HER2 aberrations and heterogeneity in cancers of the digestive system: Implications for pathologists and gastroenterologists

Table 1 erbB2 overexpression and gene amplification reported frequencies in tumors of the digestive system

Primary tumor	erbB2 overexpression frequencies	HER2 amplification frequencies	Ref.
Esophageal cancer	4%-22%	4%-14%	[33-36,38,39]
Gastric cancer	13%-22%	10%-18%	[12,41-47]
Colorectal cancer	2%-11%	3%	[48-57]
Biliary tract cancer	5%-76%	1%-8%	[27,75,86,88-90]
Pancreatic cancer	0%-50%	2%-29%	[17-19,64-66,68]
Liver cancer	2%-5%	0-1%	[72-79]

Table 2 Mechanisms of resistance occurring in erbB2-tageting agents[107]

Type	Agent	Target	Mechanisms of resistance	Factors involved
Monoclonal antibodies	Trastuzumab	erbB2	Alterations in tyrosine kinase domain; overexpression of alternative erbB isoforms and dimerization receptors; loss of downstream checkpoints; dimerization and interaction with other receptors	p95HER2, MUC4 EGFR, erbB ligands (TGFα, EGF, HB), PTEN IGF1R, MET
	Pertuzumab	erbB2
	T-DM1	erbB2
Tyrosine kinase inhibitors	Lapatinib	erbB1, erbB2	Alterations in tyrosine kinase domain; acquisition of HER2 mutations; activation of further downstream signaling pathways	KIT and PDGFRA receptor signaling pathway; PI3K-AKT, mTOR
	Neratinib	erbB2, erbB4
	Afatinib	erbB1, erbB2, erbB4
	Canertinib	erbB1, erbB2, erbB4
Inhibitors of the downstream targets	Everolimus	mTOR	Activation of further downstream signaling pathways	PI3K-AKT, mTOR, MEK, MAPK
	BKM120	PI3K/AKT
	BEZ-235	PI3K/AKT/mTOR
	GS-1101	PI3K
	NVP-BKM120	PI3K
	GDC-0941	PI3K
	GSK458	PI3K/mTOR
	GDC-0980	PI3K/mTOR
	PI-103	PI3K/mTOR
hsp90 inhibitors	Tanespimycin	hsp90	Up-regulation of alternative pathways	NF-κB, MAPK
	Retaspimycin	hsp90
	AUY922	hsp90