Table 2.

Markers of toxic effects in pharmacogenetic correlative substudies of antiangiogenic agents

	Toxic effect	Cancer	Number of patients in substudy/parent trial	Genotypes and SNPs assessed	Findings
Bevacizumab
E21004,22	Hypertension ≥grade 3–4	Breast	363/722	VEGFA: –2578 C/A, –1154 G/A, –1498 C/T, –634 G/C, 936 C/T; VEGFR3*: 889 G/A, 1416 A/T	VEGFA –1498 TT, –634 CC associated with decreased risk of hypertension
Sunitinib
Kim et al37	Hypertension (SBP >150 mm Hg and/or DBP ≥90 mm Hg)	Renal	63/NA	VEGFA: –2578 C/A, –22459 ins/del, –1498 C/T, –1154 G/A, –634 G/C, 936 C/T; VEGFR3*; 889 G/A, 1416 A/T	VEGFA –2578 CC, –1498 TT, –634 CC associated with decreased risk of hypertension
van Erp et al50	Thrombocytopenia, leucopenia, hand-foot syndrome, mucosal inflammation, any toxic effect >grade 2	Renal, GIST, other	219/NA	VEGFR3*: –604 A/G, –92 G/A, 54 T/C, 889 G/A, 1416 A/T; VEGFR3†: 1480 A/G; ABCB3: 1236 T/C, 2677 G/T, 3435 C/T; ABCG3: –15622 C/T, 34 G/A, 421 C/A, 1143 C/T (rs2622604); CYP3A3: 2455 A/G; CYP3A3: –163 A/G: CYP3A3: 6986 A/G; FLT3: 738 T/C; PDGFRA: 1580 T/C, –1171 C/G, –735 G/A, –573 G/T; NR3I3: –24113 G/A, 7635 A/G, 8055 C/T, 10620 C/T, 10799 G/A, 25385 C/T, NR3I3: 5719 C/T, 7738 A/C, 7837 T/G; RET 2251 G/A (rs1799939)	CYP3A3 2455 GG, FLT3 738 TT, CAG absent in NR3I3 haplotype associated with increased risk of leucopenia; VEGFR3* 1191 TT, copy of TT in ABCG3 haplotype associated with increased risk of toxic effects; CYP3A 2455 GG associated with increased risk of mucosal inflammation; copy of TTT in ABCB3 haplotype associated with increased risk of hand-foot syndrome
Garcia-Donas et al35	Mucositis, hand-foot syndrome, hypertension, anaemia, thrombocytopenia, any toxic effect ≥grade 3–4, adverse events leading to dose reductions	Renal	95/101	VEGFA: –634 C/G, –2578C/A, –1154 G/A; VEGFR3*: 889 G/A, 1416 A/T; VEGFR3†: 1480 A/G, 330+31 T/G, 3971 G/T; ABCB3: 1236 T/C, 2677 G/T, 3435 C/T; ABCG3: 421 C/A; CYP3A3: –392 A/G; CYP3A3: 6986 A/G; IL3: –251 T/A; PDGFRA: 1580 T/C	Dose reductions associated with CYP3A3*3 (6986 GG) high-metabolising allele; VEGFA –2578 AA, –1154 AA, VEGFR3* 1416 TT‡ associated with increased risk of hypertension
Axitinib
AXIS41,42	Hypertension ≥grade 3–4	Renal	249/723	VEGFA: –2578 C/A, –1498 C/T, –1154 G/A, –634 C/G, 936 C/T; VEGFR3§: rs9513070, rs9554316, rs9554320, rs9582036, rs111458691; VEGFR3*: 889 G/A, 1416 A/T, –604 A/G; HIF3A: 1772 C/T, 1790 G/A	None; rate of hypertension in subgroup not reported

SNPs=single-nucleotide polymorphisms. SBP=systolic blood pressure. DBP=diastolic blood pressure. GIST=gastrointestinal stromal tumour.

^*Approved symbol KDR.

^†Approved symbol FLT3.

^‡Significant before adjustment; none significant after adjustment for multiple comparisons.

^§Approved symbol FLT3.