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Correlations between circulating tumor cell phenotyping and 18F-fluorodeoxyglucose positron emission tomography uptake in non-small cell lung cancer

  • Original Article – Clinical Oncology
  • Published:
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Abstract

Purpose

The epithelial-to-mesenchymal transition (EMT) phenotype-based subsets of circulating tumor cells (CTCs) might be predictors of tumor progression. We evaluated the clinical properties of different phenotypic CTCs in patients with non-small cell lung cancer (NSCLC). Secondly, we explored the association between different phenotypic CTCs and the uptake of 18F-fluorodeoxyglucose (FDG) by the primary tumor on a positron emission tomographic (PET) scan.

Methods

Venous blood samples from 34 pathologically confirmed Stage IIB-IVB NSCLC patients were collected prospectively. CTCs were immunoassayed using a SE-i·FISH®CTC kit. We identified CTCs into cytokeratin positive (CK+) and cytokeratin negative (CK) phenotypes. CTC classifications were correlated with the maximum standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Overall survival (OS) and progression-free survival (PFS) curves were produced using the Kaplan–Meier method.

Results

CTCs were detected in 91.2% of NSCLC patients. CTC counting was associated with TNM stage (P = 0.014) and distant metastasis (P = 0.007). The number of CKCTCs was also positively associated with TNM stage (P = 0.022) and distant metastasis (P = 0.007). Both total CTC counting and CKCTC counting did not show association with SUVmax value (P = 0.959, P = 0.903). Kaplan–Meier survival analysis demonstrated that patients with ≥ 7 CTCs had shorter OS (P = 0.003) and PFS (P = 0.001) relative to patients with < 7 CTCs). Notably, the number of CKCTCs can act as independent risk factors for PFS (P = 0.044) and OS (P = 0.043) in NSCLC patients. However, SUVmax value was not associated with OS (P = 0.895) and PFS (P = 0.686).

Conclusion

The CTC subpopulations could be useful evidence for testing metastasis and prognosis in NSCLC patients. The SUVmax value of the primary tumor was not related to prognosis in patients with NSCLC.

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References

  • Aktas B, Tewes M, Fehm T et al (2009) Stem cell and epithelial–mesenchymal transition markers are frequently over expressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46

    Article  PubMed  PubMed Central  Google Scholar 

  • Allemani C, Matsuda T, Di Carlo V et al (2018) Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 391(10125):1023–1075

    Article  PubMed  PubMed Central  Google Scholar 

  • Bayarri-Lara C, Ortega FG, Ladrón C, de Guevara A et al (2016) Circulating tumor cells identify early recurrence in patients with non-small cell lung cancer undergoing radical resection. PLoS ONE 11(2):e0148659

    Article  PubMed  PubMed Central  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    PubMed  Google Scholar 

  • Cabel L, Proudhon C, Gortais H et al (2017) Circulating tumor cells: clinical validity and utility. Int J Clin Oncol 22(3):421–430

    Article  PubMed  Google Scholar 

  • Chang H, Lee SJ, Lim J et al (2019) Prognostic significance of metabolic parameters measured by (18)F-FDG PET/CT in limited-stage small-cell lung carcinoma. J Cancer Res Clin Oncol 145(5):1361–1367

    Article  CAS  PubMed  Google Scholar 

  • Debieuvre D, Locher C, Asselain B et al (2019) Evidence of slight improvement in five-year survival in non-small-cell lung cancer over the last 10 years: Results of the French KBP-CPHG real-world studies. Bull Cancer 106(4):283–292

    Article  PubMed  Google Scholar 

  • de Wit S, van Dalum G, Lenferink AT et al (2015) The detection of EpCAM(+) and EpCAM(-) circulating tumor cells. Sci Rep 5:12270

    Article  PubMed  PubMed Central  Google Scholar 

  • Endo K, Oriuchi N, Higuchi T et al (2006) PET and PET/CT using 18F-FDG in the diagnosis and management of cancer patients. Int J Clin Oncol 11(4):286–296

    Article  PubMed  Google Scholar 

  • Gale D, Lawson ARJ, Howarth K et al (2018) Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA. PLoS ONE 13(3):e0194630

