Circulating Tumor Cell Number Is Associated with Primary Tumor Volume in Patients with Lung Adenocarcinoma

  • Kang, Byung Ju (Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine) ;
  • Ra, Seung Won (Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine) ;
  • Lee, Kyusang (Liquid Biopsy and Precision Medicine Division, Clinomics Inc.) ;
  • Lim, Soyeoun (Department of Radiology, Ulsan University Hospital) ;
  • Son, So Hee (Liquid Biopsy and Precision Medicine Division, Clinomics Inc.) ;
  • Ahn, Jong-Joon (Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine) ;
  • Kim, Byung Chul (Liquid Biopsy and Precision Medicine Division, Clinomics Inc.)
  • Received : 2019.07.06
  • Accepted : 2019.09.16
  • Published : 2020.01.31


Background: Circulating tumor cells (CTCs) are frequently detected in patients with advanced-stage malignant tumors and could act as a predictor of poor prognosis. However, there is a paucity of data on the relationship between CTC number and primary tumor volume in patients with lung cancer. Therefore, our study aimed to evaluate the relationship between CTC number and primary tumor volume in patients with lung adenocarcinoma. Methods: We collected blood samples from 21 patients with treatment-naive lung adenocarcinoma and 73 healthy individuals. To count CTCs, we used a CTC enrichment method based on fluid-assisted separation technology. We compared CTC numbers between lung adenocarcinoma patients and healthy individuals using propensity score matching, and performed linear regression analysis to analyze the relationship between CTC number and primary tumor volume in lung adenocarcinoma patients. Results: CTC positivity was significantly more common in lung adenocarcinoma patients than in healthy individuals (p<0.001). The median primary tumor volume in CTC-negative and CTC-positive patients was 10.0 ㎤ and 64.8 ㎤, respectively. Multiple linear regression analysis showed that the number of CTCs correlated with primary tumor volume in lung adenocarcinoma patients (β=0.903, p=0.002). Further subgroup analysis showed a correlation between CTC number and primary tumor volume in patients with distant (p=0.024) and extra-thoracic (p=0.033) metastasis (not in patients with distant metastasis). Conclusion: Our study showed that CTC numbers may be associated with primary tumor volume in lung adenocarcinomas patients, especially in those with distant metastasis.


  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
  2. Zhou J, Dong F, Cui F, Xu R, Tang X. The role of circulating tumor cells in evaluation of prognosis and treatment response in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 2017;79:825-33.
  3. Lortet-Tieulent J, Soerjomataram I, Ferlay J, Rutherford M, Weiderpass E, Bray F. International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women. Lung Cancer 2014;84:13-22.
  4. O'Flaherty L, Wikman H, Pantel K. Biology and clinical significance of circulating tumor cell subpopulations in lung cancer. Transl Lung Cancer Res 2017;6:431-43.
  5. Yap TA, Lorente D, Omlin A, Olmos D, de Bono JS. Circulating tumor cells: a multifunctional biomarker. Clin Cancer Res 2014;20:2553-68.
  6. Han Y, Su C, Liu Z. Methods for detection of circulating cells in non-small cell lung cancer. Front Biosci (Landmark Ed) 2014;19:896-903.
  7. Karachaliou N, Mayo-de-Las-Casas C, Molina-Vila MA, Rosell R. Real-time liquid biopsies become a reality in cancer treatment. Ann Transl Med 2015;3:36.
  8. Chen Q, Ge F, Cui W, Wang F, Yang Z, Guo Y, et al. Lung cancer circulating tumor cells isolated by the EpCAMindependent enrichment strategy correlate with cytokeratin 19-derived CYFRA21-1 and pathological staging. Clin Chim Acta 2013;419:57-61.
  9. Tanaka F, Yoneda K, Kondo N, Hashimoto M, Takuwa T, Matsumoto S, et al. Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res 2009;15:6980-6.
  10. Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 2011;29:1556-63.
  11. Lindsay CR, Faugeroux V, Michiels S, Pailler E, Facchinetti F, Ou D, et al. A prospective examination of circulating tumor cell profiles in non-small-cell lung cancer molecular subgroups. Ann Oncol 2017;28:1523-31.
  12. Kim TH, Lim M, Park J, Oh JM, Kim H, Jeong H, et al. FAST: size-selective, clog-free isolation of rare cancer cells from whole blood at a liquid-liquid interface. Anal Chem 2017;89:1155-62.
  13. Joffe MM, Rosenbaum PR. Invited commentary: propensity scores. Am J Epidemiol 1999;150:327-33.
  14. Kim SH, Hong SB, Yun SC, Choi WI, Ahn JJ, Lee YJ, et al. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. Am J Respir Crit Care Med 2011;183:1207-14.
  15. Sonn CH, Cho JH, Kim JW, Kang MS, Lee J, Kim J. Detection of circulating tumor cells in patients with non-small cell lung cancer using a size-based platform. Oncol Lett 2017;13:2717-22.
  16. Katoh M, Neumaier M, Nezam R, Izbicki JR, Schumacher U. Correlation of circulating tumor cells with tumor size and metastatic load in a spontaneous lung metastasis model. Anticancer Res 2004;24:1421-5.
  17. Delfau-Larue MH, van der Gucht A, Dupuis J, Jais JP, Nel I, Beldi-Ferchiou A, et al. Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma. Blood Adv 2018;2:807-16.
  18. Fu L, Zhu Y, Jing W, Guo D, Kong L, Yu J. Incorporation of circulating tumor cells and whole-body metabolic tumor volume of (18)F-FDG PET/CT improves prediction of outcome in IIIB stage small-cell lung cancer. Chin J Cancer Res 2018;30:596-604.
  19. Lopez-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control of metastasis by NK cells. Cancer Cell 2017;32:135-54.
  20. Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 2017;17:302-17.
  21. Hosokawa M, Kenmotsu H, Koh Y, Yoshino T, Yoshikawa T, Naito T, et al. Size-based isolation of circulating tumor cells in lung cancer patients using a microcavity array system. PLoS One 2013;8:e67466.
  22. Chen X, Zhou F, Li X, Yang G, Zhang L, Ren S, et al. Folate receptor-positive circulating tumor cell detected by LT-PCRbased method as a diagnostic biomarker for non-small-cell lung cancer. J Thorac Oncol 2015;10:1163-71.
  23. Wang L, Wu C, Qiao L, Yu W, Guo Q, Zhao M, et al. Clinical significance of folate receptor-positive circulating tumor cells detected by ligand-targeted polymerase chain reaction in lung cancer. J Cancer 2017;8:104-10.