Abstract LB-286: Use of circulating tumor cells to monitor pharmacodynamic responses of patients in early-stage clinical trials

AbstractLung cancer is the most fetal malignancy due to the high rate of metastasis and recurrence after treatment. A considerable number of patients with early-stage lung cancer relapse due to overlooked distant metastasis. Circulating tumor cells (CTCs) are tumor cells in blood circulation that originated from primary or metastatic sites, and it has been shown that CTCs are critical for metastasis and prognosis in various type of cancers. Here, we employed novel method to capture, isolate and classify CTC with FlowCell system and analyzed the CTCs from a cohort of 302 individuals. Our results illustrated that FlowCell-enriched CTCs effectively differentiated benign and malignant lung tumor and the total CTC counts increased as the tumor developed. More importantly, we showed that CTCs displayed superior sensitivity and specificity to predict lung cancer metastasis in comparison to conventional circulating biomarkers. Taken together, our data suggested CTCs can be used to assist the diagnosis of lung cancer as well as predict lung cancer metastasis. These findings provide an alternative means to screen early-stage metastasis.

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Early Detection and Dynamic Changes of Circulating Tumor Cells in Transgenic NeuN Transgenic (NTTg) Mice with Spontaneous Breast Tumor Development

Cancers ◽

10.3390/cancers13133294 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3294

Author(s):

Wen-Sy Tsai ◽

Tsung-Fu Hung ◽

Jia-Yang Chen ◽

Shu-Huan Huang ◽

Ying-Chih Chang

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Breast Tumor ◽

Early Stage ◽

Tumor Development ◽

P Value ◽

Vascular Density ◽

Dynamic Changes ◽

Tumor Bearing ◽

Development Methods

Background: This study used NeuN transgenic (NTTg) mice with spontaneous breast tumor development to evaluate the dynamic changes of circulating tumor cells (CTCs) prior to and during tumor development. Methods: In this longitudinal, clinically uninterrupted study, we collected 75 μL of peripheral blood at the age of 8, 12, 16, and 20 weeks in the first group of five mice, and at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability in the second group of four mice. Diluted blood samples were run through a modified mouse-CMx chip to isolate the CTCs. Results: The CTC counts of the first group of mice were low (1 ± 1.6) initially. The average CTC counts were 16 ± 9.5, 29.0 ± 18.2, and 70.0 ± 30.3 cells per 75 μL blood at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability, respectively. There was a significant positive correlation between an increase in CTC levels and tumor vascular density (p-value < 0.01). This correlation was stronger than that between CTC levels and tumor size (p-value = 0.076). The captured CTCs were implanted into a non-tumor-bearing NTTg mouse for xenografting, confirming their viability and tumorigenesis. Conclusion: Serial CTCs during an early stage of tumor progression were quantified and found to be positively correlated with the later tumor vascular density and size. Furthermore, the successful generation of CTC-derived xenografts indicates the tumorigenicity of this early onset CTC population.

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Clinical significance of circulating tumor cells and metabolic signatures in lung cancer after surgical removal

10.21203/rs.3.rs-17157/v1 ◽

2020 ◽

Author(s):

