title: OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy.
abstract: BACKGROUND
  Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters.
  
  
  METHODS
  Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected.
  
  
  RESULTS
  SLCO1B1 521C was significantly associated with increased SN-38 exposure (P<0.001), which was additive with UGT1A1*28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2-24C/T (odds ratio (OR)=0.22, 0.06-0.85) and CES1 (rs2244613; OR=0.29, 0.09-0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2-24T/T and UGT1A1*28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS.
  
  
  CONCLUSIONS
  Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Western University, Room B9-132, 339 Windermere Road, London, Ontario, Canada N6A 5A5.
authors.forename: W A
authors.initials: WA
authors.lastname: Teft
authors.affiliation: Department of Oncology, London Health Sciences Centre-Victoria Hospital, Western University, 800 Commissioners Road East, PO Box 5010, London, Ontario, Canada N6A 5W9.
authors.forename: S
authors.initials: S
authors.lastname: Welch
authors.affiliation: Department of Oncology, London Health Sciences Centre-Victoria Hospital, Western University, 800 Commissioners Road East, PO Box 5010, London, Ontario, Canada N6A 5W9.
authors.forename: J
authors.initials: J
authors.lastname: Lenehan
authors.affiliation: Department of Pathology, London Health Sciences Centre - University Hospital, Western University, 339 Windermere Road, London, Ontario, Canada N6A 5A5.
authors.forename: J
authors.initials: J
authors.lastname: Parfitt
authors.affiliation: Department of Epidemiology and Biostatistics, Kresge Building, Western University, London Ontario, Canada N6A 5C1.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Oncology, London Health Sciences Centre-Victoria Hospital, Western University, 800 Commissioners Road East, PO Box 5010, London, Ontario, Canada N6A 5W9.
authors.forename: E
authors.initials: E
authors.lastname: Winquist
authors.affiliation: 1] Department of Medicine, Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Western University, Room B9-132, 339 Windermere Road, London, Ontario, Canada N6A 5A5 [2] Department of Oncology, London Health Sciences Centre-Victoria Hospital, Western University, 800 Commissioners Road East, PO Box 5010, London, Ontario, Canada N6A 5W9 [3] Department of Physiology and Pharmacology, Medical Sciences Building, Western University, London, Ontario, Canada N6A 5C1.
authors.forename: R B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human