Establishment of a diagnostic model for clinical stage Ⅰ non-small cell lung cancer: A study based on clinical imaging features combined with folate receptor-positive circulating tumor cells tests_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

KONG Dezhi , LIU Ao , CUI Jian , LENG Xiaoliang , WO Yang , DONG Yanting ,  JIAO Wenjie

Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266071, Shandong, P.R.China;

Corresponding?author：

JIAO Wenjie, Email: jiaowj@qduhospital.cn

Keywords：

Non-small cell lung cancer; early diagnosis; nomogram; folate receptor; circulating tumor cell

DOI：

10.7507/1007-4848.202101072

Video：

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Objective To analyze the correlation between folate receptor-positive circulating tumor cells (FR⁺CTC) and the benign or malignant lesions of the lung, and to establish a malignant prediction model for pulmonary neoplasm based on clinical data, imaging and FR⁺CTC tests.Methods A retrospective analysis was done on 1 277 patients admitted to the Affiliated Hospital of Qingdao University from September 2018 to December 2019, including 518 males and 759 females, with a median age of 57 (29-85) years. They underwent CTC examination of peripheral blood and had pathological results of pulmonary nodules and lung tumors. The patients were randomly divided into a trial group and a validation group. Univariate and multivariate analyses were performed on the data of the two groups. Then the nomogram prediction model was established and verified internally and externally. Receiver operating characteristic (ROC) curve was used to test the differentiation of the model and calibration curve was used to test the consistency of the model.Results Totally 925 patients suffered non-small cell lung cancer and 113 patients had benign diseases in the trial group; 219 patients suffered non-small cell lung cancer and 20 patients had benign diseases in the verification group. The FR⁺CTC in the peripheral blood of non-small cell lung cancer patients was higher than that found in the lungs of the patients who were in favorite conditions (P<0.001). Multivariate analysis showed that age≥60 years, female, FR⁺CTC value>8.7 FU/3 mL, positive pleural indenlation sign, nodule diameter, positive burr sign, consolidation/tumor ratio<1 were independent risk factors for benign and malignant lung tumors with a lesion diameter of ≤4 cm. Thereby, the nomogram prediction model was established. The area under the ROC curve (AUC) of the trial group was 0.918, the sensitivity was 86.36%, and the specificity was 83.19%. The AUC value of the verification group was 0.903, the sensitivity of the model was 79.45%, and the specificity was 90.00%, indicating nomogram model discrimination was efficient. The calibration curve also showed that the nomogram model calibration worked well.Conclusion FR⁺CTC in the peripheral blood of non-small cell lung cancer patients is higher than that found in the lungs of the patients who carry benign pulmonary diseases. The diagnostic model of clinical stage Ⅰ non-small cell lung cancer established in this study owns good accuracy and can provide a basis for clinical diagnosis.

