title: Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer.
abstract: BACKGROUND
  Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens.
  
  
  METHODS
  We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls.
  
  
  RESULTS
  Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians.
  
  
  CONCLUSIONS
  To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Electronic address: eric_kim@urmc.rochester.edu.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: XiMing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, USA.
authors.forename: Derick R
authors.initials: DR
authors.lastname: Peterson
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kilari
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chi-Wan
authors.initials: CW
authors.lastname: Chow
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Swisher
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; The University of Ottawa and The Ottawa Hospital Cancer Center, Ottawa, ON, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zahid H
authors.initials: ZH
authors.lastname: Siddik
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D001741:Black or African American; D000368:Aged; D016190:Carboplatin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D027682:Cation Transport Proteins / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000079923:Copper Transporter 1; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D047368:Tumor Burden / Q000187:drug effects; D044465:White People
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490079:SLC31A1 protein, human; D016190:Carboplatin; D002945:Cisplatin
keywords: CTR1; Copper transporter; Drug delivery; Drug resistance; Drug transport; Non-small cell lung cancer; Platinum resistance; Transporter