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Lancet Oncol. 2014 Apr;15(4):406-14. doi: 10.1016/S1470-2045(14)70069-5. Epub 2014 Mar 11.

Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data.

Author information

1
Department of Medical Oncology and SIRIC, Institut Curie, Paris, France; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
2
Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium; University of Antwerp, Antwerp, Belgium.
3
Department of Gynecology and Obstetrics, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
4
Division of Medical Senology, European Institute of Oncology, Milan, Italy.
5
Clinical Laboratory, Hospital Arnau de Vilanova, Valencia, Spain.
6
University Hospital of Heraklion, Heraklion, Greece.
7
Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia, Brescia, Italy.
8
AZ Istituti Ospitalieri di Cremona, Cremona, Italy.
9
Department of Oncology, Hospital Clinico San Carlos, Department of Medicine, University Complutense of Madrid, Spain.
10
Imperial College and Imperial College Healthcare NHS Trust, London, UK.
11
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.
12
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
13
Hospital 12 de Octubre, Madrid, Spain.
14
IOV-IRCCS, Padova, Italy.
15
Hospital de Navarra, Pamplona, Spain.
16
Val d'Hebron Institute of Oncology, Val d'Hebron University Hospital, and Universitat Autònoma de Barcelona, Barcelona, Spain.
17
Department of Medical Oncology and Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
18
Department of Medical Oncology and SIRIC, Institut Curie, Paris, France.
19
Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium; University of Antwerp, Antwerp, Belgium; Department of Oncology, KU-Leuven, Leuven, Belgium.
20
Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy.
21
Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
22
Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
23
Frauenklinik, University of Ulm, Ulm, Germany.
24
Clinical oncology, Hospital Arnau de Vilanova, Valencia, Spain.
25
Saarland University, Homburg, Germany.
26
International Drug Development Institute, Louvain-La-Neuve, Belgium.
27
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
28
Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
29
Department of Medical Oncology and SIRIC, Institut Curie, Paris, France; Université Paris Descartes, Paris, France. Electronic address: jean-yves.pierga@curie.fr.
30
Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Sud, Villejuif, France.

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.

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

Janssen Diagnostics, the Nuovo-Soldati foundation for cancer research.

PMID:
24636208
DOI:
10.1016/S1470-2045(14)70069-5
[Indexed for MEDLINE]

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