Citation： KONG Dezhi, LIU Ao, CUI Jian, LENG Xiaoliang, WO Yang, DONG Yanting, JIAO Wenjie. Establishment of a diagnostic model for clinical stage Ⅰ non-small cell lung cancer: A study based on clinical imaging features combined with folate receptor-positive circulating tumor cells tests. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2021, 28(10): 1192-1201. doi: 10.7507/1007-4848.202101072 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Gao S, Li N, Wang S, et al. Lung cancer in People's Republic of China. J Thorac Oncol, 2020, 15(10): 1567-1576.
3.	Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med, 2011, 365(5): 395-409.
4.	Boiselle PM. Computed tomography screening for lung cancer. JAMA, 2013, 309(11): 1163-1170.
5.	Heerink WJ, de Bock GH, de Jonge GJ, et al. Complication rates of CT-guided transthoracic lung biopsy: Meta-analysis. Eur Radiol, 2017, 27(1): 138-148.
6.	Hofman P. Liquid biopsy and therapeutic targets: Present and future issues in thoracic oncology. Cancers (Basel), 2017, 9(11): 154.
7.	Rolfo C, Mack PC, Scagliotti GV, et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): A statement paper from the IASLC. J Thorac Oncol, 2018, 13(9): 1248-1268.
8.	Mateo J, Gerlinger M, Rodrigues DN, et al. The promise of circulating tumor cell analysis in cancer management. Genome Biol, 2014, 15(8): 448.
9.	Calabuig-Fari?as S, Jantus-Lewintre E, Herreros-Pomares A, et al. Circulating tumor cells versus circulating tumor DNA in lung cancer-which one will win? Transl Lung Cancer Res, 2016, 5(5): 466-482.
10.	Mayo-de-Las-Casas C, Garzón Ibá?ez M, Jordana-Ariza N, et al. An update on liquid biopsy analysis for diagnostic and monitoring applications in non-small cell lung cancer. Expert Rev Mol Diagn, 2018, 18(1): 35-45.
11.	Shivange G, Urbanek K, Przanowski P, et al. A single-agent dual-specificity targeting of FOLR1 and DR5 as an effective strategy for ovarian cancer. Cancer Cell, 2018, 34(2): 331-345.
12.	Chen X, Zhou F, Li X, et al. Folate receptor-positive circulating tumor cell detected by LT-PCR-based method as a diagnostic biomarker for non-small-cell lung cancer. J Thorac Oncol, 2015, 10(8): 1163-1171.
13.	Wei W, Zeng H, Zheng R, et al. Cancer registration in China and its role in cancer prevention and control. Lancet Oncol, 2020, 21(7): e342-e349.
14.	Horeweg N, Scholten ET, de Jong PA, et al. Detection of lung cancer through low-dose CT screening (NELSON): A prespecified analysis of screening test performance and interval cancers. Lancet Oncol, 2014, 15(12): 1342-1350.
15.	Swensen SJ, Silverstein MD, Ilstrup DM, et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med, 1997, 157(8): 849-855.
16.	Gould MK, Ananth L, Barnett PG, et al. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest, 2007, 131(2): 383-388.
17.	McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med, 2013, 369(10): 910-919.
18.	Hu B, Rochefort H, Goldkorn A. Circulating tumor cells in prostate cancer. Cancers (Basel), 2013, 5(4): 1676-1690.
19.	Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev, 1989, 8(2): 98-101.
20.	Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol, 2010, 17(6): 1471-1474.
21.	Crosbie PA, Shah R, Summers Y, et al. Prognostic and predictive biomarkers in early stage NSCLC: CTCs and serum/plasma markers. Transl Lung Cancer Res, 2013, 2(5): 382-397.
22.	Wong SC, Chan CM, Ma BB, et al. Clinical significance of cytokeratin 20-positive circulating tumor cells detected by a refined immunomagnetic enrichment assay in colorectal cancer patients. Clin Cancer Res, 2009, 15(3): 1005-1012.
23.	Brown HK, Tellez-Gabriel M, Cartron PF, et al. Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: Myth or reality? Drug Discov Today, 2019, 24(3): 763-772.
24.	Hofman V, Heeke S, Marquette CH, et al. Circulating tumor cell detection in lung cancer: But to what end? Cancers (Basel), 2019, 11(2): 262.
25.	Nunez MI, Behrens C, Woods DM, et al. High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation. J Thorac Oncol, 2012, 7(5): 833-840.
26.	Parker N, Turk MJ, Westrick E, et al. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem, 2005, 338(2): 284-293.
27.	Lou J, Ben S, Yang G, et al. Quantification of rare circulating tumor cells in non-small cell lung cancer by ligand-targeted PCR. PLoS One, 2013, 8(12): e80458.
