title: Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data.
abstract: BACKGROUND
  We aimed to assess the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with metastatic breast cancer by undertaking a pooled analysis of individual patient data.
  
  
  METHODS
  We contacted 51 European centres and asked them to provide reported and unreported anonymised data for individual patients with metastatic breast cancer who participated in studies between January, 2003, and July, 2012. Eligible studies had participants starting a new line of therapy, data for progression-free survival or overall survival, or both, and CTC quantification by the CellSearch method at baseline (before start of new treatment). We used Cox regression models, stratified by study, to establish the association between CTC count and progression-free survival and overall survival. We used the landmark method to assess the prognostic value of CTC and serum marker changes during treatment. We assessed the added value of CTCs or serum markers to prognostic clinicopathological models in a resampling procedure using likelihood ratio (LR) χ(2) statistics.
  
  
  RESULTS
  17 centres provided data for 1944 eligible patients from 20 studies. 911 patients (46·9%) had a CTC count of 5 per 7·5 mL or higher at baseline, which was associated with decreased progression-free survival (hazard ratio [HR] 1·92, 95% CI 1·73-2·14, p<0·0001) and overall survival (HR 2·78, 95% CI 2·42-3·19, p<0·0001) compared with patients with a CTC count of less than 5 per 7·5 mL at baseline. Increased CTC counts 3-5 weeks after start of treatment, adjusted for CTC count at baseline, were associated with shortened progression-free survival (HR 1·85, 95% CI 1·48-2·32, p<0·0001) and overall survival (HR 2·26, 95% CI 1·68-3·03) as were increased CTC counts after 6-8 weeks (progression-free survival HR 2·20, 95% CI 1·66-2·90, p<0·0001; overall survival HR 2·91, 95% CI 2·01-4·23, p<0·0001). Survival prediction was significantly improved by addition of baseline CTC count to the clinicopathological models (progression-free survival LR 38·4, 95% CI 21·9-60·3, p<0·0001; overall survival LR 64·9, 95% CI 41·3-93·4, p<0·0001). This model was further improved by addition of CTC change at 3-5 weeks (progression-free survival LR 8·2, 95% CI 0·78-20·4, p=0·004; overall survival LR 11·5, 95% CI 2·6-25·1, p=0·0007) and at 6-8 weeks (progression-free survival LR 15·3, 95% CI 5·2-28·3; overall survival LR 14·6, 95% CI 4·0-30·6; both p<0·0001). Carcinoembryonic antigen and cancer antigen 15-3 concentrations at baseline and during therapy did not add significant information to the best baseline model.
  
  
  CONCLUSIONS
  These data confirm the independent prognostic effect of CTC count on progression-free survival and overall survival. CTC count also improves the prognostication of metastatic breast cancer when added to full clinicopathological predictive models, whereas serum tumour markers do not.
  
  
  BACKGROUND
  Janssen Diagnostics, the Nuovo-Soldati foundation for cancer research.
authors.affiliation: Department of Medical Oncology and SIRIC, Institut Curie, Paris, France; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: François-Clément
authors.initials: FC
authors.lastname: Bidard
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium; University of Antwerp, Antwerp, Belgium.
authors.forename: Dieter J
authors.initials: DJ
authors.lastname: Peeters
authors.affiliation: Department of Gynecology and Obstetrics, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fehm
authors.affiliation: Division of Medical Senology, European Institute of Oncology, Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Nolé
authors.affiliation: Clinical Laboratory, Hospital Arnau de Vilanova, Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Gisbert-Criado
authors.affiliation: University Hospital of Heraklion, Heraklion, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mavroudis
authors.affiliation: Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grisanti
authors.affiliation: AZ Istituti Ospitalieri di Cremona, Cremona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.affiliation: Department of Oncology, Hospital Clinico San Carlos, Department of Medicine, University Complutense of Madrid, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Garcia-Saenz
authors.affiliation: Imperial College and Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cambridge Experimental Cancer Medicine Centre, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, and NIHR Cambridge Biomedical Research Centre, Cambridge, UK; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gazzaniga
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Manso
authors.affiliation: IOV-IRCCS, Padova, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Zamarchi
authors.affiliation: Hospital de Navarra, Pamplona, Spain.
authors.forename: Angela Fernandez
authors.initials: AF
authors.lastname: de Lascoiti
authors.affiliation: Val d'Hebron Institute of Oncology, Val d'Hebron University Hospital, and Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: De Mattos-Arruda
authors.affiliation: Department of Medical Oncology and Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Michail
authors.initials: M
authors.lastname: Ignatiadis
authors.affiliation: Department of Medical Oncology and SIRIC, Institut Curie, Paris, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Lebofsky
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium; University of Antwerp, Antwerp, Belgium; Department of Oncology, KU-Leuven, Leuven, Belgium.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: van Laere
authors.affiliation: Department of Gynecology and Obstetrics, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Meier-Stiegen
authors.affiliation: Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Sandri
authors.affiliation: Clinical Laboratory, Hospital Arnau de Vilanova, Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Vidal-Martinez
authors.affiliation: University Hospital of Heraklion, Heraklion, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Politaki
authors.affiliation: Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Consoli
authors.affiliation: AZ Istituti Ospitalieri di Cremona, Cremona, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.affiliation: Department of Oncology, Hospital Clinico San Carlos, Department of Medicine, University Complutense of Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Diaz-Rubio
authors.affiliation: Imperial College and Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krell
authors.affiliation: Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Dawson
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Raimondi
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Rutten
authors.affiliation: Frauenklinik, University of Ulm, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Janni
authors.affiliation: Division of Medical Senology, European Institute of Oncology, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Munzone
authors.affiliation: Clinical oncology, Hospital Arnau de Vilanova, Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Carañana
authors.affiliation: University Hospital of Heraklion, Heraklion, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Agelaki
authors.affiliation: Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Almici
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium; University of Antwerp, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Saarland University, Homburg, Germany.
authors.forename: Erich-Franz
authors.initials: EF
authors.lastname: Solomayer
authors.affiliation: Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Zorzino
authors.affiliation: International Drug Development Institute, Louvain-La-Neuve, Belgium.
authors.forename: Helene
authors.initials: H
authors.lastname: Johannes
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Department of Medical Oncology and SIRIC, Institut Curie, Paris, France; Université Paris Descartes, Paris, France. Electronic address: jean-yves.pierga@curie.fr.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Sud, Villejuif, France.
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D002272:Carcinoembryonic Antigen / Q000097:blood; D002452:Cell Count; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016013:Likelihood Functions; D008875:Middle Aged; D018396:Mucin-1 / Q000097:blood; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; C060192:MUC1 protein, human; D018396:Mucin-1