Table 1.

Efficacy markers in pharmacogenetic correlative substudies of antiangiogenic agents

	Cancer	Number of patients in substudy/parent trial	Genotypes and SNPs assessed	Findings
Bevacizumab
E2100: phase 3, paclitaxel vs paclitaxel+bevacizumab4,22	Breast	363/722	VEGFA: –2578 C/A (rs699947), –1498 C/T (rs 833061), –1154 G/A (rs1570360), –634 G/C (rs2010963), 936 C/T (rs3025039); VEGFR3*: 1416 A/T (rs1870377), 889 G/A (rs2305948)	Improved OS with paclitaxel+bevacizumab in carriers of VEGFA –2578 AA and –1154 AA
AVADO: phase 3, docetaxel vs docetaxel+bevacizumab 7·5 mg/kg or 15·0 mg/kg5,23	Breast	336/736	VEGFA: –2578 C/A, –1498 C/T, –1154 G/A, –634 G/C, 936 C/T; VEGFR3†; VEGFR3*; ADM; EGF; ERCC3; eNOS‡; IL3; IL3; CXCR3; ICAM3; TP33; WNK3	Improved PFS with docetaxel alone in carriers of VEGFA –634 CC; improved PFS with docetaxel+bevacizumab 7·5 mg/kg in carriers of VEGFA –2578 AA
Hellenic Cooperative Oncology Group: phase 3, FOLFIRI+bevacizumab vs XELIRI+bevacizumab24,25	Colon	209/285	VEGFA: –2578 C/A, –1154 G/A, –634 G/C, 936 C/T	Decreased OS with bevacizumab in carriers of VEGFA –2578 CC, –1154 GG
Formica et al: observational study, first-line FOLFIRI+bevacizumab26	Colon	40/40	VEGFA: –2578 C/A, –1512 18 bp ins/del (rs35569394), –1498 C/T, –1451 T/C (rs1005230), –1411 4G–5G (rs35864111), –1154 G/A	Improved PFS with bevacizumab for carriers of VEGFA –1154 AA, and improved response rate in carriers of VEGFA –634 GG
E4599: phase 3, paclitaxel/carboplatin vs paclitaxel/carboplatin+bevacizumab27,28	Lung	133/878	VEGFA: –1498 C/T, –1154 G/A, –634 G/C, –936 C/T; VEGFR3*: 3′UTR T/A; CXCR3: –785 C/T; COX3‡: –765G/C; EGF: –61A/G; EGFR: 497G/A; FGFR3: 388G/A; ICAM3: 469T/C; IL3: –251T/A	Improved OS and PFS with bevacizumab in carriers of SNP profile VEGFA –634GG, ICAM3 469T/C, IL3 –251T/A
Schultheis et al: phase 2, low-dose cyclophosphamide+bevacizumab29	Ovarian	53/70	VEGFA, CXCR3, CXCR3, COX3§, ADM, ARNT, EGF, EGFR, FGFR3, HIF3A, ICAM3, IGF3, IGF3R, IL3, IL3, IL3B, IL3R3, VEGFR3*, LEP, MDM3, MMP3, MMP3, MMP3, NFKB3, NRP3, PGF, TP33, CXCL33, TF, TNF	Decreased response rate with bevacizumab in carriers of IL3 A allele; improved PFS for CXCR3 785 C, and VEGFA CT genotype
AVITA: phase 3, gemcitabine/erlotinib vs gemcitabine/erlotinib+ bevacizumab30,31	Pancreatic	154/607	Total 157 SNPs in VEGFA, VEGFB, VEGFC, VEGFD¶, VEGFR3†, VEGFR3*, inducers of VEGF ligand, PlGF	Superior OS with bevacizumab in carriers of VEGFR3† rs9582036
Pazopanib
Combined trials phase 3 VEG105192 and phase 2 VEG102616, and open-label rollover VEG10776932–34	Renal	397/585	VEGFA: –2578 C/A, –1498 C/T, –1154 G/A, –634 C/G, 936 C/T; VEGFR3*: –604 A/G, 889 G/A, 1416 A/T; VEGFR3||: 1480 A/G (rs307826); ABCB3: 1236 T/C (rs1128503), 2677 G/T, (rs2032582), 3435 C/T (rs1045642); ABCG3: 34 G/A (rs2231137), 421 C/A (rs2231142), 869 C/T (rs72552713); CYP3A3: –392 A/G (rs2740574); CYP3A3: 6986 A/G (rs776746); FGF3: 224 C/T (rs1449683); FGFR3: IVS2+906 C/T (rs2981582); HIF3A: 1772 C/T, 1790 G/A; IL3: –251 T/A, 2767 A/T (rs1126647); NR3I3: –25385 C/T (rs3814055), 10620 C/T (rs1054190), 7635 A/G (rs6785049); PDGFRA: –573 G/T (rs1800812)	Decreased response rate with pazopanib in carriers of VEGFA –2578 AA, –634 GG, –1498 CC, HIF3A 1790 AG, NR3I3 –25385 TT and decreased PFS in carriers of IL3 2767 TT, –251AA, HIF3A 1790 AG
