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World Journal of
Gastroenterology
World J Gastroenterol 2019 August 7; 25(29): 3838-4042
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World Journal of
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Contents Weekly Volume 25 Number 29 August 7, 2019
EDITORIAL
3838 Healthy axis: Towards an integrated view of the gut-brain health
Boem F, Amedei A
3842 Hepatocellular carcinoma and metabolic syndrome: The times are changing and so should we
Tsoulfas G
OPINION REVIEW
3849 Improving cirrhosis care: The potential for telemedicine and mobile health technologies
Stotts MJ, Grischkan JA, Khungar V
3857 Lumen-apposing metal stents for malignant biliary obstruction: Is this the ultimate horizon of our
experience?
Anderloni A, Troncone E, Fugazza A, Cappello A, Blanco GDV, Monteleone G, Repici A
REVIEW
3870 Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma
De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F, D’Andrea M, Toffoli G
3897 Consensus on management of hepatitis C virus infection in resource-limited Ukraine and Commonwealth of
Independent States regions
Colombo MG, Musabaev EI, Ismailov UY, Zaytsev IA, Nersesov AV, Anastasiy IA, Karpov IA, Golubovska OA,
Kaliaskarova KS, AC R, Hadigal S
MINIREVIEWS
3920 Immunotherapy in colorectal cancer: Available clinical evidence, challenges and novel approaches
Tintelnot J, Stein A
3929 Hepatocellular carcinoma in the post-hepatitis C virus era: Should we change the paradigm?
Meringer H, Shibolet O, Deutsch L
ORIGINAL ARTICLE
Basic Study
3941 Honokiol-enhanced cytotoxic T lymphocyte activity against cholangiocarcinoma cells mediated by dendritic
cells pulsed with damage-associated molecular patterns
Jiraviriyakul A, Songjang W, Kaewthet P, Tanawatkitichai P, Bayan P, Pongcharoen S
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World Journal of Gastroenterology
Contents
Volume 25 Number 29 August 7, 2019
3956 Berberine prevents stress-induced gut inflammation and visceral hypersensitivity and reduces intestinal
motility in rats
Yu ZC, Cen YX, Wu BH, Wei C, Xiong F, Li DF, Liu TT, Luo MH, Guo LL, Li YX, Wang LS, Wang JY, Yao J
3972 LncRNA MEG3 acts a biomarker and regulates cell functions by targeting ADAR1 in colorectal cancer
Wang W, Xie Y, Chen F, Liu X, Zhong LL, Wang HQ, Li QC
Retrospective Cohort Study

3985 Liquid biopsy for non-invasive assessment of liver injury in hepatitis B patients
Xia WY, Gao L, Dai EH, Chen D, Xie EF, Yang L, Zhang SC, Zhang BF, Xu J, Pan SY
Retrospective Study
3996 Additional laparoscopic gastrectomy after noncurative endoscopic submucosal dissection for early gastric
cancer: A single-center experience
Tian YT, Ma FH, Wang GQ, Zhang YM, Dou LZ, Xie YB, Zhong YX, Chen YT, Xu Q, Zhao DB
Observational Study
4007 Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer
Bouché O, Ben Abdelghani M, Labourey JL, Triby S, Bensadoun RJ, Jouary T, Des Guetz G
SYSTEMATIC REVIEW
4019 Post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review for prevention and
treatment
Pekgöz M
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World Journal of Gastroenterology
Contents
Volume 25 Number 29 August 7, 2019
ABOUT COVER Editorial board member of World Journal of Gastroenterology, Herwig

Cerwenka, MD, Professor, Department of Surgery, Medical University of
Graz, Graz A-8036, Austria
AIMS AND SCOPE World Journal of Gastroenterology (World J Gastroenterol, WJG, print ISSN 1007-
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Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2019 August 7; 25(29): 3870-3896
DOI: 10.3748/wjg.v25.i29.3870 ISSN 1007-9327 (print) ISSN 2219-2840 (online)
REVIEW
Pharmacogenetics of the systemic treatment in advanced

hepatocellular carcinoma
Elena De Mattia, Erika Cecchin, Michela Guardascione, Luisa Foltran, Tania Di Raimo, Francesco Angelini,
Mario D’Andrea, Giuseppe Toffoli
ORCID number: Elena De Mattia Elena De Mattia, Erika Cecchin, Michela Guardascione, Tania Di Raimo, Francesco Angelini,
(0000-0003-4948-8767); Erika Giuseppe Toffoli, Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico
Cecchin (0000-0001-7517-7490); di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
Michela Guardascione
(0000-0001-5052-3502); Luisa Foltran Luisa Foltran, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano
(0000-0002-2313-2247); Tania Di (CRO) IRCCS, Aviano (PN) 33081, Italy
Raimo (0000-0002-2896-8211);
Francesco Angelini Tania Di Raimo, Francesco Angelini, Medical Oncology and Anatomic Pathology Unit, “San
(0000-0002-0052-6956); Mario Filippo Neri Hospital”, Rome 00135, Italy
Rosario D'Andrea
(0000-0003-4585-7473); Giuseppe Mario D’Andrea, Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
Toffoli (0000-0002-5323-4762).
Corresponding author: Elena De Mattia, PhD, Clinical and Experimental Pharmacology,
Author contributions: De Mattia E Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy. ede-
performed the literature review [email protected].
and analysis, contributed to
writing the manuscript, and
Telephone: +39-434-659765
elaborated the tables; Cecchin E Fax: +39-434-659799
conceptualized and edited the
manuscript; Guardascione M,
Foltran L and D’Andrea M
contributed to writing the Abstract
manuscript; Di Raimo T and
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver
Angelini F contributed to writing
the manuscript and elaborated the cancers. To date, most patients with HCC are diagnosed at an advanced tumor
figures; and Toffoli G was the stage, excluding them from potentially curative therapies (i.e., resection, liver
guarantor. All authors reviewed transplantation, percutaneous ablation). Treatments with palliative intent include
the manuscript. chemoembolization and systemic therapy. Among systemic treatments, the
small-molecule multikinase inhibitor sorafenib has been the only systemic
Supported by the European
Union’s Horizon 2020 Research treatment available for advanced HCC over 10 years. More recently, other small-
and Innovation Programme, No. molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have
668353. been approved for HCC treatment. The promising immune checkpoint inhibitors
(e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in
Conflict-of-interest statement: The the US nivolumab has already been approved by FDA in sorafenib refractory or
authors declare no conflict of
interest.
resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g.,
palbociclib, ribociclib), are in earlier stages of clinical development, and the c-
Open-Access: This article is an MET inhibitor tivantinib did not show positive results in a phase III study.
open-access article which was However, even if the introduction of targeted agents has led to great advances in
selected by an in-house editor and patient response and survival with an acceptable toxicity profile, a remarkable
fully peer-reviewed by external
reviewers. It is distributed in
inter-individual heterogeneity in therapy outcome persists and constitutes a
accordance with the Creative significant problem in disease management. Thus, the identification of
Commons Attribution Non biomarkers that predict which patients will benefit from a specific intervention
Commercial (CC BY-NC 4.0) could significantly affect decision-making and therapy planning. Germ-line
license, which permits others to
WJG https://www.wjgnet.com 3870 August 7, 2019 Volume 25 Issue 29

De Mattia E et al. Pharmacogenetic markers of HCC therapy outcome
distribute, remix, adapt, build variants have been suggested to play an important role in determining outcomes
upon this work non-commercially, of HCC systemic therapy in terms of both toxicity and treatment efficacy.
and license their derivative works
on different terms, provided the
Particularly, a number of studies have focused on the role of genetic
original work is properly cited and polymorphisms impacting the drug metabolic pathway and membrane
the use is non-commercial. See: translocation as well as the drug mechanism of action as predictive/prognostic
http://creativecommons.org/licen markers of HCC treatment. The aim of this review is to summarize and critically
ses/by-nc/4.0/ discuss the pharmacogenetic literature evidences, with particular attention to
Manuscript source: Invited sorafenib and regorafenib, which have been used longer than the others in HCC
manuscript treatment.
Received: March 17, 2019 Key words: Hepatocellular carcinoma; Pharmacogenetics; Genetic markers; Sorafenib;
Peer-review started: March 18, 2019 Regorafenib; Immune checkpoint inhibitors; Cytochromes; UDP glucuronosyltransferase
First decision: May 14, 2019 1A
Revised: May 23, 2019
Accepted: July 1, 2019
Article in press: July 3, 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Published online: August 7, 2019
Core tip: Patients with advanced hepatocellular carcinoma (HCC) have few effective
P-Reviewer: Jin B, Luo GH, Patel therapeutic options. Although multikinase inhibitors-such as sorafenib as first-line
JN, Sun JH, Sun XT, Wang GY treatment and regorafenib in sorafenib progressors-show some overall survival benefit,
S-Editor: Gong ZM unmet needs persist in the treatment of advanced HCC. Particularly, the identification of
L-Editor: A
potential prognostic and predictive biomarkers for better stratifying and personalizing the
E-Editor: Ma YJ
treatment remains a challenge. Germ-line polymorphisms have been suggested to
contribute significantly to inter-individual variability in HCC therapy outcome in terms
of both toxicity and effectiveness, opening new avenues for pharmacogenetic
investigation.
Citation: De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F,

