Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer

IntroductionLymphocytopenia and circulating tumor cells (CTCs) have been reported as independent prognostic factors for overall survival (OS) in metastatic breast cancer (MBC), and both have been associated with bone metastases. Our objective was to compare the prognostic significance of lymphocytopenia, CTC count, and extensive bone metastases (> 2 lesions) assessed by fluorine-18 (¹⁸F) fluorodeoxyglucose positron emission tomography/computed tomography (FDG–PET/CT) in patients with MBC.Patients and MethodsThis is a retrospective study that included patients with MBC who were starting a new line of systemic therapy. The study population consisted of patients treated at the University of Texas MD Anderson Cancer Center between 2004 and 2008 for whom baseline CTC count, lymphocyte counts, and FDG–PET/CT scans were available. Patients were stratified according to estrogen receptor status (positive vs. negative), human epidermal growth factor receptor 2 (HER2) status (amplified vs. constitutive), baseline CTC counts per 7.5 mL of blood (< 5 CTCs/7.5 mL of blood vs. ≥ 5 CTCs/7.5 mL of blood), lymphocytopenia (< 1000 vs. ≥ 1000/μL), and extensive bone metastases (> 2 vs. ≤ 2 lesions).ResultsIn 195 assessable patients, the median OS was 27 months (range, 1 to > 45 months). In multivariate analysis, lymphocytopenia, ≥ 5 CTCs/7.5 mL of blood, estrogen receptor status, and line of therapy were the only predictive factors for progression-free survival (PFS) (2P = .001, 2P = .032, 2P = .029, and 2P = .002, respectively) and OS (2P = .001, 2P = .009, 2P = .004, and 2P = .024, respectively).ConclusionCTC measurement and lymphocytopenia are independent prognostic factors for PFS and OS in patients with MBC.     

The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer

The detection of circulating tumor cells (CTCs) in the peripheral blood of metastatic breast cancer (MBC) patients is an independent marker of prognosis. This large prospective multicenter study aimed to assess the impact of CTCs on overall survival (OS) and progression free survival (PFS) in patients with predefined molecular subgroups of MBC. To this end, 468 MBC patients were divided into three subgroups based on immunohistochemical staining of the primary tumor: (1) hormone receptor-positive/HER2-negative (HorR+/HER2?), (2) HER2-positive (HER2+), and (3) HorR-negative/HER2-negative (HorR?/HER2?) patients. CTC status (<5 CTCs/7.5 ml blood (CTC-negative) vs. ≥5 CTCs/7.5 ml blood (CTC-positive)) was determined using the CellCearch^® system before patients started a new line of therapy. At baseline, 205 (42 %) patients were CTC-positive. On multivariate analysis, CTC-positivity was an independent prognostic factor for shorter PFS and OS. In HorR+/HER2? patients, median PFS [95 % CI] of CTC-negative versus CTC-positive patients was 8.60 [5.93–11.27] versus 4.33 [3.29–5.38] months (p < 0.001), in HER2+ patients 7.60 [5.40–9.79] versus 6.60 [4.20–9.00] months (p = 0.477) and in HorR?/HER2? patients 5.83 [5.09–6.78] versus 3.05 [1.81–4.29] months (p < 0.001), respectively. Median OS [95 % CI] of CTC-negative versus CTC-positive patients was as follows: not reached by either in the HorR+/HER2? subgroup (p < 0.001), not reached versus 18.07 [11.10–25.05] months (p = 0.001) in the HER2+ subgroup, and not reached versus 8.57 [4.07–13.07] months in the HorR?/HER2? subgroup (p = 0.001). In conclusion, our results strongly confirm the independent prognostic value of CTC enumeration in MBC patients. In contrast to recent reports, there was no association between primary tumor-based molecular subgroups and the impact of CTC status on OS. Hence, CTC status may help to identify patients who require aggressive therapy, especially among those with triple-negative MBC.     

