title: Multidrug and toxin extrusion 1 and human organic cation transporter 1 polymorphisms in patients with castration-resistant prostate cancer receiving metformin (SAKK 08/09).
abstract: BACKGROUND
  This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival.
  
  
  RESULTS
  Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P=0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P=0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P=0.07). OCT1 and MATE1 were not associated with PFS.
  
  
  CONCLUSIONS
  The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.
authors.affiliation: Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Joerger
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center Rotterdam/ Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
authors.affiliation: 1] Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands [2] Pharmacy Foundation of Haarlem Hospitals, Haarlem, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: Becker
authors.affiliation: Swiss Group for Clinical Cancer Research (SAKK) Coordinating Center, Bern, Switzerland.
authors.forename: S
authors.identifier: 0000000222656559
authors.initials: S
authors.lastname: Hayoz
authors.affiliation: Lady Davis Institute for Medical Research Jewish General Hospital and McGill University, Montréal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Department of Medical Oncology, Cantonal Hospital, Chur, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Cathomas
authors.affiliation: Department of Medical Oncology, Cantonal Hospital, Lucerne, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Winterhalder
authors.affiliation: Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Gillessen
authors.affiliation: Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland.
authors.forename: C
authors.identifier: 0000000221047794
authors.initials: C
authors.lastname: Rothermundt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018572:Disease-Free Survival; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008687:Metformin / Q000009:adverse effects*; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy / Q000235:genetics*
chemical_list: D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; C521869:SLC47A1 protein, human; D008687:Metformin; D017430:Prostate-Specific Antigen