Current research and treatment for gastrointestinal stromal tumors

Table 1 National Institutes of Health vs Armed Forces Institute of Pathology criteria for assessing malignant risk of gastrointestinal stromal tumors

Degree of risk	NIH criteria	AFIP criteria
Unknown	-	< 2 cm and ≤ 5 mitotic index
Very low	< 2 cm and < 5 mitotic index	≤ 5 cm and ≤ 5 mitotic index
Low	2-5 cm and < 5 mitotic index	Gastric: > 5 cm and ≤ 5 mitotic index
		Others: 2-5 cm and ≤ 5 mitotic index
Intermediate or moderate	5-10 cm and < 5 mitotic index	Gastric: > 10 cm and ≤ 5 mitotic index or > 2-5 cm and > 5 mitotic index
	> 5 cm and 6-10 mitotic index	Others: 5-10 cm and ≤ 5 mitotic index
High	> 5 cm and > 5 mitotic index	Gastric: > 5 cm and > 5 mitotic index
	> 10 cm and any mitotic index	Others: > 10 cm and > 5 mitotic index
	Any size and > 10 mitotic index

Mitotic index = number of mitoses per 50 high-power field. AFIP: Armed Forces Institute of Pathology; NIH: National Institutes of Health.

Table 2 Frequency of genetic mutations in gastrointestinal stromal tumors

KIT mutation (about 85%)	PDGFRA mutation (about 5%)	BRAF mutation (< 1%)	SDH mutation (12%-15% adult, 90% pediatric GIST)
Exon 11 (about 70%)	Exon 18 (about 5%)	Exon 15 V600E	Subunit B, C and D
Exon 9 (10%-15%)	Exon 12 (1%)
Exon 13 (1%-3%)	Exon 14 (< 0.5%)
Exon 17 (1%)	Exon 18 D842V (about 0%)

PDGFRA: Platelet-derived growth factor receptor alpha; SDH: Succinate dehydrogenase.

Table 3 Implication of gastrointestinal stromal tumors mutations and response to targeted therapy

	Imatinib[23]	Sunitinib[25]	Regorafenib[28]
KIT mutation
Exon 11	OR 63%	CB 34%	Increased sensitivity
Exon 9	OR 37%. Intermediate sensitivity. Higher dose 800 mg more effective in metastatic disease than 400 mg daily	CB 34%	Unknown
Exon 13	OR 40%. Sensitivity as primary mutation. Resistance as secondary mutation	CB 100%	Unknown
Exon 14	Resistance as secondary mutation	Unknown	Unknown
Exon 17	OR 25%. Primary mutation sensitive in vitro. Resistance as secondary mutation	CB 0%	Unknown
PDGFRA mutation
Exon 18	OR 50%	CB 0%	Unknown
Exon 12	Increased sensitivity	CB 0%	Unknown
Exon 14	Increased sensitivity in vitro	Unknown	Unknown
Exon 18 D842V	Decreased sensitivity	Decreased sensitivity	Unknown
BRAF mutation	Resistance	Resistance	Unknown
SDH mutation	Decreased sensitivity	Unknown	Increased sensitivity
No KIT, PDGFRA or BRAF mutation	OR 28%	CB 56%	Some activity

Objective response (OR) is defined as a complete or partial response by Response Evaluation Criteria for Solid Tumors (RECIST) criteria, excludes non-evaluable patients. Clinical benefit (CB) is defined as response or stable disease for 6 mo or more according to RECIST. PDGFRA: Platelet-derived growth factor receptor alpha; SDH: Succinate dehydrogenase.

Table 4 Potential treatment targets for gastrointestinal stromal tumors

Category	Name	ClinicalTrials.gov Identifier
TKI of KIT and PDGFRA	Masitinib (AB1010)	NCT00998751 (U)[57]
	Crenolanib (CP-868,596)	NCT02847429 (R), NCT01243346 (C)[58]
	AZD2171	NCT00385203 (C)[59]
	Vatalanib (PTK787)	NCT00117299 (C), NCT00655655 (A)
	OSI-930	NCT00513851 (C)
	TKI258	NCT01478373 (C), NCT01440959 (C)
	DCC-2618	NCT02571036 (R)
Biologic inhibitors of KIT and PDGFRA	Olaratumab (IMC-3G3)	NCT01316263 (C)
HSP90 inhibitors	Retaspimycin (IPI-5040)	NCT00276302 (C), NCT00688766 (T)
	BIIB021 (CNF2024)	NCT00618319 (C)
	Ganetespib (STA-9090)	NCT01039519 (C)
	AUY922	NCT01389583 (R), NCT01404650 (C)
	AT13387	NCT01294202 (C)
Inhibitors of pathways downstream of KIT and PDGFRA	RAS/RAF/MEK/ERK/MAPK inhibitors: MEK162	NCT01991379
	AKT inhibitors: perifosine	NCT00455559 (C)[60]
	mTOR inhibitors: everolimus (RAD001)	NCT01275222 (C), NCT00510354 (C), NCT02071862 (R)
	mTOR inhibitors: temsirolimus (Torisel)	NCT00700258 (R)
Cell cycle inhibitors	Alvocidib (Flavopiridol)	NCT00098579 (C)
Insulin-like growth factor pathway inhibitors	OSI-906	NCT01560260 (C)[61]

R: Recruiting; T: Terminated; C: Completed; A: Active, not recruiting; U: Unknown. PDGFRA: Platelet-derived growth factor receptor alpha.