Prognostic value of circulating tumour cells in limited-stage small-cell lung cancer: analysis of the concurrent once-daily versus twice-daily radiotherapy (CONVERT) randomised controlled trial

BackgroundThe clinical significance of circulating tumour cells (CTCs) in limited-stage small-cell lung cancer (LS-SCLC) is not well defined. We report a planned exploratory analysis of the prevalence and prognostic value of CTCs in LS-SCLC patients enrolled within the phase III randomised CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy) trial.Patients and methodsBaseline blood samples were enumerated for CTCs using CellSearch in 75 patients with LS-SCLC who were enrolled in the CONVERT trial and randomised between twice- and once-daily concurrent chemoradiation. Standard statistical methods were used for correlations of CTCs with clinical factors. Log-rank test and Cox regression analyses were applied to establish the associations of 2, 15 and 50 CTC thresholds with progression-free survival (PFS) and overall survival (OS). An optimal CTC count threshold for LS-SCLC was established.ResultsCTCs were detected in 60% (45/75) of patients (range 0–3750). CTC count thresholds of 2, 15 and 50 CTCs all significantly correlate with PFS and OS. An optimal CTC count threshold in LS-SCLC was established at 15 CTCs, defining ‘favourable’ and ‘unfavourable’ prognostic risk groups. The median OS in <15 versus ≥15 CTCs was 26.7 versus 5.9 m (P = 0.001). The presence of ≥15 CTCs at baseline independently predicted ≤1 year survival in 70% and ≤2 years survival in 100% of patients.ConclusionWe report the prognostic value of baseline CTC count in an exclusive LS-SCLC population at thresholds of 2, 15 and 50 CTCs. Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS independent of all other factors and predicted ≤2 years survival. These results may improve disease stratification in future clinical trial designs and aid clinical decision making.Trial registrationClinicalTrials.gov identifier: NCT00433563.     

Prognostic Value of the Combination of Circulating Tumor Cells Plus KRAS in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab

ObjectiveCirculating tumor cells (CTCs) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status were identified as prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab in analyses of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial. In this post hoc analysis of the MACRO trial, the potential additive effect of these 2 factors on patient outcomes was explored.MethodsA total of 158 of the 480 patients involved in the MACRO trial were included in the biological marker substudy. CTC isolation and enumeration were centralized and performed using the CellSearch System (Veridex LLC, Raritan, NJ) in 7.5 mL of whole blood. Evaluation of KRAS status was performed retrospectively by the standard method used at each center. PFS and OS were analyzed by the Kaplan–Meier method according to CTC count and KRAS status.ResultsPatients with < 3 CTC per 7.5 mL blood at baseline and KRAS wild-type tumors had a median PFS of 14.2 months compared with 6.2 months in patients with ≥ 3 CTCs and KRAS mutated tumors (P < .0001; hazard ratio, 3.0; 95% confidence interval, 1.8-5.2). Similar findings were observed for OS (28.9 and 13.7 months, respectively, P = .0004; hazard ratio 2.8; 95% confidence interval, 1.6-4.9). Multivariate analyses showed that CTC count ≥ 3 and KRAS status were the only independent prognostic factors for both PFS and OS.ConclusionsThis post hoc analysis showed that CTC count and KRAS status were independent prognostic factors for outcomes in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy. These factors should be taken into account in the design of future phase III trials.     

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer

Background: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs.Patients and methods: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of ≥3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS).Results: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), ≥65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS.Conclusion: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.     

Circulating tumor cells predict progression-free and overall survival in Chinese patients with metastatic breast cancer,HER2-positive or triple-negative (CBCSG004): a multicenter,double-blind,prospective trial