D’Andrea M, Toffoli G. Pharmacogenetics of the systemic treatment in advanced
hepatocellular carcinoma. World J Gastroenterol 2019; 25(29): 3870-3896
URL: https://www.wjgnet.com/1007-9327/full/v25/i29/3870.htm
DOI: https://dx.doi.org/10.3748/wjg.v25.i29.3870
INTRODUCTION
Liver cancer incidence is approximately 850000 new cases per year, and about 90% of
liver tumors are hepatocellular carcinoma (HCC)[1]. The dominant risk factors for
HCC vary worldwide. For most countries in Asia and Africa, hepatitis B virus
infection and aflatoxin B1 exposure are the major risk factors. In contrast, hepatitis C
virus infection, alcoholism, and metabolic syndrome play more important roles in
other areas in the world[2]. The Barcelona Clinic Liver Cancer (BCLC) staging is the
main clinical classification that stratifies patients from A to C stages, according to
prognosis, to inform treatment decisions. Early-stage cancers are potentially suitable
for therapies with curative intent such as surgical resection, liver transplantation, or
local ablation. Chemoembolization and systemic therapy represent the only
therapeutic options for intermediate or advanced HCC[1].
Surgical resection is the standard option for patients with solitary HCC at BCLC A
stage. Other criteria for selecting the best surgical candidates are absence of portal
hypertension along with well-preserved liver function. A surgical strategy is
associated with 5-year survival rates of 70%, and adjuvant therapies have yet to show
a survival advantage[1]. Liver transplantation is the best option for BCLC A tumors
with respect to Milan criteria (single tumor ≤ 5 cm or up to three nodules ≤ 3 cm in
size and no vascular invasion)[3]. Furthermore, local ablation with radiofrequency
represents a good alternative to surgery in patients with single tumors < 2 cm[4];
however, no randomized clinical trials (RCTs) have been conducted to specifically
address whether ablation is non inferior to surgery[5].
For patients with HCC at BCLC B stage, transarterial chemoembolization (TACE) is
recommended based on results from RCTs and a systematic review showing survival
benefits with TACE as compared with the best supportive care[6]; more recently TACE
was found to give an objective response of 52.5%[7]. Better selection of candidates and
improvement in the procedure, such as supra-selective embolization and the use of
drug-eluting beads, have led to median survival times beyond 40 mo in referral

centers[1]. Radioembolization is an alternative embolization approach with a favorable

safety and efficacy profile, but well-designed, properly powered RCTs are still needed
to demonstrate a real benefit[1].
In advanced HCC or in intermediate HCC when chemoembolization is no longer
indicated, systemic treatment is the standard therapy. Conventional chemo-
therapeutic agents (e.g., doxorubicin, fluoropyrimidines, platinum derivates,
irinotecan) are minimally effective in HCC, with significant toxicity, and do not
improve patient survival[8-10]. HCC is also rarely amenable to radiation therapy[10].
Targeted agents based on an improved molecular characterization of HCC have
opened a new era for the treatment of patients with HCC (Figure 1). A number of
small-molecule tyrosine kinase inhibitors and immune checkpoint inhibitors have
demonstrated some survival benefit in intermediate/advanced disease (BCLC B-C);
more recently, preliminary promising data are emerging on the use of CDK4
/6inhibitors [11] . At present, the approved drugs in Europe for advanced HCC
indication are the small-molecule multikinase kinase inhibitors sorafenib, lenvatinib,
regorafenib, and cabozantinib. In particular, sorafenib and lenvatinib are approved as
first-line therapy and regorafenib and cabozantinib in patients who have progressed
or are intolerant to sorafenib. Other molecules, such as the immune checkpoint
inhibitors (e.g., nivolumab, pembrolizumab) and selective CDK4/6inhibitors (e.g.,
palbociclib, ribociclib), are still under investigation in the HCC setting in Europe
while in the US nivolumab received accelerated approval for HCC patients previously
treated with sorafenib. Among other molecules tested, the c-MET inhibitor tivantinib
has not shown positive results[12].
Based on the results of major studies conducted to date, several unmet needs
persist in the management of intermediate/advanced HCC that might be addressed
through new therapies and biomarkers for therapy stratification and a patient-tailored
approach. In this context, genetic polymorphisms, with their well-established role in
liver carcinogenesis[13,14], could be important and contribute, in combination with
clinical and molecular parameters, to predicting HCC therapy outcomes for efficacy
and for toxicity risk. The aim of this review is to critically report and discuss current
literature on the effect of germ-line variants as predictive markers of HCC systemic
therapy outcome and how they can aid in stratifying patients according to toxicity
risk, as well as the likelihood of benefit from administration of specific anti-tumor
agents.
SYSTEMIC TREATMENT OF ADVANCED HCC

The phase III SHARP trial evaluating sorafenib in previously untreated patients with
advanced HCC reported a median overall survival (OS) of 10.7 mo for the sorafenib-
treated group compared to 7.9 mo in patients who received placebo[15]. The most
common adverse effects observed in the trial included fatigue, hand–foot skin
reaction (HFSR), alopecia, gastrointestinal, and liver dysfunction. A number of studies
have investigated the role of clinical and/or biological markers in HCC patients
treated with sorafenib[15,16]. Results from the SHARP trial showed that baseline alpha
fetoprotein plasma levels > 200 ng/mL had a negative impact on OS, a finding that
has been recently confirmed in a pooled analysis [17] . A recent meta-analysis
demonstrated that the occurrence of sorafenib-related side effects (e.g., hypertension,
skin toxicities, and diarrhea) is associated with a better OS in sorafenib-treated HCC
patients[18]. In addition to the abovementioned markers, other clinical parameters have
been evaluated, such as macroscopic vascular invasion, BCLC stage and etiology of
cirrhosis[17], and Child–Pugh subgroups[19]. Some biological markers have been also
suggested as potentially related to sorafenib outcome. For instance, in the SHARP
trial [15] , baseline angiopoietin-2 (Ang-2) and vascular endothelial growth factor
(VEGF)-A plasma levels independently predicted survival in the entire patient
population and in the placebo cohort; conversely, none of the tested biomarkers
significantly predicted response to sorafenib[15]. Additionally, high insulin-like growth
factor 1 pre-treatment levels are associated with better progression-free survival (PFS)
and OS in patients with advanced HCC receiving first-line antiangiogenic therapy[20].
More recently, a study recruiting 80 HCC patients prospectively treated with
sorafenib showed that independent risk factors for poor OS were high serum
concentration of Ang-2 and hepatocyte growth factor (HGF) as well as poor
performance status before treatment[21].
In patients who tolerated but progressed on sorafenib, the other multikinase
inhibitor regorafenib has been reported to provide an OS benefit compared with
placebo of 10.6 mo vs 7.8 mo. The most common grade 3 or 4 treatment-related events
were hypertension, HFSR, fatigue, and diarrhea[22]. Preliminary data on potential

Figure 1
Figure 1 Mechanisms of action of the drugs covered in the text. Approved drugs are in the orange box while those under approval are in the grey box. Image
created with Servier Medical Art (https://smart.servier.com/). FGFR1: Fibroblast growth factor receptor; PDGFR: Platelet-derived growth factor receptor; FLT3: Fms-
related tyrosine kinase 3; VEGFR: Vascular endothelial growth factor receptor; TIE: Tyrosine kinase with immunoglobulin-like and EGF-like domains; HGFR:
Hepatocyte growth factor receptor; PD1: Programmed cell death protein-1; PDL1/2: programmed cell death protein ligand 1/2; CDK: Cyclin-dependent kinases.
biomarkers of response to regorafenib in patients with HCC have been recently

published. Particularly, a study involving a large cohort of patients enrolled in the
phase III RESORCE trial showed a significant association of OS with plasma
concentrations of some proteins involved in inflammation and/or HCC pathogenesis
as well as a number of plasma miRNAs. In addition, a somatic profile of tumor tissues
was described that suggested a potential mutational pattern associated with response
to regorafenib[23].
More recently, a phase III trial comparing lenvatinib to sorafenib in the first-line
setting showed non-inferiority of lenvatinib to sorafenib for the primary endpoint OS
and statistically significant improvement for secondary end-point PFS. The most
common any-grade adverse events described for lenvatinib were hypertension,
diarrhea, and appetite and weight reduction. In addition, there were fewer
dermatological adverse events but more hypertension for lenvatinib compared to
sorafenib [24] . Finally, the small-molecule multikinase inhibitor cabozantinib was
associated with longer OS than placebo in a phase III trial involving patients already
treated for advanced disease. In that study, incidence of grade 3 or 4 adverse events
was higher (predominantly grade 3) in the cabozantinib arm, including
palmar–plantar erythrodysesthesia and HFSR, hypertension, increased aspartate
aminotransferase (AST), fatigue, and diarrhea[25].
Other molecules not yet approved in Europe for the treatment of liver cancer are
under investigation in the HCC setting, with promising preliminary results.
Particularly, the novel class of immune checkpoint inhibitors has demonstrated
significantly improved survival outcomes for patients with HCC. A phase I/II study
trial investigated the role of the immunotherapeutic agent nivolumab in patients
whose disease progressed while receiving at least one previous line of systemic
therapy, including sorafenib, or who were intolerant to sorafenib. In this trial 262
eligible patients were treated, 48 in the dose-escalation phase and 214 in the dose-
expansion phase. During dose escalation, 12 (25%) patients had grade 3 or 4 adverse
events while 3 (6%) patients had serious adverse events (i.e., pemphigoid, adrenal
insufficiency, liver disorder); the objective response rate was 15% (95%CI: 6%-28%).
For dose expansion, the objective response rate was 20% (95%CI: 15%-26%) with
nivolumab 3 mg/kg[26]. Based on the results of this study, the U.S. Food and Drug
Administration (FDA) granted accelerated approval of nivolumab on September 2017.
A phase III randomized trial of first-line nivolumab compared with sorafenib is
ongoing (ClinicalTrials.gov Identifier: NCT02576509). Another phase II trial focused

on another immune checkpoint inhibitor, pembrolizumab, in patients with HCC pre-

treated with sorafenib. These results showed that pembrolizumab was effective and
tolerable, with fatigue and increased AST as the most frequent adverse events[27].
Several phase II/III clinical trials with immunotherapeutic agents are currently
recruiting HCC patients worldwide. One is an ongoing phase III randomized, active-
controlled trial to evaluate the safety and efficacy of lenvatinib in combination with
pembrolizumab compared with lenvatinib plus placebo in first-line therapy for
advanced HCC (ClinicalTrials.gov Identifier: NCT03713593). A phase II trial with
sorafenib and nivolumab as first-line therapy is also in progress (ClinicalTrials.gov
Identifier: NCT03439891).
Among the molecules at an earlier stage of clinical development in HCC, the
selective CDK4/6 inhibitors stand out. In an early trial, palbociclib demonstrated
activity in patients with advanced HCC after failure of first-line sorafenib. This trial
enrolled 21 patients, 4 being non-evaluable. In evaluable patients median OS was 19
wk and median time to progression was 24 wk; prolonged stability was seen in 3
patients. The most common grade 3 or 4 adverse events were neutropenia and
thrombocytopenia, and non-serious adverse events were anemia, pain, ascites, and
fatigue[11]. A phase Ib/II study of another CDK4/6 inhibitor, ribociclib, in association
with chemoembolization in advanced HCC is currently recruiting patients
(ClinicalTrials.gov Identifier: NCT02524119).
Another molecule under investigation that should be cited for completeness is
tivantinib, a selective inhibitor of the proto-oncogene MET, belonging to the class of
the small-molecule kinase inhibitors. A phase II randomized trial evaluated the
administration of tivantinib as the second-line therapy for patients with HCC. The
study showed improved PFS for tivantinib compared with placebo in a subset of
patients with high MET expression tumors, and the most common grade 3 or worse
adverse events in the tivantinib group were neutropenia and anemia [28] . On 13
November 2013, orphan designation (EU/3/13/1202) was granted for tivantinib for
the treatment of HCC in patients whose disease has stopped responding or is resistant
to sorafenib. However, a subsequent phase III trial evaluating the use of tivantinib for
second-line treatment of MET-high expressing advanced HCC showed no OS
improvement for tivantinib compared with placebo in patients previously treated
with sorafenib[12].
PHARMACOGENETICS OF APPROVED DRUGS

