Annals of Oncology Advance Access originally published online on December 4, 2007
Annals of Oncology 2008 19(5):891-897; doi:10.1093/annonc/mdm558
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breast cancer |
Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications
1 Division of Medical Oncology, Medical Care Unit
2 Unit of Laboratory Medicine
3 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milano, Italy
* Correspondence to: Dr F. Nolé, Medical Care Unit, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy. Tel: +39-02-57489-460; Fax: +39-02-57489-457; E-mail: franco.nole{at}ieo.it
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Abstract |
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 Top Abstract introductionpatients and methodsstatistical methodsresultsdiscussionfundingAcknowledgementsReferences |
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Background: This study aimed to evaluate the prognostic significance of circulating tumor cells (CTCs) detection in advanced breast cancer patients.
Patients and methods: We tested 80 patients for CTC levels before starting a new treatment and after 4, 8 weeks, at the first clinical evaluation and every 2 months thereafter. CTCs were detected using the CellSearch SystemTM.
Results: Forty-nine patients had 
5 CTCs at baseline. At the multivariate analysis, baseline number of CTCs was significantly associated with progression-free survival [hazard ratio (HR) 2.5; 95% confidence interval (CI) 1.2–5.4]. The risk of progression for patients with CTCs 5 at last available blood draw was five times the risk of patients with 0–4 CTCs at the same time point (HR 5.3; 95% CI 2.8–10.4). Patients with rising or persistent 5 CTCs at last available blood draw showed a statistically significant higher risk of progression with respect to patients with <5 CTCs at both blood draws (HR 6.4; 95% CI 2.8–14.6).
Conclusion: CTCs basal value is a predictive indicator of prognosis and changes in CTC levels during therapy may indicate a clinical response. Testing CTC levels during targeted treatments might substitute other measurement parameters for response evaluation.
Key words: advanced breast cancer, breast cancer, circulating tumor cells, novel assay technology, prognostic value, tumor markers
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introduction |
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TopAbstractintroductionpatients and methodsstatistical methodsresultsdiscussionfundingAcknowledgementsReferences |
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Despite advances in early detection of breast cancer and in adjuvant treatments of localized disease, there are still a proportion of women who have metastases at the time of diagnosis or will further develop a metastatic disease.
Nowadays, it is not possible to accurately predict the risk of metastasis development in individual patients: >80% of them receive adjuvant chemotherapy while 
40% relapse and ultimately die of metastatic breast cancer [1].
The choice of treatment for advanced disease is currently on the basis of both prognostic and predictive factors including clinical features, such as disease-free interval, previous therapy, site of disease and number of metastatic sites [2–4]. Hormone receptor and Her2/neu status are the most commonly used predictive factors for endocrine and trastuzumab therapies [5]. Chemotherapy is the treatment of choice in patients with receptor-negative tumors, acquired resistance to hormones and aggressive visceral disease. No specific predictive factors for a response to chemotherapy have been sufficiently validated to be used in a standard clinical setting [6]. Patients are usually treated with different agents with the aim of inducing serial remissions, slowing the progression of the disease, and the treatment are continued until progression becomes evident [7]. The most consistent predictors of resistance to chemotherapy are nonspecific clinical features, including progression during prior treatments or relapse within 12 months after adjuvant chemotherapy, poor performance status and increasing number of sites of disease, especially visceral.
Clinical examination, radiographic and radionuclide studies and circulating tumor markers are currently the best approach to monitor patients with metastatic disease in order to determine whether the treatment is achieving the desired goal. All these approaches have low sensitivity in predicting the response to therapy and in the early detection of progression.
New prognostic markers are urgently needed to identify patients who are at the highest risk for developing metastases or those patients who are not responding to a given treatment. This would help oncologists to better tailor treatments to individual patients.
Circulating tumor cells (CTCs) were described for the very first time at the end of the 19th century [8], and their presence in the bloodstream fits with the hematogenous theory of metastatization [9]. Many reports have evaluated their role, and although it seems that the presence of CTCs in the peripheral blood may be correlated with clinical outcome, some results are still contradictory. These different conclusions may be due, at least in part, to the different approaches which have been used to detect CTCs [10].