BackgroundThe aim of this multicenter, double-blind, prospective study was to evaluate the potential utility of circulating tumor cell (CTC) measurements in predicting responses to anticancer therapies, including response to human epidermal growth factor receptor-2 (HER-2)-targeted agents, progression-free survival (PFS), and overall survival (OS) in Chinese women with metastatic breast cancer (MBC).Patients and methodsThree hundred MBC patients planned to complete three CTC blood draws and two imaging studies.ResultsA total of 294 of the 300 MBC patients enrolled from six leading Chinese cancer centers were assessable. In multivariate Cox regression analyses, the baseline CTC number remained an independent prognostic factor for PFS [hazard ratio (HR) = 1.93; 95% confidence interval (CI) = 1.39–2.69; P < 0.001) and OS (HR = 3.76; 95% CI = 2.35–6.01; P < 0.001). Similar results were observed for CTC counts at the first follow-up visit for both PFS (P = 0.049) and OS (P < 0.001).ConclusionsEnumeration of CTCs in Chinese MBC patients provides substantial prognostic information and is an independent factor associated with PFS and OS. Moreover, we demonstrated the prognostic value in the various disease subtypes, including HER-2-positive disease irrespective of therapy.     

Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy

BackgroundWe investigated whether circulating tumor cells (CTCs) and circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy combined with bevacizumab in metastatic breast cancer patients.Patients and methodsIn a French substudy of the MO19391 trial, CTC and CEC counts (CellSearch system) at baseline and changes after two cycles of treatment were correlated with time to progression (TtP).ResultsCTC and CEC levels were not correlated in the 67 patients included. At baseline, CTC positivity was a significant prognostic marker for TtP at a threshold of 3 CTC/7.5 ml (P < 0.05) but not at 5 CTC/7.5 ml (P = 0.09). Baseline CEC levels (median 17 CEC/4 ml, range 1–769) were associated with age ≥45 years (P = 0.01), elevated lactate dehydrogenase (P < 0.01) and not with TtP at any threshold. Changes of CTC count during treatment were not a surrogate of TtP, with any of the model tested (threshold based or relative decrease in percent). However, increase in CEC count was associated with improved TtP, at the threshold of 20 CEC/4 ml (P < 0.01).ConclusionBevacizumab combined with first-line chemotherapy may modify the predictive value of CTC during treatment possibly due to impaired tumor cells intravasation through vessels endothelium. Variations in CEC levels appear to be a promising early surrogate marker of TtP under antiangiogenic treatment.     

Relationship among circulating tumor cells,CEA and overall survival in patients with metastatic colorectal cancer

BackgroundWe previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival.Patients and methodsPatients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥10 ng/ml and CEA measurements within ±30 days of the CTC collection were included.ResultsWe included 217 patients with mCRC who had a CEA value of ≥10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3–5- and 6–12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6–12 weeks.ConclusionsThis study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.     

Detection of circulating tumor cells in peripheral blood of heavily treated metastatic breast cancer patients

Background

Circulating tumor cells (CTCs) are detected in peripheral blood of breast cancer patients, and they may play an important role as a prognostic and predictive marker. We conducted this study to determine the presence of CTCs with the CellSearch System? and the clinical significance in treatment of metastatic breast cancer (MBC).

Method

Twenty-eight MBC patients were enrolled. These patients were followed by assessing CTCs, imaging studies, and serum tumor markers. Blood samples were collected before starting a new treatment and at the treatment evaluation period (2–3 months after starting chemotherapy). The cutoff for CTC level was 5.

Results

At baseline, 9 of 28 patients (32%) had ≥5 CTCs per 7.5 mL of blood. At the evaluation period, 5 of 23 patients (22%) had ≥5 CTCs. The baseline CTC number did not contribute to determine their overall survival (OS); however, CTCs at the evaluation period were available to predict their OS (p < 0.001). In two cases, both CTCs and tumor markers were available as predictors of treatment efficacy. In two other cases, although alterations of tumor markers might not reflect disease condition, CTC alteration corresponded to their condition. One patient who had multiple skeletal metastasis only, experienced a decrease in her CTCs in spite of tumor marker alteration.

Conclusions

We suggest that monitoring the number of CTCs may be helpful in predicting the efficacy of the treatment and the prognosis. CTCs might be especially useful with patients whose lesions are difficult to assess.     