Sorafenib
Sorafenib (NEXAVAR®) is an orally administered multi-targeted tyrosine kinase
inhibitor. This small molecule inhibits a number of serine/threonine and tyrosine
kinases [e.g., VEGF receptors (VEGFR1–3), platelet-derived growth factor receptor
(PDGFR), fibroblast growth factor receptor 1 (FGFR1), KIT proto-oncogene receptor
tyrosine kinase (KIT), ret proto-oncogene (RET], and fms-related tyrosine kinase 3
(FLT3)] and downstream oncogenic Raf signaling players (e.g., Raf-1 and B-Raf). Thus,
it affects multiple tumor-related signaling pathways, such as those involved in
angiogenesis, tumor proliferation, and cell apoptosis [29,30] . Although survival
improvement has been achieved with this targeted agent, only a limited number of
patients have experienced a real and long-term benefit. Moreover, a high resistance
rate and some significant and expensive toxicities further restrict the advantages of
sorafenib therapy and constitute a crucial problem in HCC management.
In recent years, some pharmacogenetic studies have focused on identifying genetic
markers that could predict risk for severe adverse events (Table 1) and discriminate
sorafenib-responsive patients from non-responders (Table 2). Details regarding the
pharmacogenetic panel analyzed, the study population (e.g., sample size, ethnicity)
and therapy (e.g., dose and schedule) characteristics, the clinical end-points evaluated
along with the main findings (e.g., statistical results) of the studies are shown in
Tables 1 and 2.
Markers of pharmacokinetics/toxicity: (1) Sofarenib metabolism: The metabolism[29,30]

of sorafenib is well-established and occurs mainly in the liver through two pathways:
Phase I oxidation mediated by cytochrome P450 3A4 (CYP3A4), and phase II
conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9) (Figure 2). In
people, specifically, the glucuronidation contributes to about 15% of the clearance of
sorafenib while the oxidation accounts for only 5%. Eight metabolites of sorafenib
have been identified (M1–M8). The most abundant in the plasma is sorafenib N-oxide
(M2), which is produced by CYP3A4 and exhibits an in vitro potency similar to the
parental drug. M2 together with the sorafenib derivatives M4, obtained by

Table 1 Published works on germ-line variants and pharmacokinetic and toxicity profiles of sorafenib in hepatocellular carcinoma patients
Pharmacogenetic Study population Therapy Clinical Main findings Ref.

panel endpoint
[32]
CYP3A4*1, CYP3A5*3, Advanced HCC Sorafenib Toxicity Rat models: CYP3A4*1 (rs2740574) and CYP3A5*3 (rs776746) were associated with the lowest (8 ± 2.5 ng/mL) and highest (67 ± 4.8
CYP2C19*2, (n = 51) ng/mL) levels of sorafenib plasma concentration, respectively (P < 0.001). CYP3A5*3 correlated with the most severe liver [change in ALT
CYP2D6*10 (Chinese) 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)
Aflatoxin-induced Clinical setting: CYP3A5*3 was associated with increased severe hepatic toxicity (change in ALT and AST blood concentration [IU/L]
HCC rat models over time, P < 0.001)
(n = 105)
[34]
9 SNPs in CYP3A5, Advanced solid cancer Sorafenib 400 PK UGT1A9 rs17868320-T allele was associated with increased grade ≥ 2 diarrhea (OR: 14.33, P = 0.015, multivariate analysis)
UGT1A9, ABCB1, (n = 54; 37% HCC) or 200 mg,
ABCG2 (whites) twice daily Toxicity
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
WJG|http://www.wjgnet.com
univariate analysis, not confirmed in multivariate)
[35]
8 SNPs in SLCO1B1, Advanced solid cancer Sorafenib Toxicity UGT1A1*28 (rs8175347) was associated with increased risk of acute hyperbilirubinemia (*28/*28 vs other, OR:5.413, P = 0.016) and of
SLCO1B3, ABCC2, (n = 114; 87% HCC) interrupting treatment (*28 vs other, OR: 3.397, P = 0.002) by multivariate analysis. The *28 allele also showed a trend towards a higher
ABCG2, UGT1A1, risk for any toxicity at grade 3 or higher (P = 0.088)
UGT1A9 (mainly whites) PFS
OS 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
3875
No SNP was associated with OS or PFS
[36]
49 SNPs in UGT1A9, Intermediate stage Sorafenib 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)
UGT1A1, CYP3A4, HCC (n = 59) 400 mg twice were independent risk factors for the development of high-grade HFSR (multivariate analysis).
CYP2B6, TNFA, daily in
VEGFA, IGF2, HIF1A (Korean) combination
with TACE
[42]
5 SNPs in ABCB1, Advanced HCC Sorafenib 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 (n = 47) 400 mg twice 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
(Caucasians) daily plasma levels
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.
August 7, 2019|Volume 25|Issue 29|

Table 2 Published works on germ-line variants and response to sorafenib in hepatocellular carcinoma patients
Pharmacogenetic panel Study Therapy Clinical Main findings Ref.

population endpoint
[48]
17 SNPs in VEGFA, VEGFC, FLT1 Advanced or Sorafenib 400 PFS Univariate analysis
(VEGFR1), KDR (VEGFR2), FLT4 (VEGF3) intermediate- mg, twice
stage HCC (n = daily
148)
(whites) OS 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
(ALICE-1) Objective
Response
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 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
3876
response
[50]
18 SNPs in KDR (VEGFR2) Advanced HCC First-line TTP Univariate analysis
(n = 78) sorafenib
(Chinese) 400, mg twice OS 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
daily with longer TTP
Response
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
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

[51]
3 SNPs in eNOS Advanced HCC First-line PFS Univariate analysis
(n = 41 training sorafenib 400 OS Training set
set; n = 87 mg, twice
validation set daily
(whites) 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
eNOS haplotype HT1 is confirmed as the only independent prognostic factor
** “4a” allele with 4 repeats; “4b” allele with 5 repeats
[52]
9 SNP in ANG2 HCC (n = 158) Sorafenib PFS 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
(whites) OS OS: 16.9 mo vs 6.5 mo, p = 0.016) with respect to the T-allele. Data were confirmed in multivariate analysis
[49]
8 SNPs in HIF1A HCC (n = 210) Sorafenib PFS Univariate analysis
(whites) OS 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)
(ALICE-2)
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
3877
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)
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.

Table 3 Published works on germ-line variants and pharmacokinetics, toxicity, and efficacy of regorafenibin solid cancer patients
Pharmacogenetic Study Therapy Clinical Main findings Ref.

panel population endpoint
[60]
3 SNPs in SLCO1B1, Advanced 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
ABCG2 solid cancer (n = 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).
= 37; no HCC)
(Japanese)
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)
[61]
3 SNPs in SLCO1B1, Advanced 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
ABCG2 solid cancer (n (ng/mL)/mg vs 12.1 (ng/mL)/mg, P = 0.226] demonstrated a tendency toward higher concentration-to-dose ratio
= 28; no HCC)
(Japanese)
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
[57]
Sequencing ofCYP34, refractory Regorafenib Toxicity UGT1A9*22 (rs383204-T10) allele was associated with acute hepatitis (descriptive study)
UGT1A9 mCRC
(n = 93)1
(whites)
[63]
17 SNPs in VEGFA, mCRC (n = Regorafenib PFS Univariate analysis
VEGFC, FLT1 (VEGFR1), 59)
KDR (VEGFR2), FLT4 (whites) OS VEGFA 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,
(VEGF3) HR: 0.49, P = 0.0038). The same genotype was also associated with better DCR (progression rate, 47% vs 74%, P = 0.02)
DCR
3878
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)
VEGFA 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).
[62]
9 SNPs in CCL3, CCL4, mCRC (n = Regorafenib PFS 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
CCL5, CCR5, PRKCD, 79 Japanese 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,
patients– 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
KLF13, and HIF1A evaluation set; OS
n = 150 Italian Toxicity 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
patients– 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
validation set) 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
1
Focused 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.

demethylation, and M5, an oxidative metabolite, inhibit VEGFR and PDGFR signaling
and members of the MAPK pathway. Given the key role of CYP3A4 and UGT1A9 in
sorafenib metabolism, inducers or inhibitors of these enzymes, such as some foods
and co-administered drugs (e.g., carbamazepine, dexamethasone, phenobarbital,
phenytoin, rifampin, rifabutin, St. John’s wort), could modify bioavailability of the
agent. Moreover, even if sorafenib is not a substrate for the cytochrome isoforms
CYP2B6, CYP2C8, and CYP2C9 and the UDP glucuronosyltransferase UGT1A1, the
biological agent in vivo inhibits activity of these enzymes with potential
pharmacological consequences and drug-interaction events. Membrane translocation
of sorafenib and its metabolites, including the inactive sorafenib-glucuronide (SG)
derivative, has been reported to be carried out by the coordinated activity of ATP-
binding cassette (ABC) and solute carrier (SLC) transporters, not yet all identified[31]
(Figure 2). An enterohepatic recirculation of sorafenib has specifically been
suggested[31]; according to this hypothesis, the drug glucuronide-conjugated SG is
extensively extruded from the hepatocytes into the bile through a process mediated
mainly by the multidrug resistance protein (MRP) 2 (encoded by ABCC2). However,
under physiological conditions, a considerable fraction of intracellular SG can also be
secreted back into the blood by some sinusoidal transport mechanisms, including
MRP3 (encoded by ABCC3). From the circulation, downstream hepatocytes can
efficiently take up SG again via the organic anion transporter family member 1B
(OATP1B1 and OATP1B3, encoded by SLCO1B1 and SLCO1B3)-type carriers,
resulting in only low SG concentrations reaching the general circulation. This
secretion-and-reuptake loop may help prevent saturation of MRP2-mediated biliary
SG secretion in hepatocytes located upstream within liver lobules, resulting in more
efficient drug detoxification. Once secreted into the bile, SG enters the intestinal
lumen, where it can be a substrate for bacterial β-glucuronidases that regenerate the
parental drug sorafenib. This sorafenib can then undergo intestinal absorption, thus
reentering the circulation. This ongoing enterohepatic recirculation of sorafenib has
been inferred to contribute to the long-lasting sorafenib plasma levels observed in
patients. In addition to these transporters, preclinical in vitro studies have identified
other membrane carriers that might translocate sorafenib and its metabolites, such as
the hepatic uptake pump organic cation transporter-1 (OCT1, encoded by SLC22A1)
and the efflux transporters P-glycoprotein (p-gp or MDR1, encoded by ABCB1) and
breast cancer resistance protein (BCRP, encoded by ABCG2)[30].
Functional polymorphic variants in genes encoding the phase I and II enzymes and
ABC/SLC transporters involved in the sorafenib pathway have been described and
could contribute to the inter-individual variability in the pharmacokinetics and
toxicity profile observed in patients treated with sorafenib. Some studies have
evaluated the role of genetic polymorphisms in predicting the bioavailability and
toxicity of sorafenib administered to patients with HCC (Table 1). The most consistent
data concern the predictive contribution of germ-line genetic variants in the oxidative
and glucuronidative pathways on outcome with sorafenib.
(2) Oxidation pathway: Guo et al [32] recently focused on some CYP450 poly-
morphisms. In preclinical aflatoxin-induced HCC rat models, CYP3A4*1B (rs2740574;
located in the 5’ untranslated region [5’UTR]) and CYP3A5*3 (rs776746; located in the
intron 3) variants were associated with the lowest and highest sorafenib plasma
concentrations, respectively. This difference in drug disposition was consistent with a
different toxicity risk; CYP3A5*3-carrier rats had the most severe liver (measured as a
change in alanine aminotransferase [ALT] and AST blood concentration [IU/L] over
time) and renal (measured as a change in blood urea nitrogen [nmol/L] and creatinin
[umol/L] blood concentration [IU/L] over time) injury, whereas CYP3A4*1-carrier
rats had the mildest toxicity outcome. This author group analyzed other CYP family
genetic variants in the same study, using additional engineered rat models. Carriers of
CYP2C19*2 (rs4244285; Pro227Pro) or CYP2D6*10 (rs1065852, Pro34Ser) had sorafenib
plasma levels and associated liver/renal toxicity that were intermediate between
those of rats carrying CYP3A5*3 or CYP3A4*1 genetic variants[32]. This preclinical
observation on rat models was confirmed in a small group of Chinese patients with
advanced hepatitis B and C viral-associated HCC treated with sorafenib. In these
patients, the CYP3A5*3 polymorphism was associated with rapid worsening of
hepatic damage, but CYP3A4*1 carriers showed only a small effect. The findings
therefore suggested that the CYP3A5*3 variant that determines decreased CYP3A5
enzymatic activity[33] could influence hepatic and renal exposure to sorafenib, with
severe associated damage.
(3) Glucuronidation pathway: Other investigations generated positive preliminary
data on the predictive contribution of genetic variants in the glucuronidation pathway
on sorafenib treatment outcome [34-36] . A study in a cohort of white patients with
advanced solid cancer, including HCC, identified the rs17868320 variant in the
promoter region of the UGT1A9 gene as a predictive factor for grade ≥ 2 diarrhea