Dawei Yang ◽

Xiaofang Yang ◽

Yang Li ◽

Peige Zhao ◽

Rao Fu ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Early Stage ◽

Effective Means ◽

Disease Recurrence ◽

Metabolic Changes ◽

Surgical Removal ◽

Targeted Metabolomics ◽

Post Surgery

Abstract Background Lung cancer (LC) remains the deadliest form of cancer globally. While surgery remains the optimal treatment strategy for individuals with early-stage LC, what the metabolic consequences are of such surgical intervention remains uncertain. Methods Negative enrichment-fluorescence in situ hybridization (NE-FISH) was used in an effort to detect circulating tumor cells (CTCs) in pre- and post-surgery peripheral blood samples from 51 LC patients. In addition, targeted metabolomics analyses, multivariate statistical analyses, and pathway analyses were used to explore surgery-associated metabolic changes. Results LC patients had significantly higher CTC counts relative to healthy controls with 66.67% of LC patients having at least 1 detected CTC. CTC counts were associated with clinical outcomes following surgery. In a targeted metabolomics analysis, we detected 34 amino acids, 164 lipids, and 24 fatty acids. When comparing LC patients before and after surgery to control patients, metabolic shifts were detected via PLS-DA and pathway analysis. Further surgery-associated metabolic changes were identified when comparing LA and LB groups. We identified SM 42:4, Ser, Sar, Gln, and LPC 18:0 for inclusion in a biomarker panel for early-stage LC detection based upon an AUC of 0.965 (95% CI = 0.900–1.000). This analysis revealed that SM 42:2, SM 35:1, PC (16:0/14:0), PC (14:0/16:1), Cer (d18:1/24:1), and SM 38:3 may offer diagnostic and prognostic benefits in LC. Conclusions These findings suggest that CTC detection and plasma metabolite profiling may be an effective means of diagnosing early-stage LC and identifying patients at risk for disease recurrence.

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Clinical Impact of Circulating Tumor Cells in Patients with Localized Prostate Cancer

Cells ◽

10.3390/cells8070676 ◽

2019 ◽

Vol 8 (7) ◽

pp. 676 ◽

Cited By ~ 11

Author(s):

Broncy ◽

Paterlini-Bréchot

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Early Stage ◽

Clinical Impact ◽

Localized Prostate Cancer ◽

Aggressive Cancer ◽

Highly Sensitive ◽

Prostate Cancers ◽

Suitable Marker

The main issue concerning localized prostate cancers is the lack of a suitable marker which could help patients’ stratification at diagnosis and distinguish those with a benign disease from patients with a more aggressive cancer. Circulating Tumor Cells (CTC) are spread in the blood by invasive tumors and could be the ideal marker in this setting. Therefore, we have compiled data from the literature in order to obtain clues about the clinical impact of CTC in patients with localized prostate cancer. Forty-three publications have been found reporting analyses of CTC in patients with non-metastatic prostate cancer. Of these, we have made a further selection of 11 studies targeting patients with clinical or pathological stages T1 and T2 and reporting the clinical impact of CTC. The results of this search show encouraging data toward the use of CTC in patients with early-stage cancer. However, they also highlight the lack of standardized methods providing a highly sensitive and specific approach for the detection of prostate-derived CTC.

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Abstract 4821: Circulating tumor cells: A key deliverable in oncology clinical trials

10.1158/1538-7445.am2014-4821 ◽

2014 ◽

Author(s):

Chengsen Xue ◽

Kasia E. Cortes ◽

Dorina Hura ◽

Melissa L. Baptiste ◽

Paradiso Renato ◽

...

Keyword(s):

Clinical Trials ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Oncology Clinical Trials

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Detection of Circulating Tumor Cells in Early-Stage Breast Cancer Metastasis to Axillary Lymph Nodes

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-07-0419 ◽

2007 ◽

Vol 13 (14) ◽

pp. 4105-4110 ◽

Cited By ~ 71

Author(s):

Taku Nakagawa ◽

Steve R. Martinez ◽

Yasufumi Goto ◽

Kazuo Koyanagi ◽

Minoru Kitago ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Metastasis ◽

Early Stage ◽

Breast Cancer Metastasis ◽

Early Stage Breast Cancer ◽

Axillary Lymph Nodes ◽

Axillary Lymph

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Clinical significance of circulating tumor cells and metabolic signatures in lung cancer after surgical removal

10.21203/rs.3.rs-17157/v2 ◽

2020 ◽

Author(s):

