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Studies assessing polymorphism biomarkers in relation to activity or efficacy of BEV

Author	Trial	Cancer	n/N*	Assessment	Finding
BEV, bevacizumab; PTX, paclitaxel; Doc, docetaxel; CTX, cyclophosphamide; CBP, carboplatin; ABC, advanced breast cancer; MBC, metastatic breast cancer; LABC, locally advanced breast cancer; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; eNOS, endothelial nitric oxide synthase; WNK-1, WNK lysine-deficient protein kinase 1; IL, interleukin; ICAM-1, intracellular adhesion molecule-1; EGF, epidermal growth factor; p53, protein 53; PGF, placental growth factor; HIF, hypoxia-inducible factor; VHL, von Hippel-Lindau; EGLN, prolyl hydroxylase domain-containing proteins; NRP1, neuropilin-1 coreceptor; VLDLR, very-low-density-lipoprotein receptor; CXCR2, chemokine (C-X-C Motif) receptor 2; DNAJC4, DnaJ heat shock protein family (Hsp40) member C4; GWAS, genome-wide association study; SNP, single nucleotide polymorphism; AGTR1, angiotensin II receptor 1; ACE, angiotensin converting enzyme; OS, overall survival; SV2C, synaptic vesicle glycoprotein 2C; PFS, progression-free survival; pCR, pathologic complete response; TTF, time to treatment failure; *, Number of patients in sub study/parent trial.
Schneider et al. (8)	E2100: phase III, PTX vs. PTX + BEV	First line ABC	363/673	VEGF: −2578 C/A (rs699947), −1498 C/T (rs833061), −1154 G/A (rs1570360), −634 G/C (rs2010963), 936 C/T (rs3025039); VEGFR-2:1416 A/T (rs1870377), 889 G/A (rs2305948)	Improved OS with PTX + BEV in carriers of VEGF −2578 AA and −1154 AA
Miles et al. (9)	AVADO: phase III, Doc vs. Doc + BEV 7.5 mg/kg or 15.0 mg/kg	First line MBC	336/736	VEGF-A (rs699947, rs2010963, rs3025039, rs833061, rs1570360); VEGFR-1 (na_5, rs9554316, rs9582036); VEGFR-2 (rs1870377, rs2305948, rs2071559, rs3034659); eNOS (rs2070744, rs1799983, na_1, na_2); WNK-1 (rs11064560, rs2158501); IL-8 (rs4073); IL-8 receptor (rs2230054, rs2234671); IL-6 (rs1800795); Adrenomedulin (na_3); ICAM-1 (rs5498); EGF (rs4444903); p53 (rs1042522)	Improved PFS with Doc alone in carriers of VEGFA−634CC; improved PFS with Doc + BEV 7.5 mg/kg in carriers of VEGFA −2578 AA
Hein et al. (10)	GeparQuinto: phase III, Anthracycline + vs. Anthracycline + Taxane + BEV	Neoadjuvant breast cancer	1,453/1,984	VEGF-A (rs2010963, rs3025000, rs3025030, rs3025033, rs3025039, rs833061, rs833068, rs699946, rs699947, rs833058, rs833060, rs4416670, rs6921438); PGF (rs1042886, rs2268613, rs2268614); VEGF-B (rs594942); VEGF-C (rs3775194, rs6828869, rs7693545, rs2046462); VEGF-D (rs6418686, rs6527518); VEGFR1 (rs11149523, rs12858139, rs1324057, rs17086609, rs1830792, rs2281827, rs2387632, rs600640, rs722503, rs7324547, rs7987291, rs7987649, rs7995976, rs9319425, rs9508021, rs9513070, rs9513115, rs9551471, rs9554320, rs9582036, rs7982639); VEGFR2 (rs10020464, rs11133360, rs12502008, rs12505758, rs12642307, rs1531289, rs1531290, rs17085262,rs1870377, rs2034965, rs2071559, rs2239702, rs2305945, rs7667298, rs7673274, rs7691507); VEGFR3 (rs10085109, rs1130378, rs1130379, rs11750142, rs12654563, rs13359473, rs2242212, rs2242214, rs307811, rs307821, rs307826, rs448012, rs7733907); HIF1A (rs11158358, rs11549465, rs1319462); HIF-2α (rs10199201, rs11125071, rs13409493, rs13412887, rs1374749, rs1562452, rs1867787, rs1868089, rs3768728, rs3768730, rs4145836, rs4952818, rs4952819, rs4953340, rs4953344, rs4953353, rs6715787, rs7565341, rs7594278, rs11689649); HIF1AN (rs2295778, rs2295779); VHL (rs1642742, rs1678607); EGLN2 (rs11881124, rs2644916, rs3733829, rs7937); EGLN1 (rs2491417, rs480902, rs2749723); EGLN3 (rs12435664,rs12435737, rs1629140, rs1680695, rs1769608, rs2236563, rs9671702); NRP1 (rs1411924, rs2070296, rs2804498, rs4934838); EP300 (rs20551, rs4820431, rs5758223); IL-8 (rs4073); VLDLR (rs10738760); CXCR2 (rs2230054); DNAJC4 (rs3741403)	VEGF-A (rs833058, rs699947, rs3025030, rs3025039), VEGFR-1 (rs7995976) were associated with a better pCR with BEV treatment, but none of them remained significant after correction for multiple testing.
Schneider et al. (11)	E5103: phase III, Doxorubicin + CTX followed PTX vs. The same chemotherapy + BEV concurrent vs. The same chemotherapy + BEV concurrent plus sequential E2100	Adjuvant breast cancer	3,431/4,033 in E5103, 185/722 in E2100	GWAS (>1 million SNPs), candidate SNPs associated with hypertension were selected in E5103, and validated in E2100	SV2C (rs6453204) predicted BEV induced hypertension
Etienne-Grimaldi et al. (12)	ATHENA: single arm, phase III, BEV + Taxane-based chemotherapy	First line LABC/MBC	137/2,251	VEGF-A: −2578C/A (rs699947), −1498T/C (rs833061), −1154G/A (rs1570360), −634 G/C (rs2010963), 936 C/T (rs3025039)	VEGF-A 936 C/T tended to be associated with TTP. VEGF-A −634 G/C related to BEV associated toxicity
Di Salvatore et al. (13)	Retrospective study, single arm, PTX + BEV ± CBP	First line MBC	31	eNOS: −786 T/C (rs2070744), −894 G/T (rs1799983), IL-8−251 T/A (rs4073), COX2−8473 C/T (rs5275)	Lower PFS and OS in IL-8 251 AA
Moreno-Muñoz et al. (14)	Retrospective study, single arm	ABC or colorectal cancer	49 breast cancer, 46 colorectal cancer	AGTR1-A1166C (rs5186), AGT-M235T (rs699), ACE I/D (rs4646994)	ACE IN/IN was associated with shorter TTF, better response to BEV in ACE IN/IN and AGTR1-1166A/A