Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Table 1 Published works on germ-line variants and pharmacokinetic and toxicity profiles of sorafenib in hepatocellular carcinoma patients

Pharmacogenetic panel	Study population	Therapy	Clinical endpoint	Main findings	Ref.
CYP3A4*1, CYP3A5*3, CYP2C19*2, CYP2D6*10	Advanced HCC (n = 51) (Chinese) Aflatoxin-induced HCC rat models (n = 105)	Sorafenib	Toxicity	Rat models: CYP3A4*1 (rs2740574) and CYP3A5*3 (rs776746) were associated with the lowest (8 ± 2.5ng/mL) and highest (67 ± 4.8 ng/mL) levels of sorafenib plasma concentration, respectively (P < 0.001); CYP3A5*3 correlated with the most severe liver (change in ALT and AST blood concentration [IU/L] over time) and renal injury (change in BUN [nmol/L) and Cr [umol/L] blood concentration [IU/L] over time) and CYP3A4*1 with the least severe injury (P < 0.001) Clinical setting: CYP3A5*3 was associated with increased severe hepatic toxicity (change in ALT and AST blood concentration [IU/L] over time, P < 0.001)	[32]
9 SNPs in CYP3A5, UGT1A9, ABCB1, ABCG2	Advanced solid cancer (n = 54; 37% HCC) (whites)	Sorafenib 400 or 200 mg, twice daily	PK Toxicity	UGT1A9 rs17868320-T allele was associated with increased grade ≥ 2 diarrhea (OR: 14.33, P = 0.015, multivariate analysis); ABCG2 rs2622604-TT genotype exhibited a greater exposure compared to the CC (sorafenib AUC, 131.8 vs 82.4 mg/L.h, P = 0.093 univariate analysis, not confirmed in multivariate)	[34]
8 SNPs in SLCO1B1, SLCO1B3, ABCC2, ABCG2, UGT1A1, UGT1A9	Advanced solid cancer (n = 114; 87% HCC) (mainly whites)	Sorafenib	Toxicity PFS OS	UGT1A1*28 (rs8175347) was associated with increased risk of acute hyperbilirubinemia (*28/*28 vs other, OR:5.413, P = 0.016) and of interrupting treatment (*28 vs other, OR: 3.397, P = 0.002) by multivariate analysis; the *28 allele also showed a trend towards a higher risk for any toxicity at grade 3 or higher (P = 0.088); SLCO1B1*1b (rs2306283-G) allele was associated with inferior risk of diarrhea (OR: 0.125, P = 0.007) and increased risk of hyperbilirubinemia (OR: 1.230, P = 0.002), and the SLCO1B1*5 (rs4149056-C) allele with higher risk of thrombocytopenia (OR: 4.219, P = 0.045) in univariate but not multivariate analysis; no SNP was associated with OS or PFS	[35]
49 SNPs in UGT1A9, UGT1A1, CYP3A4, CYP2B6, TNFA, VEGFA, IGF2, HIF1A	Intermediate stage HCC (n = 59) (Korean)	Sorafenib 400 mg twice daily in combination with TACE	Toxicity	VEGFA 1991-CC (OR: 45.68, P = 0.011), TNFA rs1800629-GG (OR:44.06, P = 0.023), and UGT1A9 rs7574296-AA (OR: 18.717, P = 0.015) were independent risk factors for the development of high-grade HFSR (multivariate analysis)	[36]
5 SNPs in ABCB1, ABCG2	Advanced HCC (n = 47) (Caucasians)	Sorafenib 400 mg twice daily	PK	ABCB1 rs2032582 (CT: 0.7 ± 0.6 kg/L vs TT:2.3 ± 2.2 kg/L, P = 0.035), ABCG2 rs2231137 (AG:0.8±0.4 kg/L vs GG:1.4 ± 1.5 kg/L, P = 0.02), ABCG2 rs2231142 (CA:0.5 ± 0.5 kg/L vs CC: 1.4 ± 1.4 kg/L, P = 0.007) heterozygous genotypes were associated with the lowest sorafenib plasma levels	[42]

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; BUN, blood urea nitrogen; Cr, creatinin; HCC, hepatocellular carcinoma; HFSR, hand–foot skin reaction; OR, odds ratio; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; SNP, single nucleotide polymorphism; vs, versus.