Sunitinib
Garcia-Donas et al: observational study35	Renal	89/101	VEGFA: –2578 C/A, –1154 G/A, –634 C/G; VEGFR3*: 889 G/A, 1416 A/T; VEGFR3||: 330+31 T/G (rs448012); 1480 A/G (rs307826), 3971 G/T (rs307821); ABCB3, 1236C/T, 2677 G/T, 3435 C/T; ABCG3: 421 C/A; CYP3A3: –392 A/G; CYP3A3: 6989 A/G; IL3: 2767 A/T; PDGFRA: 1580 T/C (rs35597368)	Decreased PFS with for carriers of SNPs in VEGFR3||; –1480 A→G, 3971 G→T
van der Veldt et al: retrospective, multicentre study36	Renal	136/136	ABCB3: 1236C/T, 2677G/T, 3435C/T; ABCG3: –15622C/T 34 G/A, 421 C/A, 1143 C/T; VEGFR3*: –604 A/G, –92 G/A (rs1531289), 54 T/C (rs7692791), 889 G/A, 1416 A/T; VEGFR3||: 1480 A/G; CYP3A3: 2455 A/G (rs1048943); CYP3A3: –163 A/C (rs762551); CYP3A3: 6986 A/G (rs776746); FLT3: 738 T/C (rs1933437); NR3I3: –25385 C/T, –24113 G/A (rs2276706), 10620 C/T, 10799 G/A (rs1054191), 7635 A/G, 8055 C/T (rs2276707); NR3I3: 5719 C/T (rs2307424), 7738 A/C (rs2307418), 7837 T/G (rs4073054); PDGFRA: –1171 C/G (rs1800810), –735 G/A (rs1800813), –573 G/T (rs1800812), 1580 T/C	Improved PFS with sunitinib in carriers of CYP3A3 6986 AA, CAT copy absent in the NR3I3 haplotype, TCG copy present in the ABCB3 haplotype
Kim et al: retrospective cohort study37	Renal	63/NA	VEGFA: –2578 C/A, –22459 ins/del, –1498 C/T, –1154 G/A, –634 G/C, 936 C/T; VEGFR3*: 889 A/G, 1416 A/T	Decreased OS with sunitinib in carriers of combined VEGFA 936 CC and VEGFR3* 889 GG
Sorafenib
E2501: randomised, placebo- controlled, phase 2, chemotherapy- resistant patients38,39	Lung	88/333	VEGFA, EGF, EGFR, IL3, CXCR3, COX3‡, VEGFR3*; ICAM3, FGFR3	Improved PFS with sorefenib in carriers of VEGFA –1498 CC, –634 CC
Anderson et al: phase 1, gemcitabine+radiotherapy+ sorafenib40	Pancreatic	19/27	VEGFA: –2578 C/A, –1498 C/T, –1154 G/A, –634 G/C, 936 C/T; VEGFR3*: 889 G/A, 1046 G/A, 1174 G/A, 1416 A/T, 2341 G/A, 2359 C/G, 2505 G/C, 2530del G, 2854 G/A, 3628 C/G, 4039 T/A	Improved OS with sorefenib in carriers of VEGFA –2578 AA, –1498 CC, –1154 AA, VEGFR3* 272 GG, 889 GG; all responders had VEGFA –7 CC, VEGFR3* 1416 AA
Axitinib
AXIS: phase 2, axitinib vs sorafenib41,42	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*: –604 A/G (rs2071559), 889 G/A, 1416 A/T; HIF3A: 1772 C/T (rs11549465), 1790 G/T (rs11549467)	Improved PFS with axitinib over sorafenib for carriers of VEGFA –2578 AA

SNPs=single-nucleotide polymorphisms. OS=overall survival. PFS=progression-free survival. FOLFIRI=leucovorin, fluorouracil, and irinotecan. XELIRI=irinotecan and capecitabine. ins/del=insertion-deletion.

^*Approved symbol KDR.

^†Approved symbol FLT3.

^‡Approved symbol NOS3.

^§Approved symbol PTGS3.

^¶Approved symbol FIGF.

^||Approved symbol FLT3.