Prognostic and predictive relevance of circulating tumor cells in patients with non-small-cell lung cancer

doi:10.1016/j.drudis.2014.06.001

Drug Discovery Today

Volume 19, Issue 10, October 2014, Pages 1671-1676

https://doi.org/10.1016/j.drudis.2014.06.001 Get rights and content

Highlights

•
CTCs can be detected in NSCLC by biological and physical techniques.
•
Expression of biomarkers to be targeted by therapy is feasible in CTCs from NSCLC.
•
Circulating tumor cells in NSCLC can provide diagnostic and prognostic indications.
•
CTC detection at different time points allows monitoring of therapy response.

Section snippets

Circulating tumor cells and lung cancer

Circulating tumor cells (CTCs) are rare cancer cells that are supposed to be shed into the bloodstream from the primary tumor or metastatic sites. During the process of malignancy, solid tumors of epithelial origin can evolve from an initial indolent disease into disease with a more aggressive phenotype and then propagate via local expansion into the blood or lymphatic circulation 1, 2. The first description of circulating tumor-like cells was made in 1869 during the autopsy of a metastatic

CTC detection

Over the years, many efforts have been concentrated on the isolation of CTCs from various cancer types, but only recently have reproducible methods been developed that can enumerate and characterize CTCs [22]. Although many techniques for CTC enrichment, taking into account the biological or physical properties of these cells, have been extensively described 23, 24, CellSearch^® (Veridex LLC), an epithelial cell adhesion molecule (EpCAM)-based immunomagnetic capture system, and isolation by size

Role of CTCs in the diagnostic performance and prognosis of lung cancer

As previously mentioned, the relevance of CTC detection has been recognized in metastatic breast 7, 8, colorectal [9] and prostate [10] cancers. However, different studies agree in asserting that the identification of CTCs in the blood could also help improve diagnosis and predict prognosis in patients with NSCLC 11, 12, 35.

One of the first efforts to test the feasibility of detecting CTCs in the blood, before and after surgery, was carried out in nine patients, who were undergoing surgery for

Molecular investigations in CTCs

The achievability of determining the presence and cellular localization of specific proteins in CTCs and executing genotyping and molecular characterization has revealed new perspectives for tailoring therapeutic strategies and monitoring treatment efficacy. In selected patients with adenocarcinoma, the therapeutic decision is based on the preliminary evaluation of EGFR mutations and ALK rearrangement, which might help to predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and ALK

Role of CTCs as predictors of response to treatment

The role of CTC enumeration has been recognized in a number of studies. However, its correlation with response to therapy requires that its evaluation proves reliable and that it follows the treatment-induced changes over time in accordance with the clinical and instrumental tumor response. To this end, various investigations have shown that the presence of CTCs during the follow-up of patients receiving chemotherapy might provide more information about the treatment response than standard

Concluding remarks

The evidence that CTCs have a significant role at tumor stage and the occurrence of metastasis in NSCLC has led to an awareness of the importance of translating CTC isolation and characterization into clinical practice, improving the techniques to standardize CTC detection. CTCs can be easily obtained through a blood draw and might serve as an additional option to determine prognosis and to monitor disease progression of NSCLC patients during treatment by repeated samplings.

Advances in

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Cited by (34)