The techniques that have been used to detect CTCs include cytometric and nucleic acid-based approaches. The cytometric approaches use immunocytochemical methods to identify and characterize the individual tumor cells. Nucleic acid-based approaches detect the DNA and RNA sequences that are differentially expressed in tumor cells and normal blood components [11]. It has been noted in the literature that, while pilot studies indicate that the identification of circulating cells may have a role in risk stratification and monitoring responses to treatment, larger longitudinal studies with standard techniques in clearly defined populations of patients are needed to establish the clinical significance of circulating breast cancer cells [11].
Recently, a new method has been proposed as a standardized and reproducible one [12]. The CellSearch SystemTM (Veridex LLC, Warren, NJ) was developed for the purpose of detecting CTCs in whole blood. The CellSearch system involves a technique of mixing a blood sample with iron particles coated with an antibody that attaches to epithelial cells. The epithelial cells are then distinguished from leukocytes by antibodies that have been tagged with a fluorescent dye so that the cancer cells can be easily distinguished and counted. Since epithelial cells are not usually found in the blood, these cells are likely cancerous cells from the breast tumor.
The currently available literature regarding the prognostic and predictive role of CTCs measured with this method demonstrate that the detection of >5 CTCs/7.5 ml of whole blood before treatment was associated with worse prognosis and that increased CTCs at any time during therapy is an indicator for disease progression [2, 3, 13, 14]. These results, although promising, however, were on the basis of the evaluation of a very well studied group of 177 metastatic breast cancer patients.
This study is aimed to evaluate the prognostic significance of CTCs detection in patients with advanced breast cancer. We investigated the association between the number of CTCs at baseline and patients’ characteristics as well as their modification during treatments.
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patients and methods |
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study design
A prospective mono-institutional study was conducted at the European Institute of Oncology. The inclusion criteria were as follows: women with histological diagnosis of breast cancer, evidence of metastatic disease from imaging studies, starting a new line of therapy and/or already treated for the advanced disease with a maximum two lines of therapy. Other criteria were as follows: adequate bone marrow (white blood cell count > 3.0 x 109/l, platelets > 100 x 109/l), renal (serum creatinine clearance < 120 µmol/l) and hepatic functions (serum bilirubin level < 20 µmol/l).
Before starting treatment, patients had to carry out a chest and abdomen computed tomography scan, a whole body bone scan and a baseline blood draw for enumeration of CTCs. Subsequently, blood samples were collected after 4 weeks, 8 weeks, at the time of the first clinical evaluation and every 2 months thereafter, until disease progression was documented. Disease status was reassessed every 9 or 12 weeks—depending on the treatment type and schedule—according to the Response Evaluation Criteria in Solid Tumors criteria [15], without knowledge of the level of CTCs.
The ethical committee approved the study protocol and all patients provided a written informed consent before entering the study.
isolation and enumeration of CTCs
To isolate and enumerate the CTCs, the CellSearch System (Veridex) was used. It consists of two instruments, one, the CellTracks AutoPrep System for the isolation and staining of the cells, the other, CellSpotter Analyzer, for the analysis and enumeration of the CTCs.
Ten milliliters of whole blood were drawn into the CellSave Preservative Tube (Veridex LLC, Raritan, NJ) containing EDTA as anticoagulant and a cellular preservative. Samples were maintained at room temperature and processed within 72 h after collection.