Figure 2
Figure 2 Schematic overview of sorafenib metabolism. Briefly, after oral administration, sorafenib enters hepatocytes by anion transporter family member
(OATP1B, encoded by SLCO1B)-type carriers and cation transporter-1 (OCT1, encoded by SLC22A1). Within the hepatocytes, sorafenib undergoes phase I
cytochrome P450 3A4 (CYP3A4)- and phase II UDP glucuronosyltransferase 1A9 (UGT1A9)-mediated metabolism to form M1-8 metabolites and sorafenib
glucuronide (SG). After conjugation, SG is extensively secreted into the bile by a process that is mainly mediated by multidrug resistance protein (MRP) 2 (encoded by
ABCC2) and breast cancer resistance protein BCRP (encoded by ABCG2) and into the bloodstream by MRP3 (encoded by ABCC3). A fraction of SG enters the
intestinal lumen, where it could be a substrate for bacterial β-glucuronidases (B-GLU) that regenerate the parental drug sorafenib, which reenters the systemic
circulation through the OATP1B3 carrier. CYP2B6, CYP2C8, CYP2C9, and UGT1A1 may interfere with sorafenib metabolism, being inhibited by sorafenib (see text for
details). Image created with Servier Medical Art (https://smart.servier.com/).
occurrence. Carriers of the polymorphic rs17868320-T allele were exposed to a higher

toxicity risk, without any impact on systemic drug exposure[34]. To explain this result,
the authors suggested that the increased intestinal expression of UGT1A9, linked to
the rs17868320 polymorphism[37,38], could cause a higher glucuronidation rate of the
sorafenib metabolite M6. M6 is the major sorafenib derivative found in the feces, and
when it is converted by UGT1A9 to the glucuronidated form, it exerts a damaging
action on enterocytes, provoking diarrhea. The discovery of novel predictive factors of
sorafenib-induced diarrhea is of particular interest, not only for the effect on patient
quality of life but also for a potential interference with oral absorption of the drug,
leading to decreased anti-tumor efficacy.
Results of another study involving Korean patients with intermediate-stage HCC
receiving sorafenib in combination with TACE suggested that the genetic
polymorphisms in UGT1A9 could also influence the development of HFSR[36]. This
common side-effect shows an ethnicity-specific incidence (i.e., higher incidence in
Asian trials compared with Western trials) and can affect treatment efficacy, causing
dose reduction or treatment discontinuation[36]. Particularly, the A allele of the intronic
variant UGT1A9 rs7574296, whose functional impact is not yet known[39], is associated
with increased HFSR risk. This preliminary result is of great clinical interest because
early detection of patients at risk for HFSR would allow for continuation of life-
prolonging therapy with minimal morbidity. Positive data also have been reported for
an additional UGT1A isoform, UGT1A1, and its promoter polymorphism UGT1A1*28
(rs8175347). A study involving predominantly white patients with advanced solid
tumor, mostly HCC, identified the UGT1A1*28 variant as a clinically significant
predictive factor in hyperbilirubinemia risk during the first 2 months of sorafenib
treatment and consequently of treatment interruption risk[35]. The UGT1A1*28 allele
also showed a trend to increased risk of developing any kind of toxicity of grade 3 or
higher. These results are consistent with a previous case report reporting severe
unconjugated hyperbilirubinemia in a sorafenib-treated patient carrying one
UGT1A1*28 polymorphic allele[40]. This genetic variant is associated with a remarkable
reduction in bilirubin glucuronidation activity of the UGT1A1 enzyme, leading to
significantly increased bilirubin concentrations[14], and also sorafenib inhibits the same
enzyme UGT1A1 [41] . Thus, use of sorafenib in patients who are homozygous for
UGT1A1*28 could lead to acute hyperbilirubinemia and a related risk of treatment
interruption. Clinicians might need to be aware of their patient’s UGT1A1*28 status to

adequately consider sorafenib therapy in cases of hereditary genetic predisposition to

hyperbilirubinemia development (e.g., patients with Gilbert’s syndrome)[40].
(4) Transporter mechanism: Genetic variants in the sorafenib transporter
mechanism also appear to influence drug availability and toxicity risk, although data
are quite preliminary. Particularly, some exploratory studies involving white patients
with advanced solid cancer, including HCC, and receiving sorafenib reported an
association of some functionally relevant genetic variants in ABCG2, ABCB1, and
SLCO1B1 genes with sorafenib pharmacokinetics and pharmacodynamics[34,35,42]. The
TT genotype for the intronic ABCG2 rs2622604 polymorphism was associated with
decreased protein expression[43], and patients treated with sorafenib and carrying the
TT genotype showed a tendency toward higher drug exposure at the plasma level.
This tendency was not, however, confirmed in the multivariate analysis probably
because of the small population[34]. Tandia and colleagues also reported an impact of
ABCG2 variants on sorafenib bioavailability[42]. In their analysis, the heterozygous
genotypes of ABCG2 rs2231137 (Val12Met), ABCG2 rs2231142 (Lys141Gln), and
ABCB1 rs2032582 (lle1145Ile) polymorphisms were associated with lower drug
plasma levels in comparison to the wild-type genotype carriers. Another group
focused instead on sorafenib-related toxicity and reported significant differences in
toxicity incidence according to two SLCO1B1 polymorphisms that alter the transport
activity of OATP1B1 in a substrate-specific manner [44] : SLCO1B1 rs2306283 (*1b,
Asn130Asp) and SLCO1B1-rs4149056 (*5, Val174Ala). Patients carrying at least one
SLCO1B1*1b (rs2306283-G) allele showed a reduced incidence of diarrhea and
increased risk for hyperbilirubinemia; patients with the SLCO1B1*5 (rs4149056-C)
allele were more likely to develop thrombocytopenia, but only in a univariate and not
in a multivariate model[35].
For background, we note that variants in MRP2- and OCT1-encoding genes also
have been suggested to modulate sorafenib bioavailability and related adverse
reactions, although mostly in other cancers. Studies performed in cancer settings other
than HCC reported a significant involvement in the modulation of sorafenib plasma
level and toxicity risk (e.g., erythema) for the promoter variant rs717620 in the ABCC2
gene (encoding MRP2)[45,46]. Particularly, a preliminary investigation, which involved
mainly white patients (n=120) with solid cancer receiving sorafenib, suggested that
the ABCC2 rs717620-TT polymorphic genotype was associated with the lowest
sorafenib plasma concentration (i.e., AUC, area under the curve) compared with CT or
CC genotype; interestingly this polymorphism seemed to modify AUC phenotype
only in patients with UGT1A1*28/*28 status. Another study, including 55 Japanese
patients with advanced renal cell carcinoma treated with sorafenib, indicated that the
ABCC2 rs717620-CC genotype was associated with significantly increased risk of
developing grade 3 or higher HFSR respect to CT genotype (35 vs. 0%, P=0.032). For
what concerns OCT1 genetic variants, an ex vivo investigation of HCC tumor samples
demonstrated that two novel exonic polymorphisms in the SLC22A1 (gene encoding
OCT1) (i.e., Arg61Ser fs*10 and Cys88Ala fs*16) were associated with decreased
expression of the OCT1 transporter and dramatically affected the ability of sorafenib
to reach active intracellular concentrations[47].
Markers of response: (1) Mechanism of action: Sorafenib exerts its pharmacological

effect through inhibition of cell surface and downstream intracellular kinases
involved in several tumor cell signaling pathways, including proliferation,
angiogenesis, and apoptosis. Therefore, data from in vitro analysis and animal models
have demonstrated that sorafenib exerts its anticancer activity by repressing
proliferation of HCC cells and tumor growth, inducing HCC cell apoptosis, and
reducing tumor angiogenesis and related pathways (e.g., inflammation) [29,30] . In
addition to kinase inhibition, other mechanisms implicated in the activity of sorafenib
include MAPK-independent apoptosis induction and immunomodulatory effects.
Thus, primary and acquired resistance to sorafenib represent complex and
multifaceted phenomena for which underlying mechanisms are not completely
defined. At present, few pharmacogenetic studies have investigated the role of
inherited genetic variability in determining the response to sorafenib (Table 2).
(2) VEGF-dependent pathways: The retrospective multicenter study ALICE1
(Angiogenesis Liver CancEr) evaluated a panel of functionally relevant poly-
morphisms in genes encoding VEGF and its receptor VEGFR for their role in clinical
outcomes among white patients with advanced or intermediate-stage HCC receiving
sorafenib [48] . On univariate analysis, the rs25648-C, rs833061-T, rs699947-C, and
rs2010963-C alleles in VEGFA, rs4604006-T allele in VEGFC, rs664393-G allele in FLT1
(encoding the receptor VEGFR1), and rs2071559-C and rs2305948-C alleles in KDR
(encoding the receptor VEGFR2) emerged as potential predictive markers of longer
PFS and OS. At the multivariate level, VEGFA rs2010963-C and VEGFC rs4604006-T
alleles, together with BCLC stage, were confirmed as the only independent prognostic