    Article  PubMed  PubMed Central  Google Scholar 

  • Go SI, Song HN, Kang JH et al (2014) The clinical impact of the sum of the maximum standardized uptake value on the pretreatment with F-FDG-PET/CT in small-cell lung cancer. Oncology 86(1):1–9

    Article  CAS  PubMed  Google Scholar 

  • Hirsch FR, Scagliotti GV, Mulshine JL et al (2017) Lung cancer: current therapies and new targeted treatments. Lancet 389(10066):299–311

    Article  CAS  PubMed  Google Scholar 

  • Hou J, Zou K, Yang C, Leng X et al (2018) Clinicopathological and prognostic significance of circulating tumor cells in patients with esophageal cancer: a meta-analysis. Onco Targets Ther 11:8053–8061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Feng M, He Q et al (2017) Prognostic value of pretreatment 18F-FDG PET-CT for nasopharyngeal carcinoma patients. Medicine (Baltimore) 96(17):e6721

    Article  CAS  Google Scholar 

  • Kandathil A, Kay FU, Butt YM et al (2018) Role of FDG PET/CT in the eighth edition of TNM staging of non-small cell lung cancer. Radiographics 38(7):2134–2149

  • Kanyilmaz G, Benli Yavuz B, Aktan M, et al (2019) Prognostic importance of 18F-fluorodeoxyglucose uptake by positron emission tomography for stage III non-small cell lung cancer treated with definitive chemoradiotherapy. Rev Esp Med Nucl Imagen Mol S2253–654X(19)30059–9

  • Karachaliou N, Sosa AE, Barron FB et al (2017) Pharmacological management of relapsed/refractory NSCLC with chemical drugs. Expert Opin Pharmacother 18(3):295–304

    Article  CAS  PubMed  Google Scholar 

  • Kim CY, Hong CM, Kim DH et al (2013) Prognostic value of whole-body metabolic tumor volume and total lesion glycolysis measured on 18F-FDG PET/CT in patients with extranodal NK/T-cell lymphoma. Eur J Nucl Med Mol Imaging 40(9):1321–1329

    Article  CAS  PubMed  Google Scholar 

  • Krebs MG, Sloane R, Priest L et al (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 29(12):1556–1563

    Article  PubMed  Google Scholar 

  • Lapa P, Oliveiros B, Marques M et al (2017) Metabolic tumor burden quantified on [(18)F]FDG PET/CT improves TNM staging of lung cancer patients. Eur J Nucl Med Mol Imaging 44(13):2169–2178

    Article  PubMed  Google Scholar 

  • Liao S, Lan X, Cao G et al (2013) Prognostic predictive value of total lesion glycolysis from 18F-FDG PET/CT in post-surgical patients with epithelial ovarian cancer. Clin Nucl Med 38(9):715–720

    Article  PubMed  Google Scholar 

  • Liu H, Zhang X, Li J et al (2015) The biological and clinical importance of epithelial mesenchymal transition in circulating tumor cells. J Cancer Res Clin Oncol 141(2):189–201

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Li J, Cadiha BL et al (2019) Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis. Sci Adv 5(6): eaav4275

  • Lucci A, Hall CS, Lodhi AK et al (2012) Circulating tumor cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 13(7):688–695

    Article  PubMed  Google Scholar 

  • Mego M, Cierna Z, Janega P et al (2015) Relationship between circulating tumor cells and epithelial to mesenchymal transition in early breast cancer. BMC Cancer 15:533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melissa AF, Steven JF, Samuel RJ-B et al (2020) Circulating tumor cells are associated with recurrent disease in patients with early stage non-small cell lung cancer treated with stereotactic body radiation therapy. Clin Cancer Res 2158

  • Milaki G, Messaritakis I, Koinis F et al (2017) Prognostic value of chemotherapy-resistant CK19mRNA-positive circulating tumor cells in patients with advanced/metastatic non-small cell lung cancer. Cancer Chemother Pharmacol 80(1):101–108

