Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

Table 2

Main features and pharmacological implications of the HER2 gene SNPs reviewed in HER2-positive breast cancer patients. ILC: invasive lobular carcinoma; IDC: invasive ductal carcinoma; MDC: mixed ductal and lobular carcinoma. These mutations are found also in HER2-negative breast cancer [28, 29, 32, 34, 77].

Mutation	Exon	Tumor type	Protein domain	Mutation impact	Pharmacological implications	Study design	References
L755S	19	ILC; IDC; MDC	TKD, C-α helix	Activation	Trastuzumab/lapatinib resistance; Neratinib/afatinib sensitivity	Breast cancer HER2+ patients, in vitro studies	[40, 41]
					Lapatinib resistance	Breast cancer HER2+ patients, in vitro studies	[42, 43]
					Trastuzumab resistance; Afatinib/neratinib sensitivity	MANO method and xenograft	[44]
					Afatinib/neratinib sensitivity	MANO method and xenograft	[41, 44]
V777L	20	ILC; IDC	TKD, C-α helix, C-terminal tail	Activation	Trastuzumab resistance; Lapatinib/neratinib sensitivity	Breast cancer HER2+ patients	[45]
					Trastuzumab resistance; Lapatinib/neratinib/afatinib sensitivity	MANO method and xenograft	[44]
					Trastuzumab + lapatinib sensitivity	Breast cancer HER2+ patient	[31]
					Neratinib sensitivity	Breast cancer HER2+ patient	[35]
D769Y	19	ILC; IDC	TKD, C-α helix	Activation	Neratinib sensitivity; Trastuzumab/lapatinib resistance	Xenograft study	[42]
					Trastuzumab resistance; Afatinib/lapatinib/neratinib sensitivity	MANO method and xenograft	[44]
D769H	19	IDC	TKD, C-α helix	Activation	Neratinib sensitivity	Breast cancer HER2+ patient	[28]
					Trastuzumab/pertuzumab sensitivity	Breast cancer HER2+ patient	[46]
					Trastuzumab/afatinib/lapatinib/neratinib sensitivity	MANO method and xenograft	[44]
I767M	19	IDC; ILC; MDLC	TKD, C-α helix	Inconclusive	Trastuzumab/lapatinib/afatinib/neratinib sensitivity	In vitro breast cell cultures; MANO method; xenotransplant; breast cancer HER2+ patients	[44, 47]
V842I	21	IDC; ILC	TKD, c-loop	Activation	Lapatinib/trastuzumab resistance	MANO method and xenograft	[44]
K753E	18	IDC	TKD, C-α helix	Likely neutral	Lapatinib/trastuzumab resistance; Neratinib sensitivity	Breast cancer HER2+ tumors	[32, 41]
R678Q	17	IDC	JMD	Activation	Trastuzumab/lapatinib/afatinib/; Neratinib sensitivity	MANO method and xenograft	[44]
I655V	16	IDC	TMD	Activation	Trastuzumab sensitivity	Breast cancer HER2+ patients	[48]
					No correlation with trastuzumab efficacy		[49–51]
					Trastuzumab resistance		[52]
					No correlation with trastuzumab-induced cardiotoxicity		[53]
					Correlation with trastuzumab-induced cardiotoxicity		[50]
S310F	8	IDC; ILC	ECD, subdomain II, furin-like domain CR1	Activation	Neratinib/trastuzumab sensitivity	Breast cancer HER2+ patients	[33, 54]
					Trastuzumab/lapatinib/afatinib/neratinib sensitivity	MANO method and xenograft	[44]
S310Y	8	ILC	ECD, subdomain II, furin-like domain CR1	Activation	Neratinib/trastuzumab sensitivity	Breast cancer HER2+ patients	[33, 55]
		IDC; MDLC			Trastuzumab/lapatinib/afatinib/neratinib sensitivity	MANO method and xenograft	[44]