factors predicting outcome in terms of PFS and OS. Moreover, the combination of
VEGFA rs2010963 and VEGFC rs4604006 markers further improved patient
stratification according to recurrence risk and survival probability. Patients
expressing both favorable alleles showed longer PFS and OS compared to those
expressing only one or none. The same favorable alleles were also significantly
associated with a better objective response. The significant impact of VEGFA
rs2010963 and VEGFC rs4604006 genetic variants, alone and in combination, on PFS
and OS was also confirmed in the subsequent multicenter study ALICE-2 [49] .
Collectively, these findings suggest an impact of polymorphisms that might influence
the level of circulating VEGF, such as rs2010963, located in the 5’UTR region of the
VEGFA gene, and rs4604006, located in one of the intronic sequences of the VEGFC
gene. The result would be a crucial effect on a drug such as sorafenib that targets this
pathway. Another study also confirmed the key involvement of the angiogenesis
process in modulating sorafenib treatment. Results from this Chinese cohort with
advanced HCC suggested positive results with polymorphisms in KDR encoding the
receptor VEGR2, whose dysfunction is correlated with decreased antiapoptotic effects
of VEGF among other vascular alterations[50]. Particularly, the AA genotype of the
rs1870377 variant was associated with longer time to progression and with OS as well
as with better objective response. The T allele of the rs2071559 variant was associated
with longer OS. Both polymorphisms were reported to affect VEGFR2 functionality
and/or expression level, thus potentially interfering with sorafenib’s mechanism of
action[50]. The rs1870377 allele is a missense variant (Gln472His) located in the fifth
NH2-terminal Ig-like domains within the extracellular region, which are important for
ligand binding. Rs1870377, which is linked to a significant decrease in VEGF binding
efficiency to VEGFR2, causes an altered protein phosphorylation pattern. Rs2071559 is
a promoter variant that alters the binding affinity of this regulatory region for the
transcriptional factor E2F, leading to decreased expression of the VEGF receptor. The
same group reported preliminary data for another functionally relevant missense
polymorphism, rs2305948 (Val297Ile), located in the third NH2-terminal Ig-like
domains of the receptor. This variant was associated with differences in progression
risk, with longer time to progression for the AA genotype, but only in the univariate
and not in the multivariate model.
(3) Other pathways: Pharmacogenetic interest also has focused on different genetic
targets in VEGF-dependent pathways. In particular, the Italian multicenter ePHAS
study[51] focused on polymorphisms in the endothelial nitric oxide synthase (eNOS)
gene, given the direct correlation between activation of the VEGF signaling pathway
and stimulation of the vasodilator nitric oxide. This study, including training and
validation populations of white patients with HCC undergoing sorafenib treatment,
found in both cohorts a significant association of lower PSF and OS with a specific
eNOS haplotype (i.e., HT1:T-4b), derived by the combination of a rs2070744 T-to-C
substitution in the 5’UTR region and the intronic VNTR 27bp 4a/4b polymorphism
(i.e., “4a” the allele with 4 repeats and “4b” the allele with 5 repeats). The rs2070744
variant was suggested to coordinate with the VNTR 27bp 4a/4b variant and directly
affect gene transcription efficiency, resulting in altered eNOS expression levels that
could in turn affect activation of VEGF signaling, and eventually sorafenib
cytotoxicity. Particularly, the rs2070744-T and VNTR 27bp 4b alleles seemed to be
associated with higher eNOS protein levels and activity, and consequently with
increased basal NO production that could contribute to the sorafenib resistance. On
the other hand, more recent preliminary results of another multicenter study, the
ALICE-2[49], have highlighted a predictive role of polymorphisms in the gene encoding
hypoxia–inducible factor α subunit (HIF1α) on sorafenib efficacy. HIF1α stabilization
in hypoxic conditions upregulates VEGF expression by binding the VEGFA promoter,
increasing angiogenesis. For this reason, HIF1α represents another player in the
VEGF-dependent pathway that could be involved in sorafenib efficacy. Moreover,
overexpression of HIF-1α in HCC is associated with tumor angiogenesis, invasion,
metastasis, treatment resistance, and poor prognosis. The ALICE-2 study, which
involved white patients with HCC treated with sorafenib, showed that HIF1A
rs1951795, rs10873142, and rs12434438 variants contribute to discriminating patients
according to different progression and survival probabilities. Multivariate analysis
confirmed the predictive role only for the HIF1A rs124344308 polymorphism with the
GG genotype, associating it with poorer PFS and OS independently from VEGF
markers (i.e., VEGFA rs2010963; VEGFC rs4604006). An additional clinical study[52]
with a similar patient cohort generated positive data for genetic markers in another
key angiogenic factor, Ang-2. By binding to its receptor Tie2, Ang-2 cooperates with
the VEGF pathway in regulating angiogenesis and maintaining normal physiological
vascular functions. In cancer, this protein is suggested to contribute to determining
tumor aggressiveness and metastatic phenotype. In addition, a high baseline level of
Ang-2 correlates with shorter OS in patients with advanced HCC without affecting

clinical response to sorafenib[53]. A preliminary study by Marisi et al[52] explored for the
first time the role of an Ang-2 genetic variant in sorafenib therapy outcome. These
authors found that in particular, the GG genotype of the synonymous polymorphism
rs55633437 (Thr238Thr) was associated with significantly longer PFS and OS
compared to other genotypes.
Regorafenib
Regorafenib (STIVARGA®) is an oral small molecule inhibitor with an almost identical
structure to sorafenib with which it shares most of the pharmacokinetic and
pharmacodynamic properties[54]. Regorafenib, similarly to sorafenib, blocks multiple
membrane-bound and intracellular kinases involved in normal cellular functions and
pathologic processes such as tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis
(KIT, RET, RAF-1, BRAF), and modulation of the tumor microenvironment (PDGFR,
FGFR). However, the small but significant difference in the chemical structure confers
on regorafenib a stronger inhibition power of the targeted angiogenic and oncogenic
kinases than sorafenib, resulting in higher pharmacological potency[54]. The liver
metabolism of regorafenib, even if less well-characterized, is comparable with that of
sorafenib and occurs through an oxidative process mediated by CYP3A4 and
glucuronidation mediated by UGT1A9[54]. Two major and six minor metabolites of
regorafenib have been identified in human plasma. The main circulating metabolites
are M2 (N-oxide) and M5 (N-oxide and N-desmethyl), which show similar steady-
state plasma concentrations and efficacy compared to the parental drug, as studied in
in vitro and in vivo models[54-56]. Moreover, regorafenib and its metabolites M2 and M5
are suggested substrates of some ABC/SLC membrane transporters, such as MDR1,
BCRP, MRP2, and OATP1B1, and thought to undergo enterohepatic recycling similar
to that of sorafenib[54-56]. Regorafenib and its major metabolites are also reported to
inhibit a number of cytochromes (CYP2C8, CYP2C9, CYP2B6, CYP3A4, CYP2D6),
UGT1A enzymes (UGT1A9, UGT1A1), and transporters (BCRP) and induce others
(CYP1A2, CYP2B6, CYP2C19, CYP3A4) with potential alteration in the exposure of co-
administered drugs[55-58].
Since the recent introduction of regorafenib as a second-line treatment for HCC, no
pharmacogenetic data have been published regarding potential genetic markers that
could predict the risk of severe toxicity and response to the targeted drug in patients
with liver cancer. However, given the similar metabolism and mechanism of action
between regorafenib and sorafenib, the same genes and related variants suggested to
modulate sorafenib therapy may also influence regorafenib. In support of this
hypothesis are preliminary results from recent studies performed in other cancer
settings, where regorafenib has been used for a long time. Details regarding the
pharmacogenetic panel analyzed, the study population (e.g., disease, sample size,
ethnicity) and therapy (e.g., dose and schedule) characteristics, the clinical end-points
evaluated along with the main findings (e.g., statistical results) of the studies are
shown in Table 3.
Markers of pharmacokinetics/toxicity: Regarding potential markers of regorafenib

toxicity, preliminary positive data have been generated for variants in genes encoding
the metabolic enzymes UGT1A9, BCRP, and OATP1B1. A descriptive study [57]
assessed CYP3A4 and UGT1A9 genetic variability by sequencing the germline DNA of
three patients with metastatic colorectal cancer (mCRC) experiencing severe toxic
hepatitis after sorafenib treatment and reported that two patients were heterozygous
for the UGT1A9*22 (rs3832043) polymorphism. This variant consisted of a single base
insertion of thymidine in the promoter region and it is likely to increase gene
expression and enzymatic function[59]. The high-activity UGT1A9*22 allele probably
affects hepatic metabolism of regorafenib, setting the stage for hepatotoxicity. This
finding warrants strict liver monitoring during regorafenib treatment for patients
with unfavorable UGT1A9 genotypes. However, further investigations are needed to
explore the exact mechanism by which an altered activity of UGT1A9 could contribute
to the occurrence of hepatotoxicity. Another preliminary investigation of a small
cohort of Japanese patients with solid cancer and receiving regorafenib[60] showed that
the presence of the SLCO1B1*1b (rs2306283-G) allele protected against the
development of grade ≥ 2 hepatic injury and anemia, two of the most important
regorafenib-related adverse drug reactions. The authors speculated that these
associations could arise from a change in the pharmacokinetic profile of the biological
agent, resulting from an inherited alteration in transporter activity of OATP1B1, as
determined by the functional *1b variant haplotype[44]. The same work also showed
that the loss-of-function rs2231142-A allele of the ABCG2 gene correlated with inferior
blood platelet counts (Plt) without an effect on risk for treatment-related grade ≥ 2
adverse reactions. A subsequent study from the same group[61], monitoring a small
cohort of Japanese patients with solid cancer for 28 days after regorafenib

