Table 2.

Published works on germ-line variants and response to sorafenib in hepatocellular carcinoma patients

Pharmacogenetic panel	Study population	Therapy	Clinical endpoint	Main findings	Ref.
17 SNPs in VEGFA, VEGFC, FLT1 (VEGFR1), KDR (VEGFR2), FLT4 (VEGF3)	Advanced or intermediate-stage HCC (n = 148) (whites) (ALICE-1)	Sorafenib 400 mg, twice daily	PFS OS Objective Response	Univariate analysis VEGFA (rs25648-C, rs833061-T, rs699947-C, rs2010963-C), VEGFC (rs4604006-T), VEGFR1 (rs664393-G), and VEGFR2 (rs2071559-C, rs2305948-C) alleles were associated with longer PFS and OS; Multivariate analysis VEGFA rs2010963-C allele (PFS, 6.9 mo vs 4.0 mo, HR: 0.25, P = 0.0376; OS, 17.0 vs 9.3 mo, HR: 0.28, P = 0.0201), VEGFC rs4604006-T allele (PFS, 10.1 mo vs 4.3 mo, HR: 0.22, P = 0.004; OS, 22.0 mo vs 13.0 mo, HR: 0.25, P = 0.04) and BCLC C stage (PFS, 7.6 mo vs 4.5 mo, HR: 0.17, P = 0.0163; OS, 21.0 mo vs 10.7 mo, HR: 0.36, P = 0.0015) were independent prognostic factors predicting PFS and OS. Patients with both the favorable alleles of VEGFA rs2010963 and VEGFC rs4604006 showed improved PFS and OS compared to those with only one or none (PFS: P = 0.0004; two favorable alleles: 11.4 mo, one favorable and one unfavorable: 5.6 mo, two unfavorable: 3.4 mo; OS: P = 0.0001, two favorable alleles: 22.7 mo, one favorable and one unfavorable, 15.1 mo, two unfavorable, 8.8 mo). VEGFA rs2010963-C (P = 0.0343) and VEGFC rs4604006-T (P = 0.0028) alleles were also associated with a better objective response	[48]
18 SNPs in KDR (VEGFR2)	Advanced HCC (n = 78) (Chinese)	First-line sorafenib 400, mg twice daily	TTP OS Response	Univariate analysis VEGFR2 rs1870377-AA (5.8 mo vs 4.0 mo, P = 0.001) and rs2305948-AA (5.8 mo vs 4.5 mo, P = 0.016) genotypes were associated with longer TTP; VEGFR2 rs1870377-AA genotype (15.0 mo vs 9.6 mo, P = 0.001) and rs2071559-T allele (13.0 mo vs 9.0 mo, P = 0.007) were associated with longer OS; VEGFR2 rs1870377-AA (P = 0.011) and rs2305948-AA (P = 0.047) genotypes were associated with a better response; Multivariate analysis Major vascular invasion (HR: 2.51, P = 0.021) and VEGFR2 rs1870377-AA (HR: 0.68, P = 0.005) were independent factors in TTP; performance status (HR: 2.36, P = 0.017), VEGFR2 rs1870377-AA (HR: 0.35, P = 0.003) and rs2071559-CC (HR: 2.25, P = 0.036) were independent factors in OS	[50]
3 SNPs in eNOS	Advanced HCC (n = 41 training set; n = 87 validation set (whites)	First-line sorafenib 400 mg, twice daily	PFS OS	Univariate analysis Training set Patients homozygous for the eNOSHT1 haplotype (HT1:T-4b by combining eNOS rs2070744 T>C and eNOS VNTR 27bp 4a/b** variants) had a lower median PFS (2.6 mo vs 5.8 mo, HR: 5.43, P < 0.0001) and OS (3.2 mo vs 14.6 mo, HR: 2.35 P = 0.024) than those with other haplotypes; Validation set Patients homozygous for HT1 had a lower median PFS (2.0 mo vs 6.7 mo, HR: 5.16, P < 0.0001) and OS (6.4 mo vs 18.0 mo, HR: 3.01, P < 0.0001) than those with other haplotypes; Multivariate analysis eNOS haplotype HT1 is confirmed as the only independent prognostic factor. ** “4a” allele with 4 repeats; “4b” allele with 5 repeats	[51]
9 SNP in ANG2	HCC (n = 158) (whites)	Sorafenib	PFS OS	ANG2 rs55633437-GG genotype was associated with a better PFS (median PFS: 4.67 mo vs 2.94 mo, P = 0.03) and OS (median OS: 16.9 mo vs 6.5 mo, P = 0.016) with respect to the T-allele; Data were confirmed in multivariate analysis	[52]
8 SNPs in HIF1A	HCC (n = 210) (whites) (ALICE-2)	Sorafenib	PFS OS	Univariate analysis HIF1A rs1951795, rs10873142, and rs12434438 emerged as significant predictors of PFS and OS; the extended analysis of VEGF/VEGFR SNPs confirms the results of ALICE-1 study (see above); Multivariate analysis HIF1A rs12434438, VEGFA rs2010963, and VEGFC rs4604006 were confirmed as independent prognostic factors. The combination of the favorable alleles of rs2010963 and rs4604006 compared to only one or to none, identifies three populations with different PFS (respectively: 10.8 mo vs 5.6 mo vs 3.7 mo, P < 0.0001) and OS (respectively: 19.0 mo vs 13.5 mo vs 7.5 mo, P < 0.0001). HIF1A rs12434438-GG genotype was associated with a poor outcome independently of VEGF markers (PFS: 2.6 mo, P < 0.0001; OS: 6.6 mo, P < 0.0001)	[49]

HCC: Hepatocellular carcinoma; HFSR: Hand–foot skin reaction; mo., months; OR: Odds ratio; OS: Overall survival; PFS: Progression-free survival; SNP: Single nucleotide polymorphism; TTP: Time to progression.