Mesenchymal marker and LGR5 expression levels in circulating tumor cells correlate with colorectal cancer prognosis

Purpose

The presence of circulating tumor cells (CTCs) has been found to correlate with colorectal cancer (CRC) prognosis, whereas epithelial-mesenchymal transition (EMT) in CTCs has been found to be associated with CRC metastasis. LGR5 is a known target of Wnt signaling and plays an important role in CRC development. The aim of this study was to assess the clinical relevance of EMT and LGR5 expression in CTCs from CRC patients.

Methods

Sixty-six CRC patients were included in this study. The detection and expression of EMT phenotypes in CTCs from these patients were assessed using CanPatrol? CTC enrichment and mRNA in situ hybridization (ISH), respectively. LGR5 expression in the CTCs was assessed using mRNA ISH.

Results

CTCs were detected in 86.4% (57/66) of the CRC patients included. Both the numbers of total CTCs and of CTCs displaying a mesenchymal phenotype (M+ CTCs) were found to significantly correlate with advanced disease stages and the occurrence of metastasis (p?<?0.05). An adjusted multivariate analysis also indicated that the number of M+ CTCs significantly correlated with the occurrence of metastasis (p?=?0.031). Additionally, we found that a high LGR5 expression level significantly correlated with the occurrence of metastasis (p?<?0.05). We also found that the presence of ≥ 6 CTCs or?≥?3 M+ CTCs per 5 ml blood significantly correlated with disease progression (p?<?0.05). Patients with ≥ 6 CTCs or?≥?3 M+ CTCs per 5 ml blood were found to exhibit poorer progression-free survival (PFS) and overall survival (OS) rates (p?<?0.05 in all cases). Using Cox regression analyses, we found that only total CTC numbers remained as independent prognostic factors for a worse PFS (p?=?0.043).

Conclusions

From our data we conclude that CTC numbers and EMT phenotypes may serve as prognostic markers for disease progression and metastasis in CRC patients. In addition, we conclude that LGR5 expression in CTCs may serve as a marker for CRC metastasis.

     

Clinical tumor stage is the most important predictor of pathological complete response rate after neoadjuvant chemotherapy in breast cancer patients

Purpose

Circulating tumor cell (CTC) is a well-established prognosis predictor for metastatic breast cancer (MBC), and CTC-cluster exhibits significantly higher metastasis-promoting capability than individual CTCs. Because measurement of CTCs and CTC-clusters at a single time point may underestimate their prognostic values, we aimed to analyze longitudinally collected CTCs and CTC-clusters in MBC prognostication.

Methods

CTCs and CTC-clusters were enumerated in 370 longitudinally collected blood samples from 128 MBC patients. The associations between baseline, first follow-up, and longitudinal enumerations of CTCs and CTC-clusters with patient progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models.

Results

CTC and CTC-cluster counts at both baseline and first follow-up were significantly associated with patient PFS and OS. Time-dependent analysis of longitudinally collected samples confirmed the significantly unfavorable PFS and OS in patients with ≥5 CTCs, and further demonstrated the independent prognostic values by CTC-clusters compared to CTC-enumeration alone. Longitudinal analyses also identified a link between the size of CTC-clusters and patient OS: compared to the patients without any CTC, those with 2-cell CTC-clusters and ≥3-cell CTC-clusters had a hazard ratio (HR) of 7.96 [95 % confidence level (CI) 2.00–31.61, P = 0.003] and 14.50 (3.98–52.80, P < 0.001), respectively.

Conclusions

In this novel time-dependent analysis of longitudinally collected CTCs and CTC-clusters, we showed that CTC-clusters added additional prognostic values to CTC enumeration alone, and a larger-size CTC-cluster conferred a higher risk of death in MBC patients.

     

Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial

BackgroundPancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients.Patients and methodsAn LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch®) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection.ResultsSeventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia.ConclusionsThe evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients.     

