TY - JOUR
T1 - Clinical validity of circulating tumour cells in patients with metastatic breast cancer
T2 - A pooled analysis of individual patient data
AU - Bidard, François Clément
AU - Peeters, Dieter J.
AU - Fehm, Tanja
AU - Nolé, Franco
AU - Gisbert-Criado, Rafael
AU - Mavroudis, Dimitrios
AU - Grisanti, Salvatore
AU - Generali, Daniele
AU - Garcia-Saenz, Jose A.
AU - Stebbing, Justin
AU - Caldas, Carlos
AU - Gazzaniga, Paola
AU - Manso, Luis
AU - Zamarchi, Rita
AU - de Lascoiti, Angela Fernandez
AU - De Mattos-Arruda, Leticia
AU - Ignatiadis, Michail
AU - Lebofsky, Ronald
AU - van Laere, Steven J.
AU - Meier-Stiegen, Franziska
AU - Sandri, Maria Teresa
AU - Vidal-Martinez, Jose
AU - Politaki, Eleni
AU - Consoli, Francesca
AU - Bottini, Alberto
AU - Diaz-Rubio, Eduardo
AU - Krell, Jonathan
AU - Dawson, Sarah Jane
AU - Raimondi, Cristina
AU - Rutten, Annemie
AU - Janni, Wolfgang
AU - Munzone, Elisabetta
AU - Carañana, Vicente
AU - Agelaki, Sofia
AU - Almici, Camillo
AU - Dirix, Luc
AU - Solomayer, Erich Franz
AU - Zorzino, Laura
AU - Johannes, Helene
AU - Reis-Filho, Jorge S.
AU - Pantel, Klaus
AU - Pierga, Jean Yves
AU - Michiels, Stefan
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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) χ2 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.
AB - 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) χ2 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.
UR - http://www.scopus.com/inward/record.url?scp=84897445481&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(14)70069-5
DO - 10.1016/S1470-2045(14)70069-5
M3 - Article
C2 - 24636208
AN - SCOPUS:84897445481
SN - 1470-2045
VL - 15
SP - 406
EP - 414
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 4
ER -