title: Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer.
abstract: BACKGROUND
  Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.
  
  
  METHODS
  Patients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([(11)C]lapatinib)-PET. Less than 20 μg of [(11)C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted.
  
  
  RESULTS
  Six patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [(11)C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [(11)C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [(11)C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib.
  
  
  CONCLUSIONS
  Increased lapatinib uptake was observed in brain metastases but not in normal brain.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01290354.
authors.affiliation: Imanova Centre for Imaging Sciences, Imperial College London, Hammersmith Hospital, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK. Azeem.Saleem@Imanova.co.uk.
authors.forename: Azeem
authors.initials: A
authors.lastname: Saleem
authors.affiliation: Imanova Centre for Imaging Sciences, Imperial College London, Hammersmith Hospital, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Searle
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Kenny
authors.affiliation: Imanova Centre for Imaging Sciences, Imperial College London, Hammersmith Hospital, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK.
authors.forename: Mickael
authors.initials: M
authors.lastname: Huiban
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK.
authors.forename: Kasia
authors.initials: K
authors.lastname: Kozlowski
authors.affiliation: Division of Brain Sciences, Imperial College Department of Imaging, Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Waldman
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Woodley
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, Duncan Building, Daulby Street, Liverpool, L69 3GA, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Palmieri
authors.affiliation: Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Road, W6 8RF, London, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Lowdell
authors.affiliation: GlaxoSmithKline Oncology, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Clinical Imaging and Medicines Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Murphy
authors.affiliation: Clinical Imaging and Medicines Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors.forename: Mike R
authors.initials: MR
authors.lastname: Lau
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK.
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Coombes
keywords: Blood-brain barrier; Her-2-positive breast cancer; Lapatinib bio-distribution in brain metastases; PET imaging