Circulating tumor cell telomerase activity as a prognostic marker for overall survival in SWOG 0421: A phase III metastatic castration resistant prostate cancer trial

Circulating tumor cells (CTC) are promising biomarkers in metastatic castration resistant prostate cancer (mCRPC), and telomerase activity (TA) is a recognized cancer marker. Therefore, we hypothesized that CTC TA may be prognostic of overall survival (OS) in mCRPC. To test this, we used a novel Parylene‐C slot microfilter to measure live CTC TA in S0421, a phase III SWOG‐led therapeutic trial. Blood samples underwent CTC capture and TA measurement by microfilter, as well as parallel enumeration by CellSearch (Janssen/J&J). Cox regression was used to assess baseline (pre‐treatment) TA versus OS, and recursive partitioning was used to explore potential prognostic subgroups and to generate Kaplan‐Meier (KM) OS curves. Samples were obtained from 263 patients and generated 215 TA measures. In patients with baseline CTC count ≥5 (47% of patients), higher CTC TA was associated with hazard ratio 1.14 (p = 0.001) for OS after adjusting for other clinical covariates including CTC counts and serum PSA at study entry. Recursive partitioning identified new candidate risk groups with KM OS curve separation based on CTC counts and TA. Notably, in men with an intermediate range baseline CTC count (6–54 CTCs/7.5 ml), low versus high CTC TA was associated with median survival of 19 versus 12 months, respectively (p = 0.009). Baseline telomerase activity from CTCs live‐captured on a new slot microfilter is the first CTC‐derived candidate biomarker prognostic of OS in a large patient subgroup in a prospective clinical trial. CTC telomerase activity thus merits further study and validation as a step towards molecular CTC‐based precision cancer management.     

Circulating Tumor Cells Following First Chemotherapy Cycle: An Early and Strong Predictor of Outcome in Patients With Metastatic Breast Cancer

We investigated the prognostic significance of circulating tumor cells (CTCs) determined immediately before the second cycle of chemotherapy in patients with metastatic breast cancer (MBC). The CTC counts were taken at baseline, before the first cycle of chemotherapy (CTC‐0), and on day 21 before commencing the second cycle of chemotherapy (CTC‐21) in consecutive MBC patients. The study's primary objectives were to analyze relationships between CTC‐21 count and overall survival (OS). Based on the current literature, the CTC measurements were dichotomized as 0–4 versus ≥5 CTCs. Of 117 patients recruited, 99 were evaluable. Patients with 0–4 CTCs on day 21 had a significantly better OS than those with ≥5 CTCs (median OS: 38.5 months vs. 8.7 months). They also had a significantly better progression‐free survival (PFS; median: 9.4 months vs. 3.0 months) and clinical benefit rate (77% vs. 44%). The OS of patients whose baseline CTCs were ≥5 but dropped to <5 on day 21 was apparently similar to those who had <5 CTCs at baseline. In a Cox regression analysis, CTC‐21 was the only independent variable significantly predicting OS and PFS. Our data indicate that CTCs determined immediately before the second cycle of chemotherapy is an early and strong predictor of treatment outcome in MBC patients.     

Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects

BackgroundThe identification of dynamic biomarkers in advanced gastric and oesogastric junction adenocarcinoma (GOA) could help to tailor strategies for each patient. Enumeration of circulating tumour cells (CTCs) is approved by the US Food and Drug Administration in breast, colon and prostate cancer but is not in advanced GOA. Our study aims to establish the optimal threshold and the clinical significance of CTC count in advanced GOA before and during treatment.MethodsOne hundred six patients with untreated advanced GOA were included in the ancillary study of the PRODIGE 17-ACCORD 20 trial. CTCs were detected in the peripheral blood using the CellSearch system on day 0 (D0) and day 28 (D28). The prognostic value of CTCs at D0 and D28 was analysed by testing several thresholds.ResultsAt baseline, median CTC count was 1 (range, 0–415). While CTCs ≥1, 2 or 3 at D0 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS), CTCs ≥2 were the optimal threshold, on D0 or D28. CTCs ≥2 at D28 were also predictive of disease control. Taking into account both D0 and D28 CTC count defined 3 groups (low/low, high/low and low-high/high) with significantly different PFS (p = 0.0002) and OS (p = 0.003).ConclusionQuantification of CTCs at baseline and during treatment may be a useful prognostic tool in advanced GOA, as it is associated with worse PFS and OS. A threshold ≥2 CTCs seems to have the best discriminant value. Change in CTC count between baseline and D28 could help to tailor treatment to each individual patient.     

