Critical analysis of the potential for therapeutic targeting of mammalian target of rapamycin (mTOR) in gastric cancer

Figures & data

Table 1 mTOR expression (phosphorylated or not) on immunohistochemistry and clinical outcomes

	n	TMA	Positive or overexpression definition	%	Relation to clinico- pathological factors	Relation to survival	Reference
p-mTOR	1,072	Yes	Stronger staining than normal tissue	47	N, stage	Worse on UA and MA	52
	181	No	Weak intensity >20% of cells, or strong intensity > 10%	51	N, stage	Worse on UA and MA^**	53
	109	No	Cytoplasmic staining > 10% of cells	63	T, N, stage, recurrence	Worse on UA not associated with MA	51
	290^*	Yes	Weak intensity >25% of cells or moderate or strong intensity	45	N, differentiated type	Not associated on UA and MA by the expression in the primary site but worse on UA and MA by the expression in N	54
mTOR	1,072	Yes	Stronger staining than normal tissue	51	Differentiated type, T, stage (inversely)	Better on UA not associated with MA	52
	412	Yes	Any staining	62	Intestinal type	Better on UA and MA	58
	33	No	Cytoplasmic staining, any staining	52	T^* N, stage, differentiated type	Not evaluated	57

Notes:

* Represents patients with pathological subserosal invasion;

** represents not significant, but P-value <0.1.

Abbreviations: MA, multivariate analysis; mTOR, mammalian target of rapamycin; N, metastatic lymph nodes; p-mTOR, phosphorylated mTOR; T, depth of tumor invasion; TMA, tissue microarray; UA, univariate analysis.

Table 2 Clinical trials of everolimus against metastatic gastric cancer

Phase	Treatment arm	Chemotherapy line	n	Main endpoint	Results	Reference
I	Everolimus	2nd or more	9	MTD	RD and MTD was 10 mg/day	71
I	Everolimus + mitomycin C	2nd or more	16	MTD	RD and MTD of everolimus was 10 mg/day	72
I	Everolimus + capecitabine	3rd or more	15	MTD	RD and MTD of everolimus was 10 mg/day	75
II	Everolimus	2nd, 3rd	53	DCR	DCR 56% (no CR/PR) Median OS 10.1 M, median PFS 2.7 M	73
II	Everolimus	2nd	54	ORR/DCR	ORR 3.9% (no CR), DCR 39% Median OS 8.3 M, median PFS 1.7 M	74
II	Everolimus + capecitabine	3rd or more	47	ORR	ORR 11% (no CR), DCR 49% Median OS 4.9 M, median PFS 2.6 M	76
III	Everolimus versus placebo (GRANITE-1)	2nd, 3rd	656	OS	ORR 4.5% versus 2.1% Median OS 5.4 M versus 4.3 M Median PFS 1.7 M versus 1.4 M	77

Abbreviations: CR, complete response; DCR, disease control rate; M, months; MTD, maximum-tolerated dose; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RD, recommended dose.