    Article  CAS  PubMed  Google Scholar 

  • Morgan TM, Wang X, Qian X et al (2019) Measurement of circulating tumor cells in squamous cell carcinoma of the head and neck and patient outcomes. Clin Transl Oncol 21(3):342–347

    Article  CAS  PubMed  Google Scholar 

  • Pantel K, Alix-Panabières C (2019) Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol 16(7):409–424

    Article  CAS  PubMed  Google Scholar 

  • Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends Cell Biol 29(3):212–226

    Article  CAS  PubMed  Google Scholar 

  • Pecot CV, Bischoff FZ, Mayer JA et al (2011) A novel platform for detection of CK+ and CK- CTCs. Cancer Discov 1(7):580–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rolfo C, Mack PC, Scagliotti GV et al (2018) Liquid biopsy for advanced non-small cell lung cancer (NSCLC): a statement paper from the IASLC. J Thorac Oncol 13(9):1248–1268

    Article  PubMed  Google Scholar 

  • Satelli A, Mitra A, Brownlee Z et al (2015) Epithelial–mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clin Cancer Res 21(4):899–906

    Article  CAS  PubMed  Google Scholar 

  • Seban RD, Mezquita L, Berenbaum A, et al (2019) Baseline metabolic tumor burden on FDG PET/CT scans predicts outcome in advanced NSCLC patients treated with immune checkpoint inhibitors. Eur J Nucl Med Mol Imaging

  • Sun Y, Wu G, Cheng KS, Chen A et al (2019) CTC phenotyping for a preoperative assessment of tumor metastasis and overall survival of pancreatic ductal adenocarcinoma patients. EBioMedicine 46:133–149

    Article  PubMed  PubMed Central  Google Scholar 

  • Sundling KE, Lowe AC (2019) Circulating tumor cells: overview and opportunities in cytology. Adv Anat Pathol 26(1):56–63

    Article  CAS  PubMed  Google Scholar 

  • Syrigos K, Fiste O, Charpidou A et al (2018) Circulating tumor cells count as a predictor of survival in lung cancer. Crit Rev Oncol Hematol 125:60–68

    Article  PubMed  Google Scholar 

  • Togo S, Katagiri N, Namba Y et al (2017) Sensitive detection of viable circulating tumor cells using a novel conditionally telomerase-selective replicating adenovirus in non-small cell lung cancer patients. Oncotarget 8(21):34884–34895

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu B, Zhu X, Liang Z et al (2018) Clinical usefulness of 18F-FDG PET/CT for the detection of distant metastases in patients with non-small cell lung cancer at initial staging: a meta-analysis. Cancer Manag Res 10:1859–1864

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Shi H, Jiang T et al (2018) Circulating tumor cells with karyotyping as a novel biomarker for diagnosis and treatment of nasopharyngeal carcinoma. BMC Cancer 18(1):1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao XH, Wang ZR, Chen CL et al (2019) Molecular detection of epithelial–mesenchymal transition markers in circulating tumor cells from pancreatic cancer patients: Potential role in clinical practice. World J Gastroenterol 25(1):138–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng H, Cui Y, Li X, Du B et al (2019) Prognostic significance of 18F-FDG PET/CT metabolic parameters and tumor galectin-1 expression in patients with surgically resected lung adenocarcinoma. Clin Lung Cancer 20(6):420–428

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Dong F, Cui F, Xu R et al (2017) The role of 467 circulating tumor cells in evaluation of prognosis and treat- 468 ment response in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 79(4):825–833

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by grants from the Natural Science Fund of Yangzhou City (Nos. YZ2017114, YZ2017121).

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Contributions

XXX conceived and directed this study. XXX, JRB, KY and NL performed the experiments and acquired the data. XXX, JRB and NL analyzed and interpreted the data. JRB and KY wrote and revised the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work is appropriately investigated and resolved.

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Correspondence to Xingxiang Xu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all participants included in our study.

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Bian, J., Yan, K., Liu, N. et al. Correlations between circulating tumor cell phenotyping and 18F-fluorodeoxyglucose positron emission tomography uptake in non-small cell lung cancer. J Cancer Res Clin Oncol 146, 2621–2630 (2020). https://doi.org/10.1007/s00432-020-03244-4

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