Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Table 3 Published works on germ-line variants and pharmacokinetics, toxicity, and efficacy of regorafenibin solid cancer patients

Pharmacogenetic panel	Study population	Therapy	Clinicalendpoint	Main findings	Ref.
3 SNPs in SLCO1B1, ABCG2	Advanced solid cancer (n = 37; no HCC) (Japanese)	Regorafenib	Toxicity	SLCO1B1*1b (rs2306283-G) allele was associated with lower incidences of increased grade ≥ 2 AST (8% vs 42%, P = 0.03) and anemia (16% vs 50%, P = 0.048); a similar tendency was observed for the incidence of increased grade ≥ 2 ALT (4% vs 25%, P = 0.09) and total bilirubin (12% vs 25%, P = 0.37); ABCG2 rs2231142 was associated with different blood platelet counts (Plt, CC: 29.4 ± 10.7 *104/μL, CA + AA: 21.4 ± 11.3*104/μL, P = 0.03)	[60]
3 SNPs in SLCO1B1, ABCG2	Advanced solid cancer (n = 28; no HCC) (Japanese)	Regorafenib	PK	SLCO1B1*5 (rs4149056-C) allele (17.3 [ng/mL]/mg vs 11.5 (ng/mL)/mg, P = 0.167) and SLCO1B1*1b (rs2306283-G/rs4149056-T) non-carriers (14.0 [ng/mL]/mg vs 12.1 (ng/Ml)/mg, P = 0.226) demonstrated a tendency toward higher concentration-to-dose ratio. Drug concentrations were higher in the group with grade ≥ 2 total bilirubin elevation (3.45 µg/mL vs 1.76 µg/mL, P = 0.01) and thrombocytopenia (3.45 µg/mL vs 1.76 µg/mL, P = 0.02) compared with the group with grades 0-1	[61]
Sequencing ofCYP34, UGT1A9	refractory mCRC (n = 93)1 (whites)	Regorafenib	Toxicity	UGT1A9*22 (rs383204-T10) allele was associated with acute hepatitis (descriptive study)	[57]
17 SNPs in VEGFA, VEGFC, FLT1 (VEGFR1), KDR (VEGFR2), FLT4 (VEGF3)	mCRC (n = 59) (whites)	Regorafenib	PFS OS DCR	Univariate analysisVEGFA rs2010963-CC vs to CG + GG genotype was associated with both longer OS (9.0 mo vs 6.5 mo, HR: 0.52, P = 0.049) and PFS (2.2 mo vs 1.8 mo, HR: 0.49, P = 0.0038); the same genotype was also associated with better DCR (progression rate, 47% vs 74%, P = 0.02); VEGFR2 rs1870377 (TT: 1.97 mo, AT: 1.84 mo, AA: 1.12 mo; P = 0.0061) and VEGFR3 rs307805 (AA: 1.91 mo, AG: 2.07 mo, GG: 2.3 mo; P = 0.0492) were associated with OS only; VEGFR1 rs664393 was associated with PFS only (CC: 2.01 mo, CT: 1.84 mo, TT: 1.48 mo; P < 0.0001); Multivariate analysisVEGFA rs2010963 (Exp(B): 2.77, P = 0.009) and ECOG performance status (Exp(B): 2.80, P = 0.004) were independent predictors of OS; the combination of these two parameters further stratified patients into three groups with progressively different OS (P < 0.0001); VEGFA rs2010963 was the only independent predictor of PFS (P = 0.005)	[63]
9 SNPs in CCL3, CCL4, CCL5, CCR5, PRKCD, KLF13, and HIF1A	mCRC (n = 79 Japanese patients–evaluation set; n = 150 Italian patients–validation set)	Regorafenib	PFS OS Toxicity	CCL4 rs1634517-CC and CCL3 rs1130371-GG were associated with longer PFS in the evaluation set (2.5 mo vs 2.0 mo, HR: 1.54, P = 0.043; 2.5 mo vs 2.0 mo, HR: 1.48, P = 0.064) and longer PFS (2.3 mo vs 1.8 mo, HR: 1.74, P < 0.001; 2.3 mo vs 1.8 mo, HR: 1.66, P = 0.002) and OS (7.9 mo vs 4.4 mo, HR: 1.65, P = 0.004; 7.9 mo vs 4.4 mo, HR: 1.65, P = 0.004) in the validation set; these associations were confirmed by multivariate analysis; in the evaluation set, the CCL5 rs2280789-GG genotype vs the A allele (12.9 mo vs 7.9 mo, HR: 0.45, P = 0.032) and the rs3817655-TT genotype respect to A allele (12.9 mo vs 7.9 mo, HR: 0.50, P = 0.055) was associated with longer OS by multivariate analysis; the analysis in the validation set was not possible because of the low SNP frequencies; in the evaluation set, the CCL5 rs2280789-GG genotype was associated with higher incidence of grade ≥ 3 HFRS compared to the A allele (53% vs 27%, P = 0.078), and similarly, the CCL5 rs3817655-TT genotype vs the A allele (56% vs 26%, P = 0.026); the same variants in addition to the CCL5 rs1799988 were also associated with different distribution by genotype of the incidence of grade ≥ 3 hypertension; in the validation set, the CCL5 rs2280789-G allele was associated with inferior incidence of grade ≥ 3 diarrhea vs AA genotype (0% vs 10%, P = 0.034) and KLF13 rs2241779-A allele with inferior incidence of grade ≥ 3 rash respect to CC genotype (10% vs 30%, P = 0.010); CCL3 rs1130371 and CCL4 rs1634517 were associated with different distributions by genotype of the incidence of grade ≥ 3 AST/ALT	[62]

¹Focused on 3 patients presented severe toxic hepatitis. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; DCR: Disease control rate; HCC: Hepatocellular carcinoma; HFSR: Hand–foot skin reaction; mo., months; OR: Odds ratio; OS: Overall survival; PFS: Progression-free survival; PK: Pharmacokinetic; SNP: Single nucleotide polymorphism.