Prognostic significance of circulating tumor cells in advanced non-small cell lung cancer patients treated with docetaxel and gemcitabine

Purpose

To evaluate the association in the change of circulating tumor cell (CTC) levels and clinical outcomes (PFS and OS) in patients with advanced non-small cell lung cancer (NSCLC) treated homogenously with docetaxel and gemcitabine administered every 2 weeks.

Methods

We prospectively evaluated 37 patients for CTC levels at baseline and after 2 months of chemotherapy (before third cycle). Detection was carried out with the CellSearch system.

Results

Nine of the 37 patients (24 %) had ≥2 CTCs at the baseline determination. Median progression-free survival (PFS) was 4.3 months (95 % CI 2.5–8.3) for patients with CTC 0–1 as compared to 9.4 months (95 % CI 1.2–12.2) for those with CTC ≥2 (p = 0.3506). Median overall survival (OS) was 8.1 (95 % CI 2.8–16.3) and 12.2 (95 % CI 1.4–12.2) months for patients with 0–1 CTCs and ≥2 CTCs, respectively (p = 0.7639). Patients with a second CTC quantification were classified as: group 1, CTC = 0–1 at baseline and CTC = 0–1 after second chemotherapy cycle (18 patients); group 2, CTC ≥2 at baseline and CTC = 0–1 after second determination (5 patients). Median PFS was 7.7 and 9.9 months for group 1 and group 2, respectively (p = 0.4467).

Conclusions

CTCs ≥2 at baseline were detected only in 24 % of this group of patients with advanced NSCLC and poor performance status. No significant differences in PFS and OS between patients with or without CTCs at baseline were observed.     

Levels of specific serum N-glycans identify breast cancer patients with higher circulating tumor cell counts

BackgroundMetastatic breast cancer (MBC) is currently an incurable condition that is primarily treated with palliative measures. Isolation of circulating tumor cells (CTCs) from the peripheral blood of these patients provides a predictive prognostic indicator, independent of the type of therapy, site of occurrence and biological characteristics of the primary disease. It has been well established that glycosylation processing pathways are disturbed in cancer, leading to alterations in the glycan content of glycoproteins.Materials and methodsThe bi-, tri- and tetraantennary glycans containing sialyl Lewis x (sLe^x) epitopes (A2F1G1, A3F1G1, A4F1G1 and A4F2G2) were quantified using normal phase high-performance liquid chromatography in combination with exoglycosidase array digestions in the glycan pools released from sera of 27 patients with advanced breast cancer (16 with CTCs <5/7.5 ml and 11 with CTCs ≥5/7.5 ml) and 13 healthy women.ResultsThe levels of all these glycans were significantly higher in patients with CTCs ≥5/7.5 ml compared with patients with CTCs <5/7.5 ml.ConclusionsAs high levels of glycans containing sLe^x epitopes were associated with CTCs, their measurement may provide a new noninvasive approach for determining prognosis in women with MBC.     

Evaluation of circulating tumor cells in patients with breast cancer: multi-institutional clinical trial in Japan