administration, showed a tendency, although not significant, to a higher drug

concentration-to-dose ratio for the SLCO1B1*5 (rs4149056-C) allele and for
SLCO1B1*1b (rs2306283-G/rs4149056-T) non-carriers. However, further investigations
are required to confirm this association and to understand the biological mechanism
underlying the observed genotype/phenotype correlation. Of interest, the results of
the same study also included a strong association between serum regorafenib
concentrations and total bilirubin levels, which could be used as a potential marker
for estimating regorafenib pharmacokinetics. In fact, liver cells take up unconjugated
bilirubin through OATP1B1, and in the hepatic cell, it is conjugated to glucuronic acid
by UGT1A1. Considering that serum bilirubin is suggested to increase because of
competitive inhibition via OATP1B1, bilirubin plasma level could be considered a
surrogate marker of drug exposure. However, further analyses are needed to clarify
the exact mechanism of competition between regorafenib and bilirubin with respect to
OATP1B1.
Beside polymorphisms in metabolic enzymes encoding genes, genetic variants
affecting the VEGFA-related pathway are also hypothesized to contribute to inter-
individual differences in toxicity risk. Particularly, a recent study[62], including an
evaluation (Japanese mCRC patients) and validation (Italian mCRC patients) cohort,
reported significant differences in toxicity incidence according to genetic variants in
the C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5)
pathway. This pathway modulate VEGFA production via endothelial progenitor cell
migration. The investigation showed that in the evaluation set, the CCL5 rs2280789-
GG and rs3817655-TT genotypes were associated with higher incidence of grade ≥ 3
HFRS. The replication of these associations according to the recessive model in the
validation set was not possible because of the low frequency of the homozygote
genotype. With respect to the risk for HFRS, the observed differences in the frequency
distribution of the rs2280789 and rs3817655 variants between the Japanese and Italian
cohorts could also explain the different incidence of severe HFRS by ethnicity noted in
clinical practice [36] . An exploratory analysis of the other toxicity types was also
performed and highlighted that, in the evaluation set, the CCL5 rs2280789, rs3817655,
and rs1799988 variants could have a predictive effect on risk for grade ≥ 3
hypertension. In the validation set, the CCL5 rs2280789 variant emerged as a
predictive marker of grade ≥ 3 diarrhea while the CCL4 rs1634517 and CCL5 rs1130371
markers were differently distributed in genotype frequencies relative to incidence of
grade ≥ 3 AST/ALT variation. Another marker of the CCL5/CCR5 pathway, the
KLF13 rs2241779, seemed to influence risk for grade ≥ 3 rash. Although these findings
should be considered exploratory, they suggest a promising candidate targets for
future pharmacogenetic studies aimed at discovering novel predictive markers to
improve the management of regorafenib-associated toxicity (e.g., personalized dosing
and other strategies to support patient care).
Markers of response: Other studies have focused on the potential role of

polymorphisms in the VEGF/VEGFR cascade and related mechanisms in modulating
the response to regorafenib treatment. The work of Giampieri and colleagues[63],
involving a small cohort of white patients with mCRC, reported that the VEGFA
rs2010963 variant is an independent predictive marker of regorafenib efficacy in terms
of disease control rate, PFS, and OS, with the CC genotype associated with a better
outcome. The integration of patient Eastern Cooperative Oncology Group (ECOG)
performance status with the VEGFA rs2010963 genotype improved stratification by
survival rate. On univariate analysis, other markers, such as VEGFR2 rs1870377,
VEGFR3 rs307805, and VEGFR1 rs664393, were suggested to contribute to
determining regorafenib outcome. In particular, the VEGFA rs2010963 variant, located
in the 5’UTR of the gene, has a potential effect on VEGFA expression and tumor
angiogenesis. The observed association is consistent with the results of other studies
reporting significant involvement of VEGFA rs2010963 in influencing other biological
agents targeting the VEGF/VEGFR cascade, such as sorafenib and bevacizumab[48,64].
Another recent investigation[62] evaluated the role on regorafenib therapy outcome
of a panel of variants from the CCL5/CCR5 pathway that is involved in the
modulation of VEGFA production. The study comprised 79 Japanese patients with
mCRC as the evaluation cohort and 150 Italian patients with mCRC as the validation
cohort. The results showed that in the evaluation set, the CCL5 rs2280789-GG and
rs3817655-TT genotypes were associated with longer OS. The replication of these
associations according to the recessive model in the validation set was not possible
because of the low frequency of the homozygote genotype. Functional analyses have
demonstrated that the G allele of the rs2280789 polymorphism, located in the
promoter region of CCL5, negatively affects transcriptional activity of RANTES,
resulting in a lower serum level of CCL5 and VEGFA[62]. A similar phenotypic effect
on CCL5 and VEGFA expression level was also suggested for the T allele of the

intronic CCL5 rs3817655 variant[62]. These functional data could help explain the
clinical impact on regorafenib outcome observed for the CCL5 rs2280789 and
rs3817655 markers. Of interest, the same study generated positive data for
polymorphisms in genes encoding other CCR5 ligands, such as CCL4 (rs1634517,
intronic variation) and CCL3 (rs1130371, synonymous variation, Pro60Pro) that were
associated with PFS and OS in both evaluation and validation cohorts. These variants
also displayed similar allelic distribution between the two ethnic groups, unlike
CCL5. From a functional point of view, the CCL4 rs1634517-C and CCL3 rs1130371-G
alleles, associated with longer PSF and OS, seemed to correlate with higher CCL5
level without any impact on VEGFA level[62].
Taken together, these data highlighted the importance of the VEGF/VEGFR
cascade and related pathway (i.e., CCL5/CCR5) in modulating the effectiveness of
regorafenib therapy. Polymorphisms in gene encoding the several members of these
pathways should be the target of future pharmacogenetic studies aimed at optimizing
regorafenib treatment outcomes.
Other approved drugs

Cabozantinib (XL-184, COMETRIQ®) is an oral tyrosine kinase inhibitor that can block
multiple oncogenic and angiogenic pathways implicated in tumor progression, worse
prognosis, and metastasis, such as PDGFR, HGFR, VEGFR2, AXL, RET, KIT, and
FLT3 [ 6 5 - 6 9 ] . Following oral administration, the median time to peak plasma
concentrations (Tmax) of cabozantinib ranged from 2 to 5 hours post-dose. This drug
undergoes hepatic metabolism by CYP3A4 and, to a minor extent, by CYP2C9[66]. In
addition, the major metabolites of cabozantinib identified in human plasma, after a
single dose oral intake (140 mg), are EXEL-1646 (M9), obtained from M16 sulfation;
EXEL-5162 (M19), obtained from the oxidation at the nitrogen of the quinolone
portion; EXEL-5366 (M7), derived from the hydrolysis at the amide bond; and EXEL-
1644 (M2a), the M7 sulfate conjugate[66,70]. Considering excretion, cabozantinib is
eliminated mostly by the feces (54%) and urine (27%)[66]. Between 2012 and 2013, the
FDA and the European Medicines Agency initially approved cabozantinib as a
treatment for patients with medullary thyroid cancer. In 2016, the drug received a
new indication as a treatment for patients with advanced renal cell carcinoma
following one prior anti-angiogenic therapy[71-73]. Recently, several clinical trials have
demonstrated that cabozantinib exhibits encouraging clinical activity in multiple
human cancers, including HCC, with manageable side-effects[25,74-77]. Based on this
evidence, cabozantinib represents an efficient alternative in the management of
sorafenib-resistant HCC. In 2018, it received FDA approval for HCC treatment[76,78].
Lenvatinib (E7080 or LENVIMA®) is an orally active multikinase inhibitor that
selectively inhibits receptors related to pro-angiogenic and oncogenic pathways such
as VEGFR1-3, FGFR 1–4, PDGFRα, and RET, and KIT proto-oncogenes[79-83]. After oral
administration, lenvatinib is rapidly absorbed, and time to peak plasma concentration
occurs from 1 to 4 hours postdose[84]. However, even if administration with food does
not affect the extent of absorption, it can decrease the rate of absorption and delay
median Tmax from 2 to 4 hours. Both in vitro plasma and in vivo serum protein-
binding assays demonstrated that lenvatinib protein binding ranges from 96.6 to
98.2%[84]. Lenvatinib is metabolized in liver microsomes mostly through CYP3A4 (>
80%) and, to a minor extent, by aldehyde oxidase and acts as a substrate for ABC
transporters, encoded by the ABCB1 and ABCG2 genes, such as BCRP and P-
glycoprotein[84-86]. Regarding excretion, the percentage of unchanged lenvatinib found
in urine and feces is 2.5% of the administered dose, suggesting that lenvatinib is
highly metabolized.
The principal metabolites of lenvatinib are derived from decyclopropylation (M1),
demethylation (M2), N-oxidation (M3), and O-dearylation (M5) [84] . The formed
metabolites are mainly excreted, approximately 64% via the biliary route in the feces,
and 25% of the metabolites formed in the liver are released into the circulation and
excreted via urine [84,87] . At first, lenvatinib was approved for the treatment of
radioiodine-refractory differentiated thyroid cancer, as a single agent, and for the
treatment of advanced renal cell carcinoma in combination with everolimus[79,88-90]. On
August 2018, based on positive results of the REFLECT trial (NCT01761266), the FDA
approved lenvatinib as a first-line treatment in patients with advanced and
unresectable HCC[91,92].
To the best of our knowledge, no studies still have investigated the correlation
between genetic polymorphisms and cabozantinib or lenvatinib treatment outcome
for either toxicity or efficacy in HCC patients. However, a very recent study by Ozeki
et al93 on Japanese patients with thyroid cancer, demonstrated for the first time an
impact of CYP3A4/5 and ABC transporter genetic variants on lenvatinib
pharmacokinetics[93]. Particularly, the CYP3A4*1G (rs2242480, intronic variation) and
ABCC2 rs717620 polymorphisms were suggested to have an effect on the steady-state

mean plasma [i.e., mean dose-adjusted C0, (ng/mL/mg)] trough concentrations of

lenvatinib. The mean dose-adjusted C 0 values of lenvatinib in patients with the
CYP3A4*1/*1 genotype and ABCC2 rs717620-T allele were significantly higher than
those in patients with the CYP3A4*1G allele and ABCC2 rs717620-CC genotype,
respectively (effect size: 0.863, P = 0.018 and effect size: 0.605, P=0.036, respectively).
Moreover, the dose-adjusted C0 of lenvatinib in patients with both the CYP3A4*1/*1
genotype and ABCC2 rs717620-T allele (median 6.70 ng/mL/mg) was about 1.5-fold
higher than that in patients with both the CYP3A4*1G/*1G and ABCC2 rs717620-CC
genotypes (median 4.42 ng/mL/mg; P = 0.007)[93]. These results demonstrated that
functionally relevant genetic variants in proteins involved in the metabolism,
translocation, and mechanism of action of cabozantinib or lenvatinib could be
important determinants of therapy outcome and represent good candidates for future
pharmacogenetic studies. With increasing therapeutic opportunities, the identification
of markers that help clinicians choose the drug most suited to that patient becomes an
urgent need. On this ground, Takeda et al. recently said that “approval of lenvatinib
opened the new era of molecular targeting therapy for HCC. It requires the use of
several molecular targeted agents appropriate for each HCC patient. To realize this
personalized medicine, the establishment of genetic or transcriptional biomarkers
needed to select the appropriate regimen is eagerly awaited’’[94].
PHARMACOGENETICS OF DRUGS UNDER INVESTIGATION

