	ND	Likely worse	[18]

¹Limited to diffuse or mixed type;

²Only stage IV;

³An independent prognostic factor on multivariate analysis;

⁴Only IHC3+. IHC: Immunohistochemistry; TMA; Tissue micro array; T: Tumor invasion depth; N: Lymph-node metastasis; M: Distant metastasis; ND: Not described; NA: Not associated.

Table 2 MET mRNA expressions and clinical outcomes in gastric cancer

	n	Overexpression		Relation to clinicopathological factors	Relation to survival	Ref.
		Cut-off value	%
Tumor	100	Value determined by nonparametric receiver operating characteristics	11	M	Worse	[34]
	100	ND	24	ND	ND	[43]
	45			N, stage, differentiated type	ND	[35]
	43	Value of mean + 2 SD in noncancerous tissue	70	NA	ND	[36]
	15			Intestinal type	ND	[22]
Serum	52	Detected	62	T, N, M, stage, recurrence, v	Worse	[37]

T: Depth of tumor invasion; N: Lymph-node metastasis; M: Distant metastasis; v: Venous invasion; ND: Not described; NA: Not associated.

Table 3 MET gene alterations and clinical outcomes in gastric cancer

	n	Definition ofpositive expression	%	Relation toclinicopatho-logical factors	Relation to survival	Ref.
FISH	4601	GA	2.2	Stage	Worse	[39]
	196	GA	6.1	ND	Worse	[32]
	170	GA or HP	15 (GA7.1 HP7.6)	ND	ND	[38]
SISH	381	GA or HP	19 (GA3.4, HP16)	Intestinal (HP), M (GA), stage (GA)	Worse2 (GA)	[12]
RT-PCR	472	> 4 copies	21	NA	Worse2	[33]
	266	> 4 copies	1.5	NA	NA	[40]
	216	≥ 5 copies	10	Unknown	Worse2	[41]
	128	≥ 4 copies	30	T, stage	Worse2	[42]
	45	≥ 7 copies	7	ND	Worse	[18]
SNP array	193	GA	4	ND	ND	[44]
	100	GA	3	ND	ND	[43]
Polymorphism analysis	34 (tumor)	Any alterations	59	T, N, M	ND	[47]
	34 (serum)	Any alterations	41	N, M	ND	[47]

¹Esophagogastric adenocarcinoma;

²An independent prognostic factor on multivariate analysis. FISH: Fluorescence in situ hybridization; SISH: Silver in situ hybridization; RT-PCR: Reverse transcription polymerase chain reaction; SNP: Single nucleotide polymorphism; GA: Gene amplification; HP: High polysomy; ND: Not described; NA: Not associated; T: Tumor invasion depth; N: Lymph-node metastasis; M: Distant metastasis.

Table 4 Development of MET-targeting agents for gastric cancer

Type	Agent	Other targets	Phase	Line	Combined therapy	Results or status	Ref.
MET selective	Tivantinib (ARQ197)	None	II	2nd/3rd	None	No CR/PR	[72]
non-ATP competitive TKI						Median PFS 1.4 mo
MET-selective	AMG 337	None	II	Any	None	Ongoing	[74]
ATP-competitive TKI			I	2nd/3rd	None	1 CR and 4 PR in 10 patients with MET -amplified tumor	[73]
Multitargeted	Foretinib	VEGFR2, RON, AXL, TIE2	II	1st (95%)	Docetaxel, Cisplatin	No CR/PR	[75]
ATP-competitive TKI	(GSK1363089)					Median OS 7.4
	Crizotinib	ALK	I			Tumor shrinkage in 2 patients with PFS 3.5 and 3.7 mo	[39]
	(PF-2341066)
MET mAb	Onartuzumab (MetMab )	None	III	1st	mFOLFOX	Ongoing	[77]
HGF mAb	Rilotumumab	None	III	1st	ECX	Suspended	[79]
	(AMG 102)	None	III	1st	CX	Suspended	[80]
		None	II	1st	ECX	Median PFS 4.2 mo	[78]
						Median OS 5.6 mo

ATP: Adenosine triphosphate; TKI: Tyrosine kinase inhibitor; mAb: Monoclonal antibody; VEGFR: Vascular endothelial growth factor receptor; ALK: Anaplastic lymphoma kinase; TIE: Tunica internal endothelial cell kinase; CR: Complete response; PR: Partial response; RFS: Relapse-free survival; OS: Overall survival; FOLFOX: Folinic acid + fluorouracil + oxaliplatin; ECX: Epirubicin + oxaliplatin + capecitabine; CX: Oxaliplatin + capecitabine.