Changing levels of circulating tumor cells in monitoring chemotherapy response in patients with metastatic breast cancer.
ABSTRACT The detection of >5 circulating tumor cells (CTCs)/7.5 ml blood in patients being treated for metastatic breast cancer (MBC) has recently been shown to be predictive for therapy efficacy. The aim of this study was to investigate whether changing CTC levels during the course of chemotherapy treatment would also be useful in monitoring response to treatment.
CTC levels were determined in 58 MBC patients at the beginning and after 3 cycles of chemotherapy. Changes in CTC level (either negative CTCs (<5 CTCs/7.5 ml blood) turning positive, vice versa, or a change of ±25%) were correlated to radiologic Response Evaluation Criteria In Solid Tumors (RECIST) criteria, as well as serum CA 15-3 measurements, and were evaluated for their capability to predict survival.
Changing CTC levels significantly correlated with response to therapy as measured by radiologic RECIST criteria (p<0.001), and serum CA 15-3 level changes (p=0.017). Patients with decreasing CTC levels survived significantly longer than patients with increasing CTC levels (17.67±5.90 months versus 4.53±0.54 months, p<0.001).
The observation of changes in CTC level during the course of chemotherapy is useful in monitoring therapy efficacy and is correlated with overall survival. Further prospective trials should investigate the clinical usefulness of determining changes in CTC level during chemotherapy of MBC.
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ABSTRACT: Detection of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is associated with poor outcome. The aim of our study was to evaluate the impact of BM status on survival in a large cohort of cervical cancer patients. 325 patients with cervical cancer were included into this prospective two-center study (University Hospitals Tuebingen, Munich, Germany). BM was collected preoperatively. DTCs were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3. DTCs were detected in 22% of all BM aspirates. The number of CK-positive cells ranged from 1 to 93 per 2 × 10(6) mononuclear cells. 18% of patients with T1 stage presented with DTCs in BM compared to 30% in T2 and 45% in T3/4 patients. Among nodal negative patients 18% had tumor cells in BM compared to 32% of nodal positive patients. Positive DTC status was associated with tumor size (p = 0.007) and nodal status (p = 0.009) but not with grading (p = 0.426). DTC status did not correlate with overall or disease-free survival. In the univariate analysis, tumor stage, nodal status, resection status and grading correlated with OS and DFS. In the multivariate analysis, only tumor stage and nodal status were independent predictors of OS and tumor stage, nodal status and grading of DFS. Tumor cell dissemination into bone marrow is thus a common phenomenon in cervical cancer and correlates with higher tumor load but lacks prognostic relevance. Alternative detection methods may be needed to establish prognostic potential. © 2013 Wiley Periodicals, Inc.International Journal of Cancer 08/2013; · 6.20 Impact Factor
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ABSTRACT: 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. 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. 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. 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. Janssen Diagnostics, the Nuovo-Soldati foundation for cancer research.The Lancet Oncology 03/2014; · 25.12 Impact Factor
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ABSTRACT: Circulating Tumor Cells (CTCs), proposed as major players in cancer dissemination, have demonstrated clinical prognostic significance in several cancer types. However, their predictive value remains unclear. Here we evaluated the clinical utility of six CTC markers (tissue specific and Epithelial to Mesenchymal Transition transcripts) both as prognostic and predictive tools in metastatic Colorectal Cancer (mCRC) patients. CTCs were immunoisolated from blood in 50 mCRC patients at baseline and at four and sixteen weeks after treatment onset. Expression levels of GAPDH, VIL1, CLU, TIMP1, LOXL3 and ZEB2 were determined by qPCR and normalized to the unspecific cell isolation marker CD45. At baseline, median Progression Free Survival (PFS) and Overall Survival (OS) for patients with high CTC-markers were 6,3 and 12,7 months, respectively, versus 12,7 and 24,2 for patients with low CTC-markers (PFS; p=0,0003; OS; p=0,044). Concerning response to therapy, PFS and OS for patients with increased CTC-markers along treatment were respectively 6,6 and 13,1 months, compared with 12,7 and 24,3 for patients presenting CTC-markers reduction (PFS; p=0,004; OS; p=0,007). Of note, CTC-markers identified therapy-refractory patients not detected by standard image techniques. Patients with increased CTC-markers along treatment, but classified as responders by computed tomography, showed significantly shorter survival times (PFS: 7,8 vs 13,2; OS: 14,4 vs 24,4; months). In conclusion, we have generated a CTC-marker panel for prognosis evaluation and the identification of patients benefiting or not from therapy in mCRC. Our methodology efficiently classified patients earlier than routine computed tomography and from a minimally invasive liquid biopsy. © 2014 Wiley Periodicals, Inc.International Journal of Cancer 04/2014; · 6.20 Impact Factor