Monitoring levels of vimentin-positive circulating cancer stem cells and tumor cells in patients with advanced EGFR-mutated non-small cell lung cancer
2021, Lung Cancer
Citation Excerpt :
The trend towards poor outcome may not be strong enough for high CCSC and CTC levels in outcome prediction. Previous studies have used a wide range of cutoff values of CTCs from 1 per 7.5 mL blood to 50 per 10 mL blood. [41] Further trial with larger sample size is needed to confirm our data as well as validate the cut-off levels.
Circulating tumor cells (CTCs) are associated with tumor spread, whereas cancer stem cells may be related to drug resistance. However, few studies have analyzed the levels of circulating cancer stem cells (CCSCs) and CTCs in patients with advanced non-small cell lung cancer (NSCLC).
Treatment-naïve patients with EGFR-mutated NSCLC who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy were recruited prospectively. The cell surface vimentin antibody was used for CTC detection and CD133 antibody for CCSC detection. CCSC and CTC levels were measured as cell count per 4 mL of blood, before treatment, after 2 and 12 weeks of treatment, and at disease progression. Data on clinical characteristics and outcomes were also collected.
At diagnosis (n = 29), the median CCSC and CTC levels were 0 (interquartile range, 0–2) and 3 (2–9), respectively. After 12 weeks, the CCSC and CTC levels were lower than those at diagnosis (CCSC: 0 (0−0), p = 0.14; CTC: 1 (0–4), p = 0.048). At disease progression, the median CCSC and CTC levels were 0 (0–1) and 1 (0–2), respectively. Patients with higher CCSC and CTC levels at diagnosis had a numerically shorter progression-free survival.
In patients with EGFR-mutated NSCLC, CCSC and CTC levels became lower after 12 weeks of EGFR-TKI therapy and remained low at disease progression. High pre-treatment CCSC and CTC levels may be associated with a trend towards poor treatment outcomes.
Jinfukang regulates integrin/Src pathway and anoikis mediating circulating lung cancer cells migration
2021, Journal of Ethnopharmacology
Citation Excerpt :
Circulating tumor cells in the peripheral blood have not attracted much attention. Recent studies have shown that CTCs can be applied to predict disease progression and survival (Alama et al., 2014; Zhou et al., 2017). Multiple lines of evidence indicate that CTCs are already present even before the primary cancer can be detected (Hu et al., 2019; Ilie et al., 2014).
Metastasis is the main cause of death in lung cancer patients. Circulating tumor cells (CTCs) may be an important target of metastasis intervention. Previous studies have shown that Jinfukang could prevent the recurrence and metastasis of lung cancer, and we have established a circulating lung tumor cell line CTC-TJH-01. However, whether Jinfukang inhibition of lung cancer metastasis is related to CTCs is still unknown.
To further explore the mechanism of Jinfukang in anti-metastasis of lung cancer from the perspective of intervention of CTCs.
CTC-TJH-01 and H1975 cells were treated with Jinfukang. Cell viability was detected by CCK8, and the cell apoptosis was detected by flow cytometry. Transwell was used to detected cell migration and invasion. Cell anoikis was detected by anoikis detection kit. Protein expression was analysis by Western blot.
Jinfukang could inhibit the proliferation, migration and invasion of CTC-TJH-01 and H1975 cells. Besides, Jinfukang could also induce anoikis in CTC-TJH-01 and H1975 cells. Analysis of the mRNA expression profile showed ECM-receptor interaction and focal adhesion were regulated by Jinfukang. Moreover, it was also find that Jinfukang significantly inhibited integrin/Src pathway in CTC-TJH-01 and H1975 cells. When suppress the expression of integrin with ATN-161, it could promote Jinfukang to inhibit migration and induce anoikis in CTC-TJH-01 and H1975 cells.
Our results indicate that the migration and invasion of CTCs are inhibited by Jinfukang, and the mechanism may involve the suppression of integrin/Src axis to induce anoikis. These data suggest that Jinfukang exerts anti-metastatic effects in lung cancer may through anoikis.
Dual-function nanostructured platform for isolation of nasopharyngeal carcinoma circulating tumor cells and EBV DNA detection
2019, Biosensors and Bioelectronics
Citation Excerpt :
According to previous studies, up to 90% of patients die from metastasis to distant sites rather than from the primary tumor (Weiss, 2000). Thus, the presence of CTCs is highly related to disease progression and has been shown to be correlated with prognosis in several cancers, including breast cancer (Rack et al., 2014), lung cancer (Alama et al., 2014; Chen and Xu, 2014), gastric cancer (Zheng et al., 2017), colorectal cancer (Negin and Cohen, 2010), head and neck cancers (Kulasinghe et al., 2015), especially NPC (He et al., 2017; Si et al., 2016; Wu et al., 2017), and many other malignancies. It has also been proposed that tumor burden affects the level of released CTCs, and an increase in tumor burden might increase the number of CTCs (Chen et al., 2018).
Circulating tumor cells (CTCs) and plasma levels of Epstein–Barr virus (EBV) DNA are sensitive prognostic tools for monitoring disease status in nasopharyngeal carcinoma (NPC) patients. Herein, we introduce a novel and low-cost platform for capturing CTCs, the Si nanowires/microscale pyramids (NWs/MPs) hierarchical substrate, which could capture NPC cells in vitro and also detect EBV DNA at very low concentrations. In this study, Si NWs/MPs hierarchical substrates with varying wire length were fabricated using a metal-assisted chemical etching method. Anti-EpCAM antibodies were further conjugated on the substrate for capturing NPC CTCs in vitro. Capture efficiency was evaluated using immunofluorescence and scanning electronic microscopy (SEM) was utilized to understand cell morphology. The Si NWs/MPs substrate was also transformed into a Surface enhanced Raman scattering (SERS) substrate by coating with Ag nanoparticles (AgNPs) for detection of EBV DNA by Raman spectroscopy. The results demonstrated that Si NWs/MPs with 20 min of etch time had the best capturing performance. Additionally, SEM observations revealed good contact of CTCs with Si NWs/MPs substrates. Moreover, the AgNPs-coated NWs/MPs substrate was shown to be a sensitive EBV DNA detector, by which the DNA detection limit can reach up to 10⁻¹³M. In conclusion, the Si NWs/MPs platform not only exhibits superior cell capturing ability, but also can sensitively detect EBV DNA at very low concentrations. This platform has great potential to become a promising diagnostic tool for monitoring disease status and prognostication of NPC patients.
Circulating tumor cell-derived organoids: Current challenges and promises in medical research and precision medicine
2018, Biochimica et Biophysica Acta - Reviews on Cancer
Traditional 2D cell cultures do not accurately recapitulate tumor heterogeneity, and insufficient human cell lines are available. Patient-derived xenograft (PDX) models more closely mimic clinical tumor heterogeneity, but are not useful for high-throughput drug screening. Recently, patient-derived organoid cultures have emerged as a novel technique to fill this critical need. Organoids maintain tumor tissue heterogeneity and drug-resistance responses, and thus are useful for high-throughput drug screening. Among various biological tissues used to produce organoid cultures, circulating tumor cells (CTCs) are promising, due to relative ease of ascertainment. CTC-derived organoids could help to acquire relevant genetic and epigenetic information about tumors in real time, and screen and test promising drugs. This could reduce the need for tissue biopsies, which are painful and may be difficult depending on the tumor location. In this review, we have focused on advances in CTC isolation and organoid culture methods, and their potential applications in disease modeling and precision medicine.
Possible applications of circulating tumor cells in patients with non small cell lung cancer
2017, Lung Cancer
Citation Excerpt :
The prognostic significance of CTCs has already been proved in metastatic breast, colorectal and prostate cancer [5–7]. Furthermore, recent experiences indicate that CTCs could play a role also in non small cell lung cancer (NSCLC) for diagnosis, biological characterization and disease monitoring [8,9]. CTCs could be particularly useful in this clinical setting since tumor tissue obtained from biopsies is often insufficient for a comprehensive histopatological-molecular analysis, patients are not always suitable to receive multiple biopsies and because of the lack of reliable tumor markers.
Recent experiences indicate that, as already reported for other types of cancer, circulating tumor cells (CTCs) may play a role also in non small cell lung cancer (NSCLC) for diagnosis, therapy monitoring and prognostic purposes. CTCs evaluation could be particularly relevant in this clinical setting not only for the objective difficulty in obtaining tumor tissue, but also because of the lack of reliable tumor markers. In the current review, we will focus on the possible applications of CTCs in NSCLC patients.
Circulating Tumor Cells as Diagnostic Markers of Early Gastric Cancer and Gastric Precancerous Lesions
2023, Oncology (Switzerland)