BACKGROUND: With the development of the CellSearch System, it has become possible to measure circulating tumor cell (CTC) levels with high reproducibility, and the CTC test is currently being used clinically for patients with metastatic breast cancer in the United States. It is imperative that the clinical significance of the CTC test also be examined in Japan. METHODS: Using the CellSearch System, CTC levels were evaluated in 57 healthy individuals and patients with benign breast disease; 30 patients with primary breast cancer (stages 1-3); and 38 patients with metastatic breast cancer. First, the relationship between CTC levels and the presence of metastasis was examined using a cutoff score of 2 CTCs per 7.5 ml whole blood. Then, the patients with metastatic breast cancer were divided into two groups, using a cutoff score of 5 CTCs per 7.5 ml blood, and progression-free survival (PFS) and overall survival (OS) were compared in the two groups. RESULTS: When the clinical cutoff score was set at 2 CTCs per 7.5 ml blood, 0% of the healthy individuals and patients with benign breast disease (0/57), 3.3% of the patients with primary breast cancer (1/30), and 50% of the patients with metastatic breast cancer (19/38) were identified as as having 2 CTCs per 7.5 ml blood. Additionally, with a cutoff score of 5 CTCs, 11 patients were reported to have 5 or more CTCs and both PFS (P = 0.0036) and OS (P = 0.04) were worse for this patient population than for the population with fewer than 5 CTCs. CONCLUSION: As concluded in a similar clinical trial in the United States, for patients with breast cancer, measuring CTC levels can be both an accurate indicator of metastases and an important measure of patient prognosis.     

Detection and prognostic significance of circulating tumour cells in patients with metastatic breast cancer according to immunohistochemical subtypes

Background:

The enumeration of circulating tumour cells (CTCs) with the EpCAM-based CellSearch system has prognostic significance in patients with metastatic breast cancer (MBC). The aim of this study was to explore potential differences in the detection and prognostic significance of CTCs in MBC according to immunohistochemical subtypes of breast cancer.

Methods:

CellSearch CTC counts were obtained from 154 MBC patients before first-line systemic treatment between November 2007 and August 2012. Patients were categorised in five subgroups according to immunohistochemical surrogate definitions of intrinsic subtypes in breast cancer based on hormone receptor status, HER2/neu status and histological grade. Differences in progression-free (PFS) and overall survival (OS) were assessed relative to the cut-off value of ⩾5 CTCs per 7.5 ml blood.

Results:

No significant differences were observed in the absolute CTC counts (P=0.120) or in CTC positivity rates according to ⩾1 and ⩾5 CTCs per 7.5 ml blood detection thresholds (P=0.165 and P=0.651, respectively) between immunohistochemical subtypes. However, very high CTC counts, defined as ⩾80 CTCs per 7.5 ml, were observed more frequently in patients with Luminal A and triple negative (TN) breast cancer (P=0.024). In the total study population, the presence of ⩾5 CTCs was the single most significant prognostic factor for both PFS and OS in multivariate analysis (P<0.001). A more limited prognostic impact, not reaching statistical significance, was observed in patients with HER2-positive disease as opposed to patients with Luminal A, Luminal B–HER2-negative and TN disease.

Conclusion:

The detection of EpCAM+CTCs was not clearly associated with any of the immunohistochemical subtypes of breast cancer in patients with MBC before first-line treatment. Potentially clinically relevant differences were however observed at very high CTC counts. Furthermore, our data suggest a lower prognostic significance of CTC evaluation in HER2-positive patients with MBC.     

Determination of cut-offs for circulating tumor cell measurement in metastatic cancer

Evaluation of: Pierga JY, Hajage D, Bachelot T et al. High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients. Ann. Oncol. DOI: 10.1093/annonc/mdr263 (2011) (Epub ahead of print).

The metastatic transformation of epithelial tumors progresses through various steps leading to the generation of circulating tumor cells (CTCs). Measurement of CTCs in the peripheral blood is being increasingly recognized as a promising tool in breast oncology. Several studies have evaluated the prognostic significance of CTCs in newly diagnosed metastatic breast cancer (MBC) patients. The IC 2006-04 was a high-powered, prospective, multicenter, observational study conceived to assess CTC changes in women with MBC treated with first-line chemotherapy. Levels ≥5 CTCs/7.5 ml blood at baseline and before the second cycle of treatment were independent prognostic factors associated with shorter progression-free and overall survival. This study provides further level II evidence for the clinical and prognostic value of CTCs in MBC, confirming data from earlier small studies. It also provides proof that CTCs should be investigated in ongoing interventional trials to see if better patient outcomes can be attained by altering treatment based on CTC levels.