The genomic understanding of HCC and the development of molecularly targeted
therapies represent a promising stepping-stone for increasing the number of effective
drugs for HCC patients. In recent years, many new drugs have been tested or are still
under investigation as an alternative to sorafenib or, most important, after sorafenib
failure. However, even if the survival benefit improvement and adverse drug event
reduction are still the main focus, the identification of predictors of good responders
could allow application of these new drugs in personalized treatments for HCC[95-98].
Furthermore, a deep understanding of the proteins involved in the metabolic pathway
and mechanism of action of these novel molecularly targeted agents could suggest
potential candidate targets (i.e., genes and polymorphisms) for future
pharmacogenetic studies. Therefore, this paragraph is focused on drugs currently
under investigation for HCC therapy by providing general information on their
metabolism, pharmacokinetics, mechanisms of action and, where available,
pharmacogenetics data.
Nivolumab
The presence of tumor-infiltrating lymphocytes expressing programmed cell death
protein-1 (PD-1, encoded by PDCD1) in HCC lesions and their correlation with
outcome paved the way for immunotherapeutic approaches for HCC treatment[98-101].
The immune checkpoint inhibitor nivolumab (MDX-1106,OPDIVO®) is a fully human
immunoglobulin (Ig) G4 (IgG4) monoclonal antibody. It binds the PD-1 receptor,
expressed on activated T-cells, blocking interaction with its ligands PD-L1 and PD-L2
on tumor cells. This inhibition leads to downregulation of the T-cell–promoted tumor
immune-escape mechanism, restoring the antitumor activity of T-cells [102,103] .
Nivolumab is intravenously administered and thus is completely bioavailable. After
initiation of the infusion, its median time to peak concentration is 1–4 hours[104,105]. As
stated on the drug label, no formal studies were conducted to characterize the specific
nivolumab metabolic pathway. However, it is thought to be degraded into small
peptides and aminoacids through canonical pathways, such as endogenous IgG, and
not by CYPP450. Similarly, no studies have addressed the specific elimination route of
nivolumab. The phase I/II CHECKMATE-040 trial (NCT01658878) demonstrated the
efficacy, safety, and tolerability of nivolumab in HCC treatment leading, on
September 2017, to its accelerated FDA approval for the treatment of HCC in patients
who previously have been treated with sorafenib[26,98]. At present, the multicenter
phase III randomized controlled CHECKMATE-459 trial (NCT02576509) is ongoing to
determine if nivolumab or sorafenib is more effective as first-line treatment for
advanced HCC. In term of pharmacogenetics, it has been demonstrated, in lung
adenocarcinoma, non–small cell lung cancer (NSCLC) and squamous cell carcinoma,
that PD-1/PD-L1 gene polymorphisms may alter the immune checkpoint functions
and affect the clinical response to nivolumab[106,107]. Patients with the CC or CG PD-L1
genotypes (rs4143815) and the GG or GT PD-L1 genotypes (rs2282055) experience a
significantly longer median PFS (2.6 months) with nivolumab treatment than patients
with the GG and TT genotypes (2.1 and 1.8 months respectively)[106]. Furthermore,
none of the patients obtained a treatment effect with the GG genotype of PD-L1

rs4143815 and the TT genotype of rs2282055. In addition, it has been demonstrated

that rs2297136, rs4143815, and rs17718883 polymorphisms of the PD-L1 gene are
associated with HCC risk and prognosis[107,108]. Even if the functional and biological
effect of PD-L1 genetic variants are still under investigation and debate, taking
together, these results reinforce the role of these polymorphisms as possible
prognostic markers for HCC development as well as markers of outcomes in
nivolumab-treated patients[108-110].
Another study analyzed 322 nivolumab-treated patients with NSCLC and assessed
the association between toxicities and polymorphisms in genes considered as
contributors to PD-1–directed T-cell responses, such as the PD-1 gene (PDCD1),
tyrosine-protein phosphatase non-receptor type 11 (PTPN11) and interferon gamma
(IFNG). The TT genotype in the PDCD1 rs2227981 polymorphism was associated with
less nivolumab toxicity. On the contrary, patients presenting one G allele in the
PTPN11 rs2301756 polymorphism or who are homozygous CC for the IFNG rs2069705
polymorphism were at increased risk for developing any grade toxicity[111]. Further
investigations are required to confirm these preliminary data and to test their validity
also in the HCC setting.
Pembrolizumab
Pembrolizumab (lambrolizumab or MK-3475 or KEYTRUDA ® ) is a high-affinity
humanized IgG4 monoclonal antibody that can bind with to the cell surface receptor
PD-1, antagonizes receptor interaction with its known ligands PD-L1 and PD-L2, and
allows the immune system to destroy cancer cells[98]. The antibody, intravenously
administered, is immediately and completely bioavailable, does not bind to plasma
proteins, and undergoes catabolism to small peptides and single aminoacids via
general protein degradation routes[112]. In terms of clearance, a correlation has been
demonstrated between clearance rate and increasing body weight, explaining the
rationale for dosing on an mg/kg basis, whereas age, sex, race, and tumor burden
have no clinically important effect on clearance. Furthermore, mild or moderate renal
and hepatic impairments do not differ in clinically important way in clearance
compared to patients with normal functions[112]. In 2016, Truong et al. published the
first case report of a 75-year-old man with advanced HCC responsive to pem-
brolizumab, on a compassionate use basis, after failure of sorafenib therapy[113]. Since
2016, several observational and interventional phase I/II/III studies, such as the
KEYNOTE-224 and the KEYNOTE-240 trials, continue investigating the safety and
efficacy of pembrolizumab, alone or in combination with other drugs/procedures, in
patients with advanced HCC who progressed on or were intolerant to first-line
systemic therapies (e.g., NCT02940496, NCT02658019, NCT03062358, NCT03753659,
NCT02702401) [83,114] . In 2016, considering a cohort of patients with metastatic
melanoma treated with pembrolizumab or nivolumab, it has been demonstrated that
28% of responsive tumors were significantly enriched in non-synonymous single-
nucleotide variations in disparate breast cancer type 2 susceptibility protein (BRCA2)
domains. Specifically, one in the N-terminal nucleophosmin–interacting region
(rs775903570, Val950Leu), one in the DNA polymerase eta–interacting domain
(Ser1792Phe), four in the helical domain critical for Fanconi anemia group D2
(FANCD2) interaction (His2361Tyr [rs786203493], Pro2505Ser, Ser2522Phe,
His2537Tyr), and one between these two interacting domains (Glu2115Lys)[115]. The
authors, according to the disposition of the highlighted loss-of-function mutations
and known role of BRCA2 in DNA repair, suggested that enhanced responsiveness
could arise from cellular stress resulting from defective DNA repair that leads to
increased cell death and anti-tumor immunity[115,116].
Furthermore, Al-Samkari et al[117] recently published a case report of a 58-year-old
woman with aggressive metastatic breast cancer who developed hemophagocytic
lymphohistiocytosis (HLH) while undergoing experimental treatment with
pembrolizumab, resulting in critical illness and multi-organ system failure. Next-
generation sequencing revealed that she was heterozygous for germ-line perforin-1
(PRF1) c.272C>T (rs35947132, p.Ala91Val). Several studies have demonstrated that
PRF1 rs35947132 is aberrantly post-translationally processed and results in reduced
perforin expression together with partial loss of lytic activity. The rs35947132
polymorphism is a genetic risk factor for the development of HLH in patients exposed
to certain environmental triggers. Taking all these findings together, the authors
postulated that in the presence of the PRF1 polymorphism, pembrolizumab treatment
could ignite a dramatic adverse drug event such as HLH [117] . Once again, these
interesting pharmacogenetic results stress the hypothesis that the presence of genetic
variations could affect, in this case, pembrolizumab therapy outcome, giving the
possibility to investigate and, so, to extend their spectrum of action to other
oncological fields, such as HCC therapy.

Palbociclib and ribociclib

Palbociclib (PD-0332991, IBRANCE®) and ribociclib (LEE-011,KISQALI®) are oral,
specific inhibitors of the cyclin-dependent kinases CDK4 and CDK6[118,119]. Through
CDK inhibition, both drugs prevent the formation of the cyclin D-CDK4/6 complex
and retinoblastoma protein phosphorylation. Accordingly, cells cannot switch from R
to G1 phase and proceed through the cell cycle[120,121]. In addition to canonical CDK4/6
retinoblastoma signaling, palbociclib shows in vitro and in vivo antiHCC activity by
inducing cell autophagy and apoptosis via a mechanism involving 5’ AMPactivated
protein kinase activation and protein phosphatase 5 inhibition[122]. Palbociclib is slowly
absorbed, with a median Tmax generally observed between 6 to 12 hours, while
ribociclib is rapidly absorbed, with median Tmax ranging from 1 to 5 hours. Binding
of palbociclib to human plasma proteins in vitro is approximately 85%, while binding
of ribociclib is approximately 70%, with no concentration dependence in either case.
Following oral administration, palbociclib and ribociclib undergo extensive hepatic
metabolism mainly by CYP3A; palbociclib also is metabolized through the
sulfotransferase enzyme SULT2A1[123,124]. The major primary metabolic pathways for
palbociclib involve oxidation and sulfonation, with acylation and glucuronidation
contributing as minor pathways. For ribociclib, the primary metabolic pathways
involve oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and
combinations thereof. Phase II conjugates of ribociclib phase I metabolites involved N-
acetylation, sulfation, cysteine conjugation, glycosylation, and glucuronidation.
Palbociclib and ribociclib are the major circulating drug-derived entities in plasma
(23% and 46%, respectively), and their clinical activity traces primarily to the parent
drug, with negligible contribution from circulating metabolites. Both drugs are
eliminated mostly (69%–74%) via the feces, but also (17%–23%) via the urine.
Following encouraging results from clinical trials, palbociclib and ribociclib have been
approved, between 2015 and 2017, by the FDA and European Medicines Agency for
hormone receptor-positive, human epidermal growth factor receptor 2-negative
(HR+/HER2-) advanced or metastatic breast cancer therapy in combination with an
aromatase inhibitor, such letrozole, or with fulvestrant (FASLODEX®), a selective
estrogen receptor degrader, in women with disease progression after endocrine
therapy [125-134] . The effects of palbociclib and ribociclib as a treatment for other
malignancies, including HCC, are of great clinical interest and under current
investigation (NCT01356628, NCT02524119).
Tivantinib
Tivantinib (ARQ197) is a selective, orally available, non-ATP competitive c-MET
inhibitor currently under clinical investigation in patients with cancer[135,136]. Indeed,
upregulation of the c-MET pathway, including its only known ligand HGF, is found
in multiple cancers, such as HCC, and is associated with poor prognosis and
metastases[136-139]. Conversely, tivantinib also revealed an anti-proliferative activity that
was not restricted to only c-MET–dependent cell lines[140]. In fact, several in vitro and in
vivo studies have demonstrated that tivantinib can affect microtubule dynamics by
disrupting mitotic spindles. It also can promote G2/M cell cycle arrest and apoptosis
by inhibiting the anti-apoptotic molecules myeloid cell leukemia-1 and B-cell
lymphoma-extra large and increasing Cyclin B1 expression[140-144]. Indeed, despite
controversies regarding its mechanism of action, two phase II clinical trials
(NCT01575522, NCT00988741) have demonstrated that tumors with high levels of
MET present a high degree of response to tivantinib treatment [145,146] . In term of
pharmacokinetics, tivantinib is metabolized by CYP2C19, CYP3A4/5, UGT1A9, and
alcohol dehydrogenase isoform 4 [147] . CYP2C19 shows catalytic activity for the
formation of the hydroxylated metabolite (M5), whereas CYP3A4/5 catalyzes
formation of M5 and its stereoisomer (M4). Moreover, CYP3A4/5 represents the
major cytochrome isoform involved in the elimination of M4, M5, and the keto-
metabolite (M8), and together with UGT1A9, involved in the glucuronidation of M4
and M5[147]. Finally, the alcohol dehydrogenase isoform 4, through a sequential keto-
metabolite of M4 and M5 and through M8, leads to the formation of M6[147]. Between
2010 and 2014, two phase I trials (NCT01069757, NCT01656265) in Japanese patients
with advanced solid tumors examined the safety, pharmacokinetics, and preliminary
efficacy of tivantinib as a single agent to determine recommended phase II dose
according to CYP2C19 polymorphisms[148,149]. Recently, two Phase III trials, the METIV-
HCC (NCT02029157) and the JET-HCC (NCT01755767), were conducted to determine
if tivantinib is effective as a second-line treatment MET in patients with diagnostic-
high HCC who have already been treated once with another systemic therapy. This
trial also further evaluated the safety profile of the experimental drug in this
population [12,150] . Unfortunately, no statistically significant differences between
tivantinib and placebo in terms of OS or PFS were identified in either trial.

