{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:44:39Z","timestamp":1790444679158,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T00:00:00Z","timestamp":1611792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Surgical resection is often the preferred treatment for non-small cell lung cancer (NSCLC) patients. Predictive biomarkers after surgery can help monitoring and treating patients promptly, so as to improve the clinical outcome. In this study, we evaluated one potential candidate biomarker, the folate receptor-positive circulating tumor cell (FR<jats:sup>+<\/jats:sup>CTC), by investigating its prognostic and predictive significance in NSCLC patients who underwent surgery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this prospective, observational study, we enrolled NSCLC patients who were eligible to receive surgery. Prior to operation, peripheral blood was collected from each patient for an FR<jats:sup>+<\/jats:sup>CTC analysis. FR<jats:sup>+<\/jats:sup>CTCs were isolated by negative enrichment using immunomagnetic beads to deplete leukocytes and then quantitatively detected by a ligand-targeted polymerase chain reaction (PCR) method. These patients were then given standard care and were actively followed up for seven years. At the end of the follow-up period, the association between the FR<jats:sup>+<\/jats:sup>CTC level and the prognosis in these patients was evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, preoperative FR<jats:sup>+<\/jats:sup>CTC level was not significantly different among NSCLC patients with adenocarcinoma or non-adenocarcinoma subtypes (<jats:italic>P<\/jats:italic> = 0.24). However, between patients with low- and high-risk pathological adenocarcinoma subtypes, the preoperative FR<jats:sup>+<\/jats:sup>CTC level was significantly different (<jats:italic>P<\/jats:italic> = 0.028). Further, patients with lower preoperative FR<jats:sup>+<\/jats:sup>CTC level had longer relapse-free survival (RFS) and overall survival (OS) than those with higher preoperative FR<jats:sup>+<\/jats:sup>CTC level (RFS: not reached vs. 33.3 months, <jats:italic>P<\/jats:italic> = 0.018; OS: not reached vs. 72.0 months, <jats:italic>P<\/jats:italic> = 0.13). In a multivariate COX regression analysis, FR<jats:sup>+<\/jats:sup>CTC level (HR = 4.10; 95% CI, 1.23\u201313.64; <jats:italic>P<\/jats:italic>=0.022) and pathological stage (HR = 3.16; 95% CI, 1.79\u201310.14; <jats:italic>P<\/jats:italic> = 0.0011) were independent prognostic factors of RFS. Moreover, FR<jats:sup>+<\/jats:sup>CTC level together with adenocarcinoma subtypes provided additional information on risk for disease recurrence compared with FR<jats:sup>+<\/jats:sup>CTC or adenocarcinoma subtype alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study demonstrated that the preoperative FR<jats:sup>+<\/jats:sup>CTC level was a potential predictor for the prognosis of NSCLC patients underwent surgery. Further, when preoperative FR<jats:sup>+<\/jats:sup>CTC level is considered together with primary tumor proliferation characteristics, its prognostic value supplements that of these conventional pathological features.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2020.621435","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T13:07:43Z","timestamp":1611839263000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Preoperative Folate Receptor-Positive Circulating Tumor Cell Level Is a Prognostic Factor of Long Term Outcome in Non-Small Cell Lung Cancer Patients"],"prefix":"10.3389","volume":"10","author":[{"given":"Hang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjian","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqing","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"Ca-a Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21338","article-title":"Cancer Statistics in China, 2015","volume":"66","author":"Chen","year":"2016","journal-title":"Ca-a Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.jtho.2015.09.009","article-title":"The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer","volume":"11","author":"Goldstraw","year":"2016","journal-title":"J Thorac Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10552-014-0457-4","article-title":"The presence of clustered circulating tumor cells (CTCs) and circulating cytokines define an aggressive phenotype in metastatic colorectal cancer","volume":"25","author":"Divella","year":"2014","journal-title":"Cancer Causes Control"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-17-2312","article-title":"Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance)","volume":"24","author":"Magbanua","year":"2018","journal-title":"Clin Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040766","article-title":"Circulating tumor cells, disease progression, and survival