CTCs in primary breast cancer (I)
Frauenklinik Innenstadt der Ludwig-Maximilians-University Munich - Campus Innenstadt, Maistrasse 11, 80337, München, Germany.Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2012; 195:179-85. DOI: 10.1007/978-3-642-28160-0_16
The prognostic and predictive value of circulating tumor cells (CTCs) in primary breast cancer patients is subject of several recent publications. In the context of neoadjuvant chemotherapy CTCs were detected in 22-23% of patients before and in 10-17% after systemic treatment. These findings did not correlate with primary tumor characteristics or tumor response rates. One major trial evaluated the prognostic value of CTCs in 2.026 primary breast cancer patients after tumor resection but before adjuvant chemotherapy. The prevalence of CTCs was 22%. In multivariate analysis, the presence of CTCs before treatment was shown to be an independent predictor for both disease-free (hazard ratio; HR 1.88) and overall survival (HR 1.91). Results demonstrate that not only the mere presence but also the quantity of CTCs is associated with worse outcome. The risk for recurrence or tumor-related death increased with higher numbers of CTCs detected (≥5 CTCs: HR 4.04 for DFS and 3.05 for OAS; p < 0.05). In subsequent analyses of smaller subgroups within this trial, using a cutoff for positivity of >1 CTC, 10% of patients with the detection of CTCs before chemotherapy remained CTC-positive after completion of chemotherapy. Eight percentage of initially negative patients showed CTCs immediately after chemotherapy. Early data demonstrate that persisting CTCs after cytostatic treatment correlate with a decreased disease-free survival (p = 0.0623). Increasing evidence confirms the prognostic relevance of CTCs in primary breast cancer. CTC detection could help to identify patients with increased risk for relapse. Present trials will show whether CTCs can also be used as a valid tool for treatment monitoring or direct treatment target.
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- "To date, CTCs have mainly been studied in metastatic breast cancer; there is evidence that they play a prognostic role in this patient setting and are capable of predicting response to therapy and overall outcome    . Several studies on CTCs and EBC have been performed in which a CTC positivity rate ranging from 9.4 to 48.6% was observed in patients     . In EBC, the presence of one or more CTCs per 7.5 mL of blood predicted early recurrence and lower overall survival (OS) . "
ABSTRACT: Although circulating tumor cells (CTCs) have been studied in early breast cancer (EBC), their value in this setting is still not fully understood. We isolated and studied CTCs in the peripheral blood (PB) of 48 EBC patients pre-surgery and one and 6 months post-surgery using an approach involving EpCAM-independent enrichment and a dielectrophoresis-based device. Method feasibility and the correlation between CTCs and primary tumor features were evaluated. CTCs were found in 27.1 % of pre-surgery patients, 20.9% of patients one-month post-surgery, and about 33% of patients 6-months post-surgery. CTCs were recovered singly for further molecular characterization. Pre-surgery CTC-positive patients more frequently had negative prognostic features, i.e. high proliferation, large tumor dimension, lymph node positivity and negative receptor status than the other subgroup. In particular, vascular invasion showed a statistically significant correlation with CTC-positivity. Our procedure proved feasible and capable of recovering CTCs from EBC patients. Furthermore, our results suggest that CTCs may be linked to vascular invasion and to other known negative prognostic factors. Copyright © 2015. Published by Elsevier Ireland Ltd.
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- "In another study, detection of ≥1 CTC/7.5 ml by CellSearch® at the time of surgery and before the administration of adjuvant chemotherapy in 24% of 302 patients was associated with decreased PFS and OS . In the SUCCESS study, ≥1 CTC/23 ml were detected by CellSearch® in 21.5% of 2,026 patients with early breast cancer before adjuvant chemotherapy and the detection was independently associated with poor outcome . In another study ≥1 CTC/30 ml of blood were detected in 19% of 404 patients with stage-I to -III breast cancer before surgery and their detection was independently associated with shorter distant disease-free survival . "
ABSTRACT: Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch(R) system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement. CellSearch(R) images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (kappa) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test. For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median kappa of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and >=3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median kappa of 0.74 (range 0.25 to 0.90). The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are required.
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- "The analysis was performed within 72 h after blood draw. CTCs were detected using a modified ficoll procedure to reduce the 22.5 ml of peripheral blood draw to 7.5 ml that was then processed using CellSearch Ò (Veridex, Raritan, NJ, USA) as previously described in a large multicenter study that included 2026 patients . Briefly after the ficoll procedure, samples were further enriched with cells expressing epithelial-cell adhesion molecule (EPCAM) and EPCAM-positive cells were labeled with the fluorescent nucleic acid dye 4,2-diamidino-2-phenylindole dihydrochloride (DAPI) and fluorescently labeled monoclonal antibodies against pan-cytokeratin and CD45. "
ABSTRACT: The role of circulating tumor cells (CTCs) in HER2-positive breast cancer patients receiving neoadjuvant therapy is unclear. We describe the CTC detection rate, HER2 phenotyping and pathological complete response (pCR) in patients enrolled in the NeoALTTO phase III trial. Participation in the CTC sub-study was optional. CTC evaluation was performed centrally using CellSearch(®) at baseline, week 2 and week 18 (prior to surgery) of neoadjuvant therapy. Samples for CTC analysis were available for 51/455 patients randomized. At baseline, week 2 and week 18, we detected ≥1 CTC/22.5 ml in 5/46 (11%), 4/41 (10%), and 5/31 (16%) patients and ≥1 HER2-positive CTC/22.5 ml in 2/46 (4%), 2/41 (5%), and 3/31 (10%) patients with evaluable samples, respectively. 11/51 patients (21%) had ≥1 CTC/22.5 ml in at least one time point. pCR was observed in 3/11 (27.3%) versus 17/40 (42.5%) patients with detectable and no detectable CTCs, respectively (p = 0.36). No pCR was observed in the three patients with detectable HER2-positive CTCs prior to surgery. Numerically lower pCR rates were observed in patients with detectable CTCs, yet the study remains underpowered. A meta-analysis of CTC studies in this setting is warranted.
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