title: Intraoperative imaging of folate receptor alpha positive ovarian and breast cancer using the tumor specific agent EC17.
abstract: BACKGROUND
  Intraoperative fluorescence imaging of the folate-receptor alpha (FRα) could support completeness of resection in cancer surgery. Feasibility of EC17, a FRα-targeting agent that fluoresces at 500nm, was demonstrated in a limited series of ovarian cancer patients. Our objective was to evaluate EC17 in a larger group of ovarian cancer patients. In addition, we assessed the feasibility of EC17 in patients with breast cancer.
  
  
  METHODS
  Two-to-three hours before surgery 0.1mg/kg EC17 was intravenously administered to 12 patients undergoing surgery for ovarian cancer and to 3 patients undergoing surgery for biopsy-proven FRα-positive breast cancer. The number of lesions/positive margins detected with fluorescence and concordance between fluorescence and tumor- and FRα-status was assessed in addition to safety and pharmacokinetics.
  
  
  RESULTS
  Fluorescence imaging in ovarian cancer patients allowed detection of 57 lesions of which 44 (77%) appeared malignant on histopathology. Seven out of these 44 (16%) were not detected with inspection/palpation. Histopathology demonstrated concordance between fluorescence and FRα- and tumor status. Fluorescence imaging in breast cancer patients, allowed detection of tumor-specific fluorescence signal. At the 500nm wavelength, autofluorescence of normal breast tissue was present to such extent that it interfered with tumor identification.
  
  
  CONCLUSIONS
  FRα is a favorable target for fluorescence-guided surgery as EC17 produced a clear fluorescent signal in ovarian and breast cancer tissue. This resulted in resection of ovarian cancer lesions that were otherwise not detected. Notwithstanding, autofluorescence caused false-positive lesions in ovarian cancer and difficulty in discriminating breast cancer-specific fluorescence from background signal. Optimization of the 500nm fluorophore, will minimize autofluorescence and further improve intraoperative tumor detection.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.|Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Quirijn R J G
authors.initials: QR
authors.lastname: Tummers
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.|Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Charlotte E S
authors.initials: CE
authors.lastname: Hoogstins
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Katja N
authors.initials: KN
authors.lastname: Gaarenstroom
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cor D
authors.initials: CD
authors.lastname: de Kroon
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mariette I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Vuyk
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cohen
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN, USA.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Vahrmeijer
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D005189:False Positive Reactions; D005240:Feasibility Studies; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D058975:Folate Receptor 1 / Q000032:analysis*; D005492:Folic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007430:Intraoperative Care; D008163:Luminescent Measurements; D008875:Middle Aged; D009426:Netherlands; D061848:Optical Imaging / Q000379:methods*; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D011237:Predictive Value of Tests; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; C548696:FOLR1 protein, human; D005456:Fluorescent Dyes; D058975:Folate Receptor 1; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate
keywords: breast cancer; fluorescence; folate-receptor alpha; image-guided surgery; ovarian cancer