in metastatic breast cancer","volume":"351","author":"Cristofanilli","year":"2004","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2007.15.8923","article-title":"Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer","volume":"26","author":"Cohen","year":"2008","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(08)70340-1","article-title":"Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data","volume":"10","author":"Scher","year":"2009","journal-title":"Lancet Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2010.28.7045","article-title":"Evaluation and Prognostic Significance of Circulating Tumor Cells in Patients With Non-Small-Cell Lung Cancer","volume":"29","author":"Krebs","year":"2011","journal-title":"J Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080458","article-title":"Quantification of Rare Circulating Tumor Cells in Non-Small Cell Lung Cancer by Ligand-Targeted PCR","volume":"8","author":"Lou","year":"2013","journal-title":"PLoS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1593\/tlo.13535","article-title":"Folate Receptor-Positive Circulating Tumor Cells as a Novel Diagnostic Biomarker in Non-Small Cell Lung Cancer","volume":"6","author":"Yu","year":"2013","journal-title":"Trans Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2016.06.017","article-title":"Circulating Tumor Cells Detected in the Tumor-Draining Pulmonary Vein Are Associated with Disease Recurrence after Surgical Resection of NSCLC","volume":"11","author":"Crosbie","year":"2016","journal-title":"J Thorac Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148659","article-title":"Circulating Tumor Cells Identify Early Recurrence in Patients with Non-Small Cell Lung Cancer Undergoing Radical Resection","volume":"11","author":"Bayarri-Lara","year":"2016","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.drup.2014.10.002","article-title":"The folate receptor as a rational therapeutic target for personalized cancer treatment","volume":"17","author":"Assaraf","year":"2014","journal-title":"Drug Resist U"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703875104","article-title":"In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry","volume":"104","author":"He","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.7150\/jca.16856","article-title":"Clinical Significance of Folate Receptor-positive Circulating Tumor Cells Detected by Ligand-targeted Polymerase Chain Reaction in Lung Cancer","volume":"8","author":"Wang","year":"2017","journal-title":"J Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1097\/jto.0000000000000606","article-title":"Folate Receptor-Positive Circulating Tumor Cell Detected by LT-PCR-Based Method as a Diagnostic Biomarker for Non-Small-Cell Lung Cancer","volume":"10","author":"Chen","year":"2015","journal-title":"J Thorac Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2018.11.014","article-title":"Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR-Mutated Advanced Non-Small-Cell Lung Cancer Patients Treated With First-Line EGFR Tyrosine Kinase Inhibitors","volume":"20","author":"Jiang","year":"2019","journal-title":"Clin Lung Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17039","article-title":"Predictive and prognostic value of folate receptor-positive circulating tumor cells in small cell lung cancer patients treated with first-line chemotherapy","volume":"8","author":"Shen","year":"2017","journal-title":"Oncotarget"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.02.028","article-title":"Value of folate receptor-positive circulating tumour cells in the clinical management of indeterminate lung nodules: A non-invasive biomarker for predicting malignancy and tumour invasiveness","volume":"41","author":"Zhou","year":"2019","journal-title":"Ebiomedicine"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.23717","article-title":"Quantitation of circulating tumor cells in blood samples from ovarian and prostate cancer patients using tumor-specific fluorescent ligands","volume":"123","author":"He","year":"2008","journal-title":"Int J Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur J Cancer"},{"key":"B23","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.lungcan.2014.11.010","article-title":"Close association of IASLC\/ATS\/ERS lung adenocarcinoma subtypes with glucose-uptake in positron emission tomography","volume":"87","author":"Nakamura","year":"2015","journal-title":"Lung Cancer"},{"key":"B24","article-title":"Clinical implication of minimal presence of solid or micropapillary subtype in early-stage lung adenocarcinoma","volume-title":"Thorac Cancer","author":"Choi","year":"2020"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-9473(02)00225-6","article-title":"On the exact distribution of maximally selected rank statistics","volume":"43","author":"Hothorn","year":"2003","journal-title":"Comput