View all citing articles on Scopus

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Published by Elsevier Ltd.

ReviewPost screenPrognostic and predictive relevance of circulating tumor cells in patients with non-small-cell lung cancer

Highlights

Section snippets

Circulating tumor cells and lung cancer

CTC detection

Role of CTCs in the diagnostic performance and prognosis of lung cancer

Molecular investigations in CTCs

Role of CTCs as predictors of response to treatment

Concluding remarks

First page preview

Clin. Colorectal Cancer

J. Urol.

Am. J. Pathol.

Lung Cancer

Crit. Rev. Oncol. Hematol.

Lancet Oncol.

Drug Discov. Today

Pharmacol. Ther.

J. Thorac. Oncol.

Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant

Clin. Cancer Res.

Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with non-malignant diseases

Clin. Cancer Res.

A case of cancer in which cells similar to those in the tumours were seen in the blood after death

Aust. Med. J.

A systems view of epithelial–mesenchymal transition signaling states

Clin. Exp. Metastasis

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

Eur. Respir. Rev.

Molecular mechanisms of epithelial–mesenchymal transition

Nat. Rev. Mol. Cell. Biol.

Circulating tumor cells, disease progression, and survival in metastatic breast cancer

N. Engl. J. Med.

Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer

J. Clin. Oncol.

Cancer statistics, 2013

CA Cancer J Clin.

Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens

Oncologist

Pemetrexed for the treatment of non-small cell lung cancer

Expert Opin. Pharmacother.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

N. Engl. J. Med.

Genetically abnormal circulating cells in lung cancer patients: an antigen-independent fluorescence in situ hybridization-based case–control study

Cancer Res.

Simultaneous phenotypic and genetic characterization of single circulating tumor cells from colon cancer patients

Histol. Histopathol.

Enrichment, detection and clinical significance of circulating tumor cells

Lab Chip

Considerations in the development of circulating tumor cell technology for clinical use

J. Transl. Med.

Detection of circulating tumor cells in breast cancer may improve through enrichment with anti-CD146

Breast Cancer Res. Treat.

Review
Post screen
Prognostic and predictive relevance of circulating tumor cells in patients with non-small-cell lung cancer