During the AutoPrep procedure, the sample is treated with a special mix of ferrofluids coated with epithelial cells-specific anti-EpCAM antibodies to immunomagnetically enrich epithelial cells; after magnetic separation unbound cells and remaining plasma are aspirated. Then the staining reagents are added (a mixture of two phycoerythrin-conjugated antibodies that bind to cytokeratin 8, 18, 19, an antibody to CD45 conjugated to allophycocyanin and a nuclear dye—4',6-diamidino-2-phenylindole (DAPI)—to fluorescently label the cells) in conjunction with a permeabilization buffer to fluorescence label the immunomagnetically labeled cells. After a second magnetic separation, the excess staining reagents are aspirated. In the final step, the cells are resuspended in a special device, a sort of cartridge, which consists of a chamber and two magnets that orient immunomagnetically labeled cells for analysis using the four-color semiautomated fluorescence microscope CellSpotter Analyzer. Images frames covering the entire surface of the cartridge for each of the four fluorescent filter cubes are captured. The images containing objects that meet predetermined criteria are automatically presented in a Web-enabled browser from which the final selection of cells is made by the operator. The criteria used are round or oval morphology, a DAPI positivity, positivity for cytokeratin and negative staining for CD45. Results are expressed as number of cells/7.5 ml of blood.
Data from the literature show a total imprecision of 8.2% for 319-cell spikes and 15.4% for 58-cell spikes [16].
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statistical methods |
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TopAbstractintroductionpatients and methodsstatistical methodsresultsdiscussionfundingAcknowledgementsReferences |
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The main objective of this study was to demonstrate the predictive value of the number of CTCs in patients with metastatic breast cancer treated with current therapy.
In a previous work by Cristofanilli et al. [2], 50% of the patients had five or more CTCs/7.5 ml, and their hazard ratio (HR) of disease progression was 1.8.
On the basis of our experience, patients were unequally distributed between the two classes, with 60% having five or more CTCs/7.5 ml and 40% <5. To detect an HR of 1.8 between the two classes of patients, with 80% power and 10% significance level, 75 patients were required.
Correlation between characteristics of population and number of CTCs at baseline (dichotomized as 5 versus <5) were analyzed by means of the chi-square test, the Fisher’s exact test or the Mantel–Haenszel test for trend.
Primary end points were progression-free survival (PFS), calculated from baseline blood draw to any disease progression or last visit date in case of no progression, and overall survival (OS), calculated from baseline blood draw to death from any cause or to last follow-up date if the patient was alive at the end of follow-up.
PFS curves were plotted using the Kaplan–Meier method. The log-rank test was used to assess survival differences between groups in the univariate analysis.
In the survival analysis, we used 5 CTCs/7.5 ml as the main cut-off point in order to permit direct and straightforward comparisons with previous studies [2]. We then used 20 CTCs/7.5 ml as the second arbitrary cut-off point because it was a round number that guaranteed similar number of patients in each strata.
When groups were defined on the basis of CTCs values at both baseline and first follow-up blood draws, survival was calculated from the date of the first blood draw.
Multivariate Cox proportional hazards regression models [17] were used to determine adjusted HRs for selected potential predictors of PFS. A time-dependent approach to the Cox model [18] was used to take into account changes in values of CTCs over the course of observation.
A bivariate linear random effect model for longitudinal data [19] was fitted to study the correlation between CTCs counts and marker CA 15-3 over the course of observation. A correlation coefficient was calculated taking into account all available information over the course of observation and dealing with intrasubject correlation. The joint evaluation of both markers was evaluated using the SAS MIXED procedure on a logarithmic transformation of the data.
All analyses were carried out with the SAS software (SAS Institute, Cary, NC). All tests were two-sided.
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results |
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A total of 80 patients were enrolled at the European Institute of Oncology from March 2005 to May 2006. Thirty-three patients were newly diagnosed with metastatic breast cancer (41%), while 28 (35%) and 19 (24%) were pretreated with one and two previous chemotherapy lines, respectively.
Median age at diagnosis of primary tumor and at first blood draw was 49 years (range 29–71) and 55 years (range 32–77), respectively. Median follow-up was 34 weeks (range 4–79).
Patients' characteristics, with stratification according to baseline number of CTCs, are summarized in Table 1. Forty-nine patients (61%) had 5 CTCs at baseline. Presence of 5 CTCs at baseline was associated with a higher number of positive lymph nodes involved at the time of primary surgery (P value for trend <0.01), with an elevated CA 15-3 value at baseline (P value 0.01), with non-overexpressing Her2/neu tumors (P value 0.01) and with the presence of bone metastases at baseline (P value 0.03). Remarkably, there were 48 patients with bone metastases and 71% of them had 5 CTCs at baseline.
