Elsevier

The Lancet Oncology

Volume 15, Issue 4, April 2014, Pages 406-414
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(14)70069-5Get rights and content

Summary

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.

Introduction

Over the past two decades, many systems for circulating tumour cell (CTC) detection have been developed.1 In 2004, CTC enumeration using the CellSearch system (Janssen Diagnostics, Raritan, NJ, USA) was shown to be significantly associated with progression-free survival and overall survival in 177 patients with metastatic breast cancer.2 The hazard ratio (HR) for the difference between late and early progression of disease reached a plateau at 5 CTC per 7·5 mL or higher. In the same cohort, changes in CTC count after the initiation of a new course of therapy were also shown to correlate with progression-free survival and overall survival.3 These results prompted the US Food and Drug Administration (FDA) to approve this CTC detection technique as a method to “monitor breast cancer treatment and indicate its effectiveness”.4

Since 2004, several other observational studies of patients with metastatic breast cancer, mainly done in European countries, have been reported using the CellSearch system.5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Most of these studies, however, reported either progression-free survival5, 6, 7 or overall survival,8 but not both endpoints, and contradictory results have been reported.7, 12 None of the reported studies had sufficient statistical power to ascertain the contribution of CTC count to prognostication above and beyond that provided by a full clinicopathological prognostication model and serum markers, or to assess prognostic effects across subgroups.15 To answer these questions, we did a pooled analysis to investigate the clinical validity of CTCs as detected by the CellSearch platform in patients with metastatic breast cancer.

Section snippets

Study design and population

The study protocol was set up by the study secretariat (F-CB, MI, KP, J-YP, SM), and discussed with investigators (appendix pp 16–22). We contacted each of the 51 European centres running a CellSearch platform between Sept 6, and Dec 31, 2012, and invited them to participate. We also searched Medline and major oncology congress abstracts to identify relevant studies (appendix pp 16–22).

Inclusion criteria were: reported and unreported studies done in European centres in patients with metastatic

Results

2400 potentially eligible patients were disclosed by 19 of the 51 centres we contacted. Two centres did not provide further data. The remaining 17 centres provided data for 2174 potentially eligible patients, of which we excluded 230 ineligible patients, leaving 1944 eligible patients from 20 studies and 17 centres (figure 1; appendix p 1–2, p 12).

We identified a high baseline CTC count (≥5 CTC per 7·5 mL) in 911 of the 1944 patients (46·9%, 95% CI 44·7–49·1). Median CTC count was 3 CTC per 7·5

Discussion

On the basis of individual patient data from both reported and unreported studies, our results provide firm evidence for the prognostic value of CTC detection at baseline and during treatment. Moreover, our analysis reports the clinical validity of early CTC changes during a new line of treatment in a specific patient, a favourable comparison with serum tumour markers, and show that these findings were not restricted to a specific subgroup (panel).

Non-European data were excluded to ensure that

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