Stat Data Anal"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1106613108","article-title":"Controversies in clinical cancer dormancy","volume":"108","author":"Uhra","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/s0169-5002(02)00009-0","article-title":"Prognostic impact of Cyfra21-1 and other serum markers in completely resected non-small cell lung cancer","volume":"36","author":"Reinmuth","year":"2002","journal-title":"Lung Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3978\/j.issn.2218-6751.2013.09.02","article-title":"Prognostic and predictive biomarkers in early stage NSCLC: CTCs and serum\/plasma markers","volume":"2","author":"Crosbie","year":"2013","journal-title":"Trans Lung Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.21037\/jtd.2018.04.08","article-title":"The role of liquid biopsy in predicting post-operative recurrence of non-small cell lung cancer","volume":"10","author":"Liang","year":"2018","journal-title":"J Thorac Dis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2007.12.018","article-title":"Bone marrow micrometastases in advanced stage non-small cell lung carcinoma patients","volume":"61","author":"Brunsvig","year":"2008","journal-title":"Lung Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1203543","article-title":"A perspective on cancer cell metastasis","volume":"331","author":"Chaffer","year":"2011","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2256","article-title":"Models, mechanisms and clinical evidence for cancer dormancy","volume":"7","author":"Aguirre-Ghiso","year":"2007","journal-title":"Nat Rev Cancer"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/science.1235226","article-title":"Circulating Tumor Cells","volume":"341","author":"Plaks","year":"2013","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.3390\/cancers11111750","article-title":"Post-Surgery Circulating Tumor Cells and AXL Overexpression as New Poor Prognostic Biomarkers in Resected Lung Adenocarcinoma","volume":"11","author":"De Miguelperez","year":"2019","journal-title":"Cancers"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.11302","article-title":"Detection of Circulating Tumour Cells and Survival of Patients with Non-small Cell Lung Cancer","volume":"37","author":"Chudasama","year":"2017","journal-title":"Anticancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s00595-016-1318-4","article-title":"Perioperative circulating tumor cells in surgical patients with non-small cell lung cancer: does surgical manipulation dislodge cancer cells thus allowing them to pass into the peripheral blood","volume":"46","author":"Sawabata","year":"2016","journal-title":"Surg Today"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-16-2072","article-title":"Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers","volume":"77","author":"Murlidhar","year":"2017","journal-title":"Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4971","DOI":"10.1038\/s41598-017-05154-x","article-title":"Circulating tumor cells in peripheral and pulmonary venous blood predict poor long-term survival in resected non-small cell lung cancer patients","volume":"7","author":"Li","year":"2017","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0593-1","article-title":"Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse","volume":"25","author":"Chemi","year":"2019","journal-title":"Nat Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4103\/jcrt.JCRT_905_17","article-title":"Folate-receptor-positive circulating tumor cells as an efficacious biomarker for the diagnosis of small pulmonary nodules","volume":"14","author":"Xue","year":"2018","journal-title":"J Cancer Res Ther"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2019.0972","article-title":"Effect of Vein-First vs Artery-First Surgical Technique on Circulating Tumor Cells and Survival in Patients With Non-Small Cell Lung Cancer A Randomized Clinical Trial and Registry-Based Propensity Score Matching Analysis","volume":"154","author":"Wei","year":"2019","journal-title":"JAMA Surg"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2010.232","article-title":"Impact of proposed IASLC\/ATS\/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases","volume":"24","author":"Yoshizawa","year":"2011","journal-title":"Modern Pathol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2020.621435\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T13:07:49Z","timestamp":1611839269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2020.621435\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,28]]},"references-count":42,"alternative-id":["10.3389\/fonc.2020.621435"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2020.621435","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,28]]},"article-number":"621435"}}