Dawei Yang ◽

Xiaofang Yang ◽

Yang Li ◽

Peige Zhao ◽

Rao Fu ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Early Stage ◽

Effective Means ◽

Disease Recurrence ◽

Metabolic Changes ◽

Surgical Removal ◽

Targeted Metabolomics ◽

Post Surgery

Abstract Background: Lung cancer (LC) remains the deadliest form of cancer globally. While surgery remains the optimal treatment strategy for individuals with early-stage LC, what the metabolic consequences are of such surgical intervention remains uncertain. Methods: Negative enrichment-fluorescence in situ hybridization (NE-FISH) was used in an effort to detect circulating tumor cells (CTCs) in pre- and post-surgery peripheral blood samples from 51 LC patients. In addition, targeted metabolomics analyses, multivariate statistical analyses, and pathway analyses were used to explore surgery-associated metabolic changes. Results: LC patients had significantly higher CTC counts relative to healthy controls with 66.67% of LC patients having at least 1 detected CTC before surgery. CTC counts were associated with clinical outcomes following surgery. In a targeted metabolomics analysis, we detected 34 amino acids, 147 lipids, and 24 fatty acids. When comparing LC patients before and after surgery to control patients, metabolic shifts were detected via PLS-DA and pathway analysis. Further surgery-associated metabolic changes were identified when comparing LA (LC patients after surgery) and LB (LC patients before surgery) groups. We identified SM 42:4, Ser, Sar, Gln, and LPC 18:0 for inclusion in a biomarker panel for early-stage LC detection based upon an AUC of 0.965 (95% CI = 0.900–1.000). This analysis revealed that SM 42:2, SM 35:1, PC (16:0/14:0), PC (14:0/16:1), Cer (d18:1/24:1), and SM 38:3 may offer diagnostic and prognostic benefits in LC. Conclusions: These findings suggest that CTC detection and plasma metabolite profiling may be an effective means of diagnosing early-stage LC and identifying patients at risk for disease recurrence.

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Detection of Circulating Tumor Cells in Resectable Pancreatic Ductal Adenocarcinoma: A Prospective Evaluation as a Prognostic Marker

Frontiers in Oncology ◽

10.3389/fonc.2020.616440 ◽

2021 ◽

Vol 10 ◽

Author(s):

Byeong Geun Song ◽

Wooil Kwon ◽

Hyemin Kim ◽

Eun Mi Lee ◽

Young Min Han ◽

...

Keyword(s):

Portal Vein ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Prognostic Marker ◽

Peripheral Blood ◽

Early Stage ◽

Portal Blood ◽

Ductal Adenocarcinoma ◽

Venous Blood Flow ◽

Porous Filter

Circulating tumor cells (CTCs) are useful biomarkers of many solid tumors, but are infrequently detected in early stage pancreatic ductal adenocarcinomas (PDACs). The first drainage of pancreatic venous blood flow come to portal vein and pass through the liver, and they finally go out for peripheral blood. We thought that comparing CTCs from portal vein and peripheral blood could enable us to understand the clinical meaning of CTCs from each different site in PDACs. Therefore, we aimed to determine 1) whether CTCs could be reliably identified in early stages (operable) of PDACs, 2) if there are any differences in the detected number of CTC in portal vein blood and peripheral blood, and 3) whether CTCs can be sensitive biomarkers for the prognosis of resectable PDAC patients. Newly diagnosed PDAC patients who underwent operation with curative intention between 2013 and 2015 were prospectively enrolled. Blood draws from portal and peripheral vein ran through the microfabricated porous filter, and anti-epithelial cell adhesion molecule (EpCAM) and anti-Plectin-1 antibodies were used for CTC identification. Baseline clinical characteristics, tumor characteristics, treatment, and clinical outcomes were assessed. The clinical stages of the 32 enrolled patients were as follows: IA/IB 1 (3.1%); IIA 9 (28.1%); IIB 17 (53.1%); III 5 (15.6%). Twenty-seven patients (84.4%) received R0 resection, while five patients (15.6%) received R1 resection. EpCAM+ CTCs were detected in 20 portal blood (62.5%) and 22 peripheral blood (68.8%). Plectin-1+ CTCs were identified in 14 portal blood (43.8%) and 16 peripheral blood (50%). Plectin-1-expressing CTCs were picked from CTC platform (microfabricated porous filter) and we could find out all KRAS mutation. Patients with detectable EpCAM+ CTC less than one in peripheral blood showed longer overall survival (OS) compared to patients with detectable CTCs more than one (35.5 months vs. 16.0 months). EpCAM and Plectin-1 successfully identified CTCs at the early stage of PDACs. Also, the number of CTCs could be a prognostic marker for survival in resectable PDACs.

