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

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.

Serial Analysis of Circulating Tumor Cells in Metastatic Breast Cancer Receiving First-Line Chemotherapy.

BACKGROUND: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. METHODS: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS. RESULTS: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. CONCLUSIONS: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper.

BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p < 0.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.

Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker. Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided. Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008). Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.

Quantification of circulating endothelial cells as a predictor of response to chemotherapy with platinum and pemetrexed in patients with advanced non-squamous non-small cell lung carcinoma.

INTRODUCTION: Circulating endothelial cells (CEC) play an important role in tumor neovascularization and may have prognostic value in cancer patients. This study was designed to investigate the role of CEC as a marker for predicting platinum plus pemetrexed first-line chemotherapy efficacy in advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: A prospective study was performed whose main objective was to study whether the numbers of CEC at baseline and prior to the second and third cycle of chemotherapy were response predictors. Sixty-nine patients received cisplatin plus pemetrexed, and peripheral blood samples were performed at baseline and after second and third cycle. Separation and CEC count were performed using inmunomagnetic separation (CellSearch). RESULTS: The CEC count in 4 mL of peripheral blood was obtained prior to the first, second, and third cycle of treatment. Baseline levels and evolution of CEC were correlated with response to treatment according to RECIST criteria after three cycles of treatment. Sixty-nine patients were included: 43 (64.2 %) received cisplatin/pemetrexed and 24 (35.8 %) carboplatin/pemetrexed. Range of baseline CEC: 8-965 (mean of 153 cel/4 mL). The results after 3 cycles were: 25 partial responses (36.2 %), 17 cases of stabilization of disease (24.6 %), 16 of progressive disease (23.2 %) and 11 non-evaluables (16 %). No significant relationship between the baseline CEC count and response was found (p value = 0.831). Increase >50 % between the first and second cycle was correlated significantly with progression disease (p = 0.008). Patients who had a baseline CEC count greater than the mean (>153 cells/4 mL) showed longer progression-free survival and global survival without statistical significance. CONCLUSIONS: In this homogeneous group of patients with NSCLC, there is no correlation between response to treatment and CEC baseline levels. The increase in CEC numbers after the first cycle could be a negative predictive factor.

Quantification of circulating endothelial cells as a predictor of response to chemotherapy with platinum and pemetrexed in patients with advanced non-squamous non-small cell lung carcinoma

Introduction: Circulating endothelial cells (CEC) play an important role in tumor neovascularization and may have prognostic value in cancer patients. This study was designed to investigate the role of CEC as a marker for predicting platinum plus pemetrexed first-line chemotherapy efficacy in advanced non-squamous non-small cell lung cancer (NSCLC). Methods: A prospective study was performed whose main objective was to study whether the numbers of CEC at baseline and prior to the second and third cycle of chemotherapy were response predictors. Sixty-nine patients received cisplatin plus pemetrexed, and peripheral blood samples were performed at baseline and after second and third cycle. Separation and CEC count were performed using inmunomagnetic separation (CellSearch). Results: The CEC count in 4 mL of peripheral blood was obtained prior to the first, second, and third cycle of treatment. Baseline levels and evolution of CEC were correlated with response to treatment according to RECIST criteria after three cycles of treatment. Sixty-nine patients were included: 43 (64.2 %) received cisplatin/pemetrexed and 24 (35.8 %) carboplatin/pemetrexed. Range of baseline CEC: 8–965 (mean of 153 cel/4 mL). The results after 3 cycles were: 25 partial responses (36.2 %), 17 cases of stabilization of disease (24.6 %), 16 of progressive disease (23.2 %) and 11 non-evaluables (16 %). No significant relationship between the baseline CEC count and response was found (p value = 0.831). Increase >50 % between the first and second cycle was correlated significantly with progression disease (p = 0.008). Patients who had a baseline CEC count greater than the mean (>153 cells/4 mL) showed longer progression-free survival and global survival without statistical significance. Conclusions: In this homogeneous group of patients with NSCLC, there is no correlation between response to treatment and CEC baseline levels. The increase in CEC numbers after the first cycle could be a negative predictive factor (AU)

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