title: Copper Transporter-CTR1 Expression and Pathological Outcomes in Platinum-treated Muscle-invasive Bladder Cancer Patients.
abstract: OBJECTIVE
  Platinum (Pt)-based neoadjuvant chemotherapy (NAC) is the standard-of-care for muscle-invasive bladder cancer (MIBC). However, the survival benefit with NAC is driven by patients with pathological response at cystectomy. Non-responders are subject to adverse effects of Pt, with delay in definitive treatment. Copper transporter receptor 1 (CTR1) plays an important role in Pt uptake and the level of expression may influence Pt sensitivity. We hypothesized that tumor CTR1 expression correlated with pathological outcome.
  
  
  METHODS
  We identified matched paraffin-embedded tissues from pre-NAC transurethral bladder tumor resection (TURBT) and post-NAC radical cystectomy (RC) specimens in 47 patients with MIBC who received Pt-based NAC. Tumor and adjacent normal tissues were stained with CTR1 antibody. CTR1 expression was determined through immunohistochemistry by two pathologists blinded to the outcome (0=undetectable; 1+=barely detectable; 2+=moderate; and 3+=intense staining). Pathological response was defined as either down-staging to non-MIBC (≤pT1N0M0) or complete pathological response (pT0). Pathological outcome was compared between the CTR1 expression groups.
  
  
  RESULTS
  Forty-three percent of TURBT and 41% of RC specimens expressed a CTR1 score of 3+. Forty-four percent of patients had a pathological response to NAC, and 17% had pT0 disease at cystectomy. In both pre-NAC TURBT and post-NAC RC specimens, a CTR1 expression score of 3+ correlated with pathological response (p=0.0076 and p=0.023, respectively).
  
  
  CONCLUSIONS
  This is the first study to demonstrate a correlation between CTR1 tumor expression and pathological outcome in Pt-treated MIBC. These findings suggest that CTR1 expression may be a biomarker for Pt sensitivity.
authors: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, U.S.A. dkilari@mcw.edu.
authors: Deepak
authors: D
authors: Kilari
authors: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, U.S.A.
authors: Kenneth A
authors: KA
authors: Iczkowski
authors: Department of Community and Preventive Medicine, University of Rochester Medical Center, Rochester, NY, U.S.A.
authors: Chintan
authors: C
authors: Pandya
authors: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, U.S.A.
authors: Adam J
authors: AJ
authors: Robin
authors: Department of Urology, University of Rochester Medical Center, Rochester, NY, U.S.A.
authors: Edward M
authors: EM
authors: Messing
authors: Department of Medicine, University of Rochester Medical Center, Rochester, NY, U.S.A.
authors: Elizabeth
authors: E
authors: Guancial
authors: Department of Medicine, University of Rochester Medical Center, Rochester, NY, U.S.A.
authors: Eric S
authors: ES
authors: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D027682:Cation Transport Proteins / Q000378:metabolism*; D000079923:Copper Transporter 1; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490079:SLC31A1 protein, human; D010984:Platinum
keywords: CTR1; Urothelial carcinoma; copper; muscle-invasive bladder cancer; platinum