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Pre-Analytical and Analytical Variables of Label-Independent Enrichment and Automated Detection of Circulating Tumor Cells in Cancer Patients

Cancers ◽

10.3390/cancers12020442 ◽

2020 ◽

Vol 12 (2) ◽

pp. 442 ◽

Cited By ~ 3

Author(s):

Claudia Koch ◽

Simon A. Joosse ◽

Svenja Schneegans ◽

Okka J. W. Wilken ◽

Melanie Janning ◽

...

Keyword(s):

Clinical Trials ◽

Cancer Patients ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Tumor Cell Line ◽

Response To Therapy ◽

Clinical Samples ◽

Blood Collection ◽

Multiple Parameters ◽

Healthy Donors

Circulating tumor cells (CTCs) are promising tools for risk prediction and the monitoring of response to therapy in cancer patients. Within the EU/IMI CANCER-ID consortium, we validated CTC enrichment systems for future inclusion into clinical trials. Due to the known heterogeneity of markers expressed on CTCs, we tested the Parsortix® system (ANGLE plc) which enables label-independent CTC enrichment from whole blood based on increased size and deformability of these tumor cells compared to leukocytes. We performed extensive comparisons both with spiked-in blood models (i.e., MDA-MB-468 tumor cell line cells spiked at very low concentration into blood from healthy donors) and validated the protocol on actual clinical samples from breast, lung, and gastrointestinal cancer patients to define optimal conditions for CTC enrichment. Multiple parameters including cassette gap, separation pressure, and cell fixatives were compared in parallel. Also, the compatibility of blood collection tubes with whole genome amplification of isolated tumor cells was demonstrated and we furthermore established a workflow for semi-automated CTC detection using a quantitative cell imager. The established workflow will contribute to supporting the use of size-based CTC enrichment platforms in clinical trials testing the clinical validity and utility of CTCs for personalized medicine.

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The Significance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma: Real-Time Monitoring and Moving Targets for Cancer Therapy

Cancers ◽

10.3390/cancers12071734 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1734 ◽

Cited By ~ 3

Author(s):

Feiyu Chen ◽

Zhangfeng Zhong ◽

Hor-Yue Tan ◽

Ning Wang ◽

Yibin Feng

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Early Stage ◽

Human Peripheral Blood ◽

Circulatory System ◽

First Line Therapy ◽

Modulate Signal ◽

Effective Diagnosis ◽

Signal Transductions

Hepatocellular carcinoma (HCC) is ranked as the sixth most common cancer around the world. With the emergence of the state-of-the-art modalities lately, such as liver transplantation, image-guided ablation, and chemoembolization, the death rate is still high due to high metastasis rate after therapy. Observation by biannual ultrasonography allows effective diagnosis at an early stage for candidates with no extrahepatic metastasis, but its effectiveness still remains unsatisfactory. Developing a new test with improved effectiveness and specificity is urgently needed for HCC diagnosis, especially for patients after first line therapy. Circulating tumor cells (CTCs) are a small sub-population of tumor cells in human peripheral blood, they release from the primary tumor and invade into the blood circulatory system, thereby residing into the distal tissues and survive. As CTCs have specific and aggressive properties, they can evade from immune defenses, induce gene alterations, and modulate signal transductions. Ultimately, CTCs can manipulate tumor behaviors and patient reactions to anti-tumor treatment. Given the fact that in HCC blood is present around the immediate vicinity of the tumor, which allows thousands of CTCs to release into the blood circulation daily, so CTCs are considered to be the main cause for HCC occurrence, and are also a pivotal factor for HCC prognosis. In this review, we highlight the characteristics and enrichment strategies of CTCs, and focus on the use of CTCs for tumor evaluation and management in patients with HCC.

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