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In Table 2, number of CTCs, at baseline, after 4 weeks (first follow-up visit), and correlation with clinical response (after 2 months) has been analyzed. One patient died before the first follow-up blood draw (the baseline number of CTCs was 15). At first clinical evaluation, 17 (22%) patients out of 79 had a partial response to therapy, with 9 of these (53%) having
5 CTCs at baseline and only one (6%) having 5 CTCs at the first follow-up visit. Among the 25 patients (32%) classified as having progressive disease at first clinical evaluation, 19 patients (76%) had 5 CTCs at baseline and 12 patients (48%) had 5 CTCs at the first follow-up visit. The remaining 37 patients (47%) were classified as having stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions); 20 of them (54%) had 5 CTCs at baseline and 11 patients (30%) had persistently elevated CTCs at the first follow-up visit.
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As expected, the number of patients decreased gradually as disease progressed. We had a total of 80 patients with a blood draw at baseline, 78 after 4 weeks, 76 after 8 weeks and then 64, 43, 21, 9, 6, 2 and 2 after, respectively, 16, 24, 32, 40, 48, 56 and 64 weeks.
A total of 25 patients (31%) had an evidence of disease progression during the follow-up period and nine died (15%). The overall median PFS was 8 months [95% confidence interval (CI) 5–13], and the median OS was not evaluable. Table 3 shows the significant predictors of PFS and OS according to the univariate analysis. Number of CTCs at baseline resulted significantly associated with PFS (P value 0.002). In Figure 1, three categories for the number of CTCs at baseline were evaluated and compared, 0–4, 5–19 and 20 CTCs; the resulting curves indicated a continuous nature of the association. When we considered CTCs baseline value as a continuous variable in the univariate survival model, it resulted as a statistically significant predictor of disease progression, with a P value of 0.047.
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CTCs changes from baseline to first follow-up resulted significantly associated with PFS (P value 0.018, see also Figure 2) and with OS (P value 0.014). Number of positive lymph nodes at the time of primary surgery and number of metastatic sites at baseline resulted significantly associated with PFS (P values 0.027 and 0.017, respectively) and were included in the multivariate analysis.
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At the multivariate analysis, number of CTCs at baseline remained significantly associated with PFS, with an adjusted HR of 2.5 (95% CI 1.2–5.4) (Table 4, Model 1). The risk of progression was much higher when considering the last available blood draw (HR 5.3; 95 % CI 2.8–10.4), which represents a more informative time-dependent measure (Table 4, Model 2). According to this model, the risk of progression for the patients with
5 CTCs at last available blood draw was 5 times the risk of patients with 0–4 CTCs at the same time point. Taking into account changes of CTCs values in time (Table 4, Model 3), patients with decreasing number of CTCs (group 2) showed a similar risk of disease progression compared with patients with persistent <5 CTCs (group 1) (HR 1.3; 95% CI 0.5–3.3), possibly indicating a therapeutic benefit in both groups. Patients with rising or persistent 5 CTCs (group 3) at last available blood draw showed a statistically significant higher risk as compared with (group 1) (HR 6.4; 95% CI 2.8–14.6), possibly indicating that the former group of patients were not responding to therapy.
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The joint evaluation between CTCs counts and marker CA 15-3 over the course of observation was then evaluated by a bivariate linear mixed model. CTCs values increased in time with increasing values of CA 15-3 and vice versa. CTCs values decreased in time with decreasing values of marker CA 15-3 and vice versa. Correlation coefficient was 0.43, significantly different from zero (P value <0.05), thus indicating a weakly positive correlation between the two markers.
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discussion |
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TopAbstractintroductionpatients and methodsstatistical methodsresultsdiscussionfundingAcknowledgementsReferences |
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The current single institution study on CTC levels detected by the CellSearch SystemTM in 80 patients with advanced breast cancer shows that changes in CTCs from baseline to the first follow-up are significantly correlated with variability of PFS and OS, adding further information to the data previously reported by Cristofanilli et al. [4].
