Evaluate the Prognostic Value of Non–Small-Cell Lung Cancer Using Blood-Based Circulating Tumor DNA: A Systematic Review and Meta-analysis

Document Type : Review Article


1 Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Pharmacology and Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

3 Helia Clinic, Dubai, United Arab Emirates


Background and objectives: This research aimed to evaluate the prognostic value(s) of non-small-cell lung cancer (NSCLC) through blood-based circulating tumor DNA (ctDNA).
Material and methods: To achieve the objectives of the study, databases at the international scale, including Web of Science, PubMed, Science Direct, Wiley, Scopus, EBSCO, Web of Knowledge, ISI, Embase, Google Scholar, and Elsevier, were searched according to PRISMA 2020-27-item checklist and respective keywords from 2019 to February 2024. Moreover, the inverse–variance method and the fixed-effect model were applied in the research. In addition, we used STATA/MP v17 for statistical analyses of the data (Sig, ˂ 0.05).
Results: Based on the search, 11 articles were chosen, considering the inclusion criteria intended for the research. The analysis demonstrated that cases suffering from higher levels of ctDNA exhibited greater levels of risk for progression-free survival and overall survival (HR 3.47, 95% CI 2.98-3.97; P-value < 0.001) and (HR 3.16, 95% CI 2.45-3.87, P-value < 0.001) than that of the cases suffering from lower levels of ctDNA.
Conclusions: Positive ctDNA was found to be related to overall survival and progression-free survival individually and collectively in non–small–cell Lung Cancer cases.


Main Subjects

[1] Wheeldon A. The respiratory system and associated disorders. British Journal of Nursing. 2023;32(13):613-9. https://doi.org/10.12968/bjon.2023.32.13.613.
[2] Gomes M, Teixeira AL, Coelho A, Araujo A, Medeiros R. The role of inflammation in lung cancer. Inflammation and cancer. 2014:1-23. https://doi.org/10.1007/978-3-0348-0837-8_1.
[3] Virno F, Di Giorgio A, Di Lauro G, Bellezza F, Carrozzini AI. Small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC): Comparative evaluation of survival after surgical treatment by computer. Lung Cancer. 1986;2:105-6.
[4] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. https://doi.org/10.3322/caac.21820.
[5] Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Lung cancer and personalized medicine: current knowledge and therapies. 2016:893:1-9. https://doi.org/10.1007/978-3-319-24223-1_1.
[6] Thanoon MA, Zulkifley MA, Mohd Zainuri MA, Abdani SR. A Review of Deep Learning Techniques for Lung Cancer Screening and Diagnosis Based on CT Images. Diagnostics. 2023;13(16):2617. https://doi.org/10.3390/diagnostics13162617.
[7] Wang PP, Liu SH, Chen CT, Lv L, Li D, Liu QY, et al. Circulating tumor cells as a new predictive and prognostic factor in patients with small cell lung cancer. Journal of Cancer. 2020;11(8):2113-22. https://doi.org/10.7150/jca.35308.
[8] Peng Y, Mei W, Ma K, Zeng C. Circulating tumor DNA and minimal residual disease (MRD) in solid tumors: current horizons and future perspectives. Frontiers in oncology. 2021;11:763790. https://doi.org/10.3389/fonc.2021.763790.
[9] Alba-Bernal A, Lavado-Valenzuela R, Domínguez-Recio ME, Jiménez-Rodriguez B, Queipo-Ortuño MI, Alba E, et al. Challenges and achievements of liquid biopsy technologies employed in early breast cancer. EBioMedicine. 2020;62:103100. https://doi.org/10.1016/j.ebiom.2020.103100.
[10] Papakonstantinou A, Gonzalez NS, Pimentel I, Suñol A, Zamora E, Ortiz C, et al. Prognostic value of ctDNA detection in patients with early breast cancer undergoing neoadjuvant therapy: A systematic review and meta-analysis. Cancer Treatment Reviews. 2022;104:102362. https://doi.org/10.1016/j.ctrv.2022.102362.
[11] Cullinane C, Fleming C, O’Leary DP, Hassan F, Kelly L, O’Sullivan MJ, et al. Association of circulating tumor DNA with disease-free survival in breast cancer: a systematic review and meta-analysis. JAMA network open. 2020;3(11):e2026921. https://doi.org/10.1001/jamanetworkopen.2020.26921.
[12] Gögenur M, Hadi NA, Qvortrup C, Andersen CL, Gögenur I. ctDNA for risk of recurrence assessment in patients treated with neoadjuvant treatment: A systematic review and meta-analysis. Annals of Surgical Oncology. 2022;29(13):8666-74. https://doi.org/10.1245/s10434-022-12366-7.
[13] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372(71). https://doi.org/10.1136/bmj.n71.
[14] Gierisch JM, Beadles C, Shapiro A, McDuffie J, Cunningham N, Bradford D. Newcastle-Ottawa scale coding manual for cohort studies. Health disparities in quality indicators of healthcare among adults with mental illness. Department of Veterans Affairs (US). 2014.
[15] Minozzi S, Cinquini M, Gianola S, Gonzalez-Lorenzo M, Banzi R. The revised Cochrane risk of bias tool for randomized trials (RoB 2) showed low interrater reliability and challenges in its application. Journal of clinical epidemiology. 2020;126:37-44. https://doi.org/10.1016/j.jclinepi.2020.06.015.
[16] Sokouti M, Shafiee-Kandjani AR, Sokouti M, Sokouti B. A meta-analysis of systematic reviews and meta-analyses to evaluate the psychological consequences of COVID-19. BMC psychology. 2023;11(1):279. https://doi.org/10.1186/s40359-023-01313-0.
[17] Wang HY, Ho CC, Lin YT, Liao WY, Chen CY, Shih JY, et al. Comprehensive Genomic Analysis of Patients With Non–Small-Cell Lung Cancer Using Blood-Based Circulating Tumor DNA Assay: Findings From the BFAST Database of a Single Center in Taiwan. JCO Precision Oncology. 2024;8:e2300314. https://doi.org/10.1200/PO.23.00314.
[18] Pan Y, Zhang JT, Gao X, Chen ZY, Yan B, