title: Assessment of the Relation between the Expression of Oxaliplatin Transporters in Colorectal Cancer and Response to FOLFOX-4 Adjuvant Chemotherapy: A Case Control Study.
abstract: BACKGROUND
  Adjuvant chemotherapy for colorectal cancer is mainly based on the combination of 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX-4). The pharmacological target of oxaliplatin remains intracellular and therefore dependent on its entry into cells. The intracellular distribution of oxaliplatin is mediated by organic cation transporters 1, 2 and 3 (OCT1, 2 and 3), copper transporter 1 (CTR1) and ATPase Cu2+ transporting beta polypeptide (ATP7B) and may modulate the efficacy of oxaliplatin-based chemotherapy. The aim of this study was to perform a retrospective study to assess the relation between the expression of oxaliplatin transporters in colorectal cancer before chemotherapy and the response to FOLFOX-4 adjuvant chemotherapy in responder and non-responder patients.
  
  
  METHODS
  This retrospective study was conducted at a single center (University Hospital of Clermont-Ferrand, France). The target population was patients with resectable colorectal cancer operated between 2006 and 2013. Inclusion criteria were defined for the responder patients as no cancer recurrence 3 years after the end of chemotherapy, and for the non-responder patients as cancer recurrence within 1 year. Other inclusion criteria were stages IIb-IV cancers, first-line adjuvant FOLFOX-4 chemotherapy, and the availability of resected primary tumor samples. Exclusion criteria were preoperative chemotherapy and/or radiotherapy, a targeted therapy, other anticancer drugs, cancer recurrence between the first and the third year after the end of chemotherapy and follow-up < 3 years. Immunostaining of oxaliplatin transporters (OCT1, 2, 3, CTR1 and ATP7B) and Ki-67 was assessed in tumor samples.
  
  
  RESULTS
  Retrospectively, 31 patients have been selected according to inclusion and exclusion criteria (15 responders and 16 non-responders). Before FOLFOX-4 regimen, OCT3 expression was significantly lower in responder patients compared to non-responders (p<0.001). According to multivariate analysis, OCT3 remains an independent criterion for adjuvant FOLFOX chemotherapy response (p = 0.039). No significant relation is reported between chemotherapy response and the expression of OCT1 (p = 0.49), OCT2 (p = 0.09), CTR1 (p = 0.45), ATP7B (p = 0.94) and Ki-67 (p = 0.34) in tumors.
  
  
  CONCLUSIONS
  High expression of OCT3 could be an independent factor related to resistance to FOLFOX-4 chemotherapy.
authors: CHU Clermont-Ferrand, Service de chirurgie et oncologie digestive, F-63003, Clermont-Ferrand, France.
authors: Bertrand
authors: B
authors: Le Roy
authors: CHU Clermont-Ferrand, Service d'anatomopathologie, F-63003, Clermont-Ferrand, France.
authors: Lucie
authors: L
authors: Tixier
authors: CHU Clermont-Ferrand, Délégation à la Recherche Clinique et à l'Innovation, F-63003, Clermont-Ferrand, France.
authors: Bruno
authors: B
authors: Pereira
authors: CHU Clermont-Ferrand, Service de chirurgie et oncologie digestive, F-63003, Clermont-Ferrand, France.|INSERM/UdA U1071, USC INRA 2018, M2iSH, F-63001, Clermont-Ferrand, France.
authors: Pierre
authors: P
authors: Sauvanet
authors: CHU Clermont-Ferrand, Service de chirurgie et oncologie digestive, F-63003, Clermont-Ferrand, France.|INSERM/UdA U1071, USC INRA 2018, M2iSH, F-63001, Clermont-Ferrand, France.
authors: Emmanuel
authors: E
authors: Buc
authors: CHU Clermont-Ferrand, Service de chirurgie et oncologie digestive, F-63003, Clermont-Ferrand, France.
authors: Caroline
authors: C
authors: Pétorin
authors: CHU Clermont-Ferrand, Service d'anatomopathologie, F-63003, Clermont-Ferrand, France.|Université d'Auvergne, R2D2 - EA 7281, F-63001, Clermont-Ferrand, France.
authors: Pierre
authors: P
authors: Déchelotte
authors: CHU Clermont-Ferrand, Service de chirurgie et oncologie digestive, F-63003, Clermont-Ferrand, France.|INSERM/UdA U1071, USC INRA 2018, M2iSH, F-63001, Clermont-Ferrand, France.
authors: Denis
authors: D
authors: Pezet
authors: CHU Clermont-Ferrand, Délégation à la Recherche Clinique et à l'Innovation, F-63003, Clermont-Ferrand, France.|INSERM U1107, Neuro-Dol, F-63001, Clermont-Ferrand, France.
authors: David
authors: D
authors: Balayssac
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077150:Oxaliplatin; D012189:Retrospective Studies; D016896:Treatment Outcome; D000099254:Organic Cation Transporter 3
chemical_list: D000251:Adenosine Triphosphatases; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D005472:Fluorouracil; D002955:Leucovorin; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000099254:Organic Cation Transporter 3; C491013:SLC22A2 protein, human; C490079:SLC31A1 protein, human; C000612464:ATP7B protein, human