Our results demonstrate that patients with a high number of CTCs at baseline and a decreased number of CTCs to <5 at the last available blood draw did not show a statistically significant higher risk of disease progression as compared with patients with <5 CTCs at both blood draws, possibly indicating a therapeutic benefit in both groups. Conversely, patients with rising or persistent 5 CTCs at last available blood draw showed a statistically significant higher risk as compared with patients with <5 CTCs at both blood draws, indicating that the former group of patients were not responding to therapy and had a worse prognosis.
In our patients, the presence 5 CTCs at baseline was associated with a higher number of positive lymph nodes involved at the time of primary surgery (P value for trend <0.01), with non-overexpressing Her2/neu tumors (P value 0.03) and with the presence of bone metastases at baseline (P value 0.06). These data, although represent a hypothesis generating association, indicate that a higher number of involved axillary nodes is a more unfavorable prognostic indicator. In addition, 71% of patients with bone metastases had 5 CTCs at baseline, indicating a possible association between bone marrow involvement and the subsequent release of CTCs in circulation. This higher prevalence of CTCs in patients with bone metastases represents an interesting finding and was never reported in previous studies using the same technology.
In the multivariate analysis, the number of CTCs at baseline remained significantly associated with PFS. The risk of progression was much higher when considering the last available blood draw which represents a more informative time-dependent measure. This information further implements the latest results published by Hayes et al. [13] showing that elevated CTCs at any time in the clinical course of a patient with metastatic breast cancer are indicators of impending progression. Therefore, if these data are validated, CTCs may represent a more objective and accurate determination of disease status than classic clinical and/or radiological assessment, and this may be an indicator for adjusting a useless therapy.
In the era of targeted and metronomic therapies, the use of a biological parameter of response to therapy might fit better than the classical criteria to the questions addressed by modern clinical trials. Consequently, the clinical implications of these results may influence the choice of more appropriate and tailored treatments and contribute to more sophisticate trial designs based also on a better stratification of the patients.
Moreover, these data may also indicate that a close monitoring of CTC levels during a given treatment might impact on an earlier change of the therapeutic strategy. Although it is not known whether this anticipated change may possibly have an impact on survival, as this question should be better addressed in randomized studies.
Serum tumor markers are a less complicated and less expensive mean of monitoring therapy than the imaging tests. Increasing levels of markers may indicate a need of changing therapy. Nowadays, the most widespread used tumor marker in breast cancer is CA 15-3. To better address this issue, we also carried out an analysis comparing CTC levels and CA 15-3. We found that elevated CA 15-3 basal value was associated with 5 CTC levels at baseline. CA 15-3 was then monitored over the course of observation and we found a correlation coefficient of 0.43, significantly different from zero (P value <0.05), indicating a weakly positive correlation between the two markers. Nonetheless, there are many previous studies indicating that monitoring of CA 15-3 levels is not a good predictor of OS and PFS [20]; therefore CTC detection seems to be a more reliable marker, although it is more expensive.
In conclusion, the results of the current study show that elevated CTC levels measured at any time in the clinical course of a patient with metastatic breast cancer, and especially at the last available follow-up, predict an imminent progression. Our analysis represents a further step toward the process of validating this method. Conversely, many questions are still open such as: should we treat with the same regimen a patient with low levels of CTC and a patient with a very high level? Can the efficacy of a treatment be assessed only by counting CTCs?
Several issues remain to be clarified: the markers used to detect tumor cells are not specific, it is not clear whether the tumor cells detected in peripheral blood represent true micrometastasis, studies have used different protocols, and finally data on long-term follow-up are lacking.
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funding |
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Schering-Plough SpA
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Acknowledgements |
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We thank nurses E. Bocchiola, L. Libutti and I. Limardi for their constant assistance and the technician M. Picozzi for his excellent technical assistance. The kits were partially provided free of charge by Veridex.
Received for publication September 6, 2007. Revision received November 6, 2007. Accepted for publication November 7, 2007.
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