CONCLUSION AND FUTURE DIRECTIONS

Despite the advantage in patient survival resulting from the introduction of targeted
agents in the therapeutic scenario of HCC, a significant inter-individual heterogeneity
in therapy outcome persists and constitutes a crucial problem in HCC management.
Moreover, with the increasing number of therapeutic options, selection of the most
appropriate treatment for each patient is a great challenge. The identification of
genetic markers that predict which patients will benefit from a specific intervention
could significantly affect decision-making and therapy planning
Most of the pharmacogenetic studies published to date have focused on sorafenib,
which has the longest track record in HCC treatment. However, these investigations,
conducted for the most part in small cohorts, have generated only quite sparse,
unreplicated data that do not permit drawing conclusions about their clinical validity.
Moreover, comparison among studies is difficult because of the high heterogeneity in
regard to the ethnic and clinical-demographic characteristics of the cohorts, study
design (e.g., retrospective/prospective analyses, low statistical power, adoption of an
internal data validation), panel of investigated genes and related variants, method of
controlling for confounding and environmental factors, and parameters for measuring
clinical outcomes. For these reasons, the pharmacogenetic data published to date
should be considered only hypothesis-generating. These data could be useful,
however, for indicating specific genes and related pathways as potential candidate
predictors of sorafenib therapy, guiding future research efforts.
Regarding the discovery of potential markers of toxicity risk after sorafenib
administration, CYP and UGT1A polymorphisms are associated with different risks
for severe adverse events. Although these findings should be considered preliminary
because of small sample sizes, lack of replication, and some negative results[151], they
surely support the need for additional pharmacogenetic research efforts to deeply
understand the real clinical utility of CYP and UGT1A markers. Other published data,
although mainly hypothesis-generating, have pointed out the clinical contribution in
determining the sorafenib-related toxicity risk of polymorphisms in ABC/SLC
membrane transporter genes. Some caveats are necessary, however. Given the
complex enterohepatic recirculation in which sorafenib appears to be involved (see
above)[31], it could be supposed that the evaluation of the combinatorial effect of
multiple ABC/SLC carriers with respect to single gene/variant analysis is a more
effective strategy for identifying inter-individual differences in the pharmacological
profile of sorafenib. Moreover, based on the results of a pilot study, evaluating
UGT1A1*28 carriers with two distinct phenotypes in relation to sorafenib exposure
based on ABCC2 rs717620 genotypes[46], the integration of inherited variability in
multiple metabolic processes, such as phase I and II metabolism and membrane
translocation, could further improve prediction of therapy outcome. Moreover, the
investigation of other pathways with closer links to the drug mechanism of action,
such as angiogenesis (e.g., VEGFA) and inflammation (e.g., tumor necrosis factor-α),
could be useful for discovering additional novel genetic markers that could contribute
to stratifying patients based on individual toxicity risk[36].
Concerning potential genetic determinants of sorafenib efficacy, recent studies have
highlighted the potential utility of inherited variability in the VEGF/VEGFR cascade
and related pathways to identify patients who could benefit from sorafenib
administration. This information can help clinicians in the selection of the most
appropriate treatment and improve clinical outcome. For example, patients with a
favorable genetic background could be administered sorafenib as soon as clinically
indicated, instead of delaying it with other therapy; patients with an unfavorable
background could be preferably included in clinical trials exploring new or upcoming
treatment options. At present, the multicenter prospective INNOVATE study is
ongoing to validate the contribution of polymorphisms in genes encoding VEGF,
eNOS, Ang-2, and HIF-1α in determining clinical outcomes in patients with advanced
HCC receiving sorafenib (NCT02786342)[152].
Only a few pharmacogenetic data, obtained for the most part in a non-HCC tumor
setting, have been published regarding the recently approved regorafenib. Globally,
these data, are only of hypothesis-generating value, but they have indicated potential
candidate genes related to the regorafenib metabolism (e.g., ABC/SLC transporters,
UGT1As) and mechanism of action (e.g., VEGFA and its receptors; the CCL5/CCR5
pathway). Their predictive power for therapy outcome could be useful to investigate
in the HCC setting. Moreover, the similar pharmacological proprieties of regorafenib
and sorafenib suggest that the genetic determinants of therapy outcome described for
sorafenib could apply for regorafenib treatment and should be further investigated.
For the more recently developed multikinase kinase inhibitors (e.g., lenvatinib,
cabozantinib), immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab), and
selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), no pharmacogenetic markers

have been identified in the HCC setting. Research efforts should respond to this lack
of information.
The discovery of biomarkers, subsequently validated in large prospective studies, is
a compelling need because they are expected to allow for more accurate selection of
patients with HCC who are potential candidates for a specific targeted agent. This
stratification could mean the ability to limit treatment to potentially responding
patients and sparing unnecessary toxicity to those who are unlikely to benefit.
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ISSN 2219-2840 (online)

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WJG https://www.wjgnet.com I August 7, 2019 Volume 25 Issue 29

Retrospective Cohort Study

WJG https://www.wjgnet.com II August 7, 2019 Volume 25 Issue 29

ABOUT COVER Editorial board member of World Journal of Gastroenterology, Herwig

RESPONSIBLE EDITORS FOR Responsible Electronic Editor: Yu-Jie Ma

NAME OF JOURNAL COPYRIGHT

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LAUNCH DATE GUIDELINES FOR ETHICS DOCUMENTS

FREQUENCY GUIDELINES FOR NON-NATIVE SPEAKERS OF ENGLISH

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EDITORIAL OFFICE STEPS FOR SUBMITTING MANUSCRIPTS

PUBLICATION DATE ONLINE SUBMISSION

WJG https://www.wjgnet.com III August 7, 2019 Volume 25 Issue 29

DOI: 10.3748/wjg.v25.i29.3870 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

Pharmacogenetics of the systemic treatment in advanced

WJG https://www.wjgnet.com 3870 August 7, 2019 Volume 25 Issue 29

Citation: De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F,

WJG https://www.wjgnet.com 3871 August 7, 2019 Volume 25 Issue 29

centers[1]. Radioembolization is an alternative embolization approach with a favorable

SYSTEMIC TREATMENT OF ADVANCED HCC

WJG https://www.wjgnet.com 3872 August 7, 2019 Volume 25 Issue 29

biomarkers of response to regorafenib in patients with HCC have been recently

WJG https://www.wjgnet.com 3873 August 7, 2019 Volume 25 Issue 29

on another immune checkpoint inhibitor, pembrolizumab, in patients with HCC pre-

PHARMACOGENETICS OF APPROVED DRUGS

Markers of pharmacokinetics/toxicity: (1) Sofarenib metabolism: The metabolism[29,30]

WJG https://www.wjgnet.com 3874 August 7, 2019 Volume 25 Issue 29

Pharmacogenetic Study population Therapy Clinical Main findings Ref.

August 7, 2019|Volume 25|Issue 29|

Pharmacogenetic panel Study Therapy Clinical Main findings Ref.

August 7, 2019|Volume 25|Issue 29|

August 7, 2019|Volume 25|Issue 29|

Pharmacogenetic Study Therapy Clinical Main findings Ref.

August 7, 2019|Volume 25|Issue 29|

WJG https://www.wjgnet.com 3879 August 7, 2019 Volume 25 Issue 29

occurrence. Carriers of the polymorphic rs17868320-T allele were exposed to a higher

WJG https://www.wjgnet.com 3880 August 7, 2019 Volume 25 Issue 29

adequately consider sorafenib therapy in cases of hereditary genetic predisposition to

Markers of response: (1) Mechanism of action: Sorafenib exerts its pharmacological

WJG https://www.wjgnet.com 3881 August 7, 2019 Volume 25 Issue 29

WJG https://www.wjgnet.com 3882 August 7, 2019 Volume 25 Issue 29

Markers of pharmacokinetics/toxicity: Regarding potential markers of regorafenib

WJG https://www.wjgnet.com 3883 August 7, 2019 Volume 25 Issue 29

administration, showed a tendency, although not significant, to a higher drug

Markers of response: Other studies have focused on the potential role of

WJG https://www.wjgnet.com 3884 August 7, 2019 Volume 25 Issue 29

Other approved drugs

WJG https://www.wjgnet.com 3885 August 7, 2019 Volume 25 Issue 29

mean plasma [i.e., mean dose-adjusted C0, (ng/mL/mg)] trough concentrations of

PHARMACOGENETICS OF DRUGS UNDER INVESTIGATION

WJG https://www.wjgnet.com 3886 August 7, 2019 Volume 25 Issue 29

rs4143815 and the TT genotype of rs2282055. In addition, it has been demonstrated

WJG https://www.wjgnet.com 3887 August 7, 2019 Volume 25 Issue 29

Palbociclib and ribociclib

WJG https://www.wjgnet.com 3888 August 7, 2019 Volume 25 Issue 29