title: Efficacy of Lapatinib in Therapy-Resistant HER2-Positive Circulating Tumor Cells in Metastatic Breast Cancer.
abstract: BACKGROUND
  To evaluate the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in therapy-resistant HER2-positive CTCs in metastatic breast cancer (MBC).
  
  
  METHODS
  Patients with MBC and HER2-positive CTCs despite disease stabilization or response to prior therapy, received lapatinib 1500 mg daily in monthly cycles, till disease progression or CTC increase. CTC monitoring was performed by immunofluorescent microscopy using cytospins of peripheral blood mononuclear cells (PBMCs) double stained for HER2 or EGFR and cytokeratin.
  
  
  RESULTS
  A total of 120 cycles were administered in 22 patients; median age was 62.5 years, 15 (68.2%) patients were post-menopausal and 20 (90.1%) had HER2-negative primary tumors. At the end of the second course, HER2-positive CTC counts decreased in 76.2% of patients; the median number of HER2-positive CTCs/patient also declined significantly (p = 0.013), however the decrease was significant only among patients presenting disease stabilization (p = 0.018) but not among those with disease progression during lapatinib treatment. No objective responses were observed. All CTC-positive patients harbored EGFR-positive CTCs on progression compared to 62.5% at baseline (p = 0.054). The ratio of EGFR-positive CTCs/total CTCs detected in all patients increased from 17.1% at baseline to 37.6% on progression, whereas the mean percentage of HER2-negative CTCs/patient increased from 2.4% to 30.6% (p = 0.03).
  
  
  CONCLUSIONS
  The above results indicate that lapatinib is effective in decreasing HER2-positive CTCs in patients with MBC irrespectively of the HER2 status of the primary tumor and imply the feasibility of monitoring the molecular changes on CTCs during treatment with targeted agents.
  
  
  BACKGROUND
  Clinical trial.gov NCT00694252.
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece; Laboratory of Tumor Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Agelaki
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kalykaki
authors.affiliation: Laboratory of Tumor Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Harris
authors.initials: H
authors.lastname: Markomanolaki
authors.affiliation: Laboratory of Tumor Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Papadaki
authors.affiliation: Laboratory of Tumor Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Galatea
authors.initials: G
authors.lastname: Kallergi
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece.
authors.forename: Dora
authors.initials: D
authors.lastname: Hatzidaki
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Kalbakis
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece; Laboratory of Tumor Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mavroudis
authors.affiliation: Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece; Laboratory of Tumor Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D002452:Cell Count; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017698:Postmenopause; D017697:Premenopause; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human