title: Correlation between clinical response to sorafenib in hepatocellular carcinoma treatment and polymorphisms of P-glycoprotein (ABCB1) and of breast cancer resistance protein (ABCG2): monocentric study.
abstract: We studied the relation between the polymorphism of P-glycoprotein (P-gp) and of breast cancer resistance protein (BCRP), encoded by ABCB1 and ABCG2 genes, respectively, and the pharmacokinetic variability and clinical response during the treatment with sorafenib of hepatocellular carcinoma.
  
  
  
  At the Paul Brousse Hospital in Villejuif, France, 47 consecutive patients with advanced HCC treated with a single agent sorafenib, were enrolled. Sorafenib exposure was measured by its plasma concentration 3 h after oral administration of 400 mg (bid) by liquid chromatography. All enrolled patients were genotyped for ABCB1 (rs2032582; rs1045642) and ABCG2 (rs2231137; rs2231142; rs2622604) by blood genomic DNA extraction and Mass ARRAY genotyping. The clinical response was evaluated after 3months of treatment according to the RECIST criteria.
  
  
  
  Significant associations between sorafenib exposure and the studied polymorphisms were observed for ABCB1 3435C>T, ABCG2 34G>A, ABCG2 1143C>T and ABCG2 421C>A, but not for ABCB1 2677G>TA SNP. In heterozygous patients for ABCB1 3435 C>T, ABCG2 34 G>A and ABCG2 1143 C>T polymorphisms were significantly associated with the lowest sorafenib plasma levels. Those patients presented a tendency to have the best clinical evolution.
  
  
  
  Heterozygous forms of the studied polymorphisms could be associated with a better therapeutic response.
authors.affiliation: Laboratory of pharmacology, Service Pharmacie, Paul Brousse Hospital, AP-HP, 14 avenue Paul Vaillant-Couturier, 94800, Villejuif, France. Mahamadou.tandia@pbr.aphp.fr.|UPRES EA 4123 Faculty of Pharmaceutical Sciences, Université Paris XI, 5 rue Jean Baptiste Clémént, 92296, Chatenay-Malabry, cedex, France. Mahamadou.tandia@pbr.aphp.fr.
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Tandia
authors.affiliation: Laboratory of pharmacology, Service Pharmacie, Paul Brousse Hospital, AP-HP, 14 avenue Paul Vaillant-Couturier, 94800, Villejuif, France.
authors.forename: Asma
authors.initials: A
authors.lastname: Mhiri
authors.affiliation: Hepatobiliary center, Paul Brousse Hospital, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Paule
authors.affiliation: Laboratory of biochemistry, Paul Brousse Hospital, Villejuif, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Saffroy
authors.affiliation: Statistical Units, Paul Brousse Hospital, Villejuif, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cailliez
authors.affiliation: Laboratory of pharmacology, Service Pharmacie, Paul Brousse Hospital, AP-HP, 14 avenue Paul Vaillant-Couturier, 94800, Villejuif, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Noé
authors.affiliation: UPRES EA 4123 Faculty of Pharmaceutical Sciences, Université Paris XI, 5 rue Jean Baptiste Clémént, 92296, Chatenay-Malabry, cedex, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.affiliation: Laboratory of pharmacology, Service Pharmacie, Paul Brousse Hospital, AP-HP, 14 avenue Paul Vaillant-Couturier, 94800, Villejuif, France.|UPRES EA 4123 Faculty of Pharmaceutical Sciences, Université Paris XI, 5 rue Jean Baptiste Clémént, 92296, Chatenay-Malabry, cedex, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bonhomme-Faivre
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004247:DNA / Q000235:genetics; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D004247:DNA; D000077157:Sorafenib
keywords: Brest cancer resistance protein (ABCG2); Drug monitoring; Hepatocellular carcinoma (HCC); P-glycoprotein (ABCB1); Single nucleotide polymorphism (SNP); Sorafenib