28.	Yu Y, Chen Z, Dong J, et al. Folate receptor-positive circulating tumor cells as a novel diagnostic biomarker in non-small cell lung cancer. Transl Oncol, 2013, 6(6): 697-702.
29.	Ning N, Zhan T, Zhang Y, et al. Improvement of specific detection of circulating tumor cells using combined CD45 staining and fluorescence in situ hybridization. Clin Chim Acta, 2014, 433: 69-75.
30.	Harper KL, Sosa MS, Entenberg D, et al. Mechanism of early dissemination and metastasis in Her2 + mammary cancer. Nature, 2016, 540(7634): 588-592.
31.	Zhu WY, Alliegro MA, Melera PW. The rate of folate receptor alpha (FR alpha) synthesis in folate depleted CHL cells is regulated by a translational mechanism sensitive to media folate levels, while stable overexpression of its mRNA is mediated by gene amplification and an increase in transcript half-life. J Cell Biochem, 2001, 81(2): 205-219.
32.	Ding C, Zhou X, Xu C, et al. Circulating tumor cell levels and carcinoembryonic antigen: An improved diagnostic method for lung adenocarcinoma. Thorac Cancer, 2018, 9(11): 1413-1420.
33.	Chang S, Hur JY, Choi YL, et al. Current status and future perspectives of liquid biopsy in non-small cell lung cancer. J Pathol Transl Med, 2020, 54(3): 204-212.
34.	李媛秋, 么鴻雁. 肺癌主要危險因素的研究進展. 中國腫瘤, 2016, 25(10): 782-786.
35.	Moon SM, Kim JH, Kim SK, et al. Clinical utility of combined circulating tumor cell and circulating tumor DNA assays for diagnosis of primary lung cancer. Anticancer Res, 2020, 40(6): 3435-3444.
36.	Zhong CH, Tong D, Zhou ZQ, et al. Performance evaluation of detecting circulating tumor cells and tumor cells in bronchoalveolar lavage fluid in diagnosis of peripheral lung cancer. J Thorac Dis, 2018, 10(Suppl 7): S830-S837.
37.	Dai F, Wang J, An H, et al. Therapy of 125 Ⅰparticles implantation inhibited the local growth of advanced non-small cell lung cancer: A retrospective clinical study. Am J Transl Res, 2019, 11(6): 3737-3749.
38.	Zhou J, Diao X, Wang S, et al. Diagnosis value of combined detection of serum SF, CEA and CRP in non-small cell lung cancer. Cancer Manag Res, 2020, 12: 8813-8819.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Gao S, Li N, Wang S, et al. Lung cancer in People's Republic of China. J Thorac Oncol, 2020, 15(10): 1567-1576.
3. Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med, 2011, 365(5): 395-409.
4. Boiselle PM. Computed tomography screening for lung cancer. JAMA, 2013, 309(11): 1163-1170.
5. Heerink WJ, de Bock GH, de Jonge GJ, et al. Complication rates of CT-guided transthoracic lung biopsy: Meta-analysis. Eur Radiol, 2017, 27(1): 138-148.
6. Hofman P. Liquid biopsy and therapeutic targets: Present and future issues in thoracic oncology. Cancers (Basel), 2017, 9(11): 154.
7. Rolfo C, Mack PC, Scagliotti GV, et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): A statement paper from the IASLC. J Thorac Oncol, 2018, 13(9): 1248-1268.
8. Mateo J, Gerlinger M, Rodrigues DN, et al. The promise of circulating tumor cell analysis in cancer management. Genome Biol, 2014, 15(8): 448.
9. Calabuig-Fari?as S, Jantus-Lewintre E, Herreros-Pomares A, et al. Circulating tumor cells versus circulating tumor DNA in lung cancer-which one will win? Transl Lung Cancer Res, 2016, 5(5): 466-482.
10. Mayo-de-Las-Casas C, Garzón Ibá?ez M, Jordana-Ariza N, et al. An update on liquid biopsy analysis for diagnostic and monitoring applications in non-small cell lung cancer. Expert Rev Mol Diagn, 2018, 18(1): 35-45.
11. Shivange G, Urbanek K, Przanowski P, et al. A single-agent dual-specificity targeting of FOLR1 and DR5 as an effective strategy for ovarian cancer. Cancer Cell, 2018, 34(2): 331-345.
12. Chen X, Zhou F, Li X, et al. Folate receptor-positive circulating tumor cell detected by LT-PCR-based method as a diagnostic biomarker for non-small-cell lung cancer. J Thorac Oncol, 2015, 10(8): 1163-1171.
13. Wei W, Zeng H, Zheng R, et al. Cancer registration in China and its role in cancer prevention and control. Lancet Oncol, 2020, 21(7): e342-e349.
14. Horeweg N, Scholten ET, de Jong PA, et al. Detection of lung cancer through low-dose CT screening (NELSON): A prespecified analysis of screening test performance and interval cancers. Lancet Oncol, 2014, 15(12): 1342-1350.
15. Swensen SJ, Silverstein MD, Ilstrup DM, et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med, 1997, 157(8): 849-855.
16. Gould MK, Ananth L, Barnett PG, et al. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest, 2007, 131(2): 383-388.
17. McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med, 2013, 369(10): 910-919.
18. Hu B, Rochefort H, Goldkorn A. Circulating tumor cells in prostate cancer. Cancers (Basel), 2013, 5(4): 1676-1690.
19. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev, 1989, 8(2): 98-101.
20. Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol, 2010, 17(6): 1471-1474.
21. Crosbie PA, Shah R, Summers Y, et al. Prognostic and predictive biomarkers in early stage NSCLC: CTCs and serum/plasma markers. Transl Lung Cancer Res, 2013, 2(5): 382-397.
22. Wong SC, Chan CM, Ma BB, et al. Clinical significance of cytokeratin 20-positive circulating tumor cells detected by a refined immunomagnetic enrichment assay in colorectal cancer patients. Clin Cancer Res, 2009, 15(3): 1005-1012.
23. Brown HK, Tellez-Gabriel M, Cartron PF, et al. Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: Myth or reality? Drug Discov Today, 2019, 24(3): 763-772.
24. Hofman V, Heeke S, Marquette CH, et al. Circulating tumor cell detection in lung cancer: But to what end? Cancers (Basel), 2019, 11(2): 262.
25. Nunez MI, Behrens C, Woods DM, et al. High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation. J Thorac Oncol, 2012, 7(5): 833-840.
26. Parker N, Turk MJ, Westrick E, et al. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem, 2005, 338(2): 284-293.
27. Lou J, Ben S, Yang G, et al. Quantification of rare circulating tumor cells in non-small cell lung cancer by ligand-targeted PCR. PLoS One, 2013, 8(12): e80458.
28. Yu Y, Chen Z, Dong J, et al. Folate receptor-positive circulating tumor cells as a novel diagnostic biomarker in non-small cell lung cancer. Transl Oncol, 2013, 6(6): 697-702.
29. Ning N, Zhan T, Zhang Y, et al. Improvement of specific detection of circulating tumor cells using combined CD45 staining and fluorescence in situ hybridization. Clin Chim Acta, 2014, 433: 69-75.
30. Harper KL, Sosa MS, Entenberg D, et al. Mechanism of early dissemination and metastasis in Her2 + mammary cancer. Nature, 2016, 540(7634): 588-592.
31. Zhu WY, Alliegro MA, Melera PW. The rate of folate receptor alpha (FR alpha) synthesis in folate depleted CHL cells is regulated by a translational mechanism sensitive to media folate levels, while stable overexpression of its mRNA is mediated by gene amplification and an increase in transcript half-life. J Cell Biochem, 2001, 81(2): 205-219.
32. Ding C, Zhou X, Xu C, et al. Circulating tumor cell levels and carcinoembryonic antigen: An improved diagnostic method for lung adenocarcinoma. Thorac Cancer, 2018, 9(11): 1413-1420.
33. Chang S, Hur JY, Choi YL, et al. Current status and future perspectives of liquid biopsy in non-small cell lung cancer. J Pathol Transl Med, 2020, 54(3): 204-212.
34. 李媛秋, 么鴻雁. 肺癌主要危險因素的研究進展. 中國腫瘤, 2016, 25(10): 782-786.
35. Moon SM, Kim JH, Kim SK, et al. Clinical utility of combined circulating tumor cell and circulating tumor DNA assays for diagnosis of primary lung cancer. Anticancer Res, 2020, 40(6): 3435-3444.
36. Zhong CH, Tong D, Zhou ZQ, et al. Performance evaluation of detecting circulating tumor cells and tumor cells in bronchoalveolar lavage fluid in diagnosis of peripheral lung cancer. J Thorac Dis, 2018, 10(Suppl 7): S830-S837.
37. Dai F, Wang J, An H, et al. Therapy of 125 Ⅰparticles implantation inhibited the local growth of advanced non-small cell lung cancer: A retrospective clinical study. Am J Transl Res, 2019, 11(6): 3737-3749.
38. Zhou J, Diao X, Wang S, et al. Diagnosis value of combined detection of serum SF, CEA and CRP in non-small cell lung cancer. Cancer Manag Res, 2020, 12: 8813-8819.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Establishment of a diagnostic model for clinical stage Ⅰ non-small cell lung cancer: A study based on clinical imaging features combined with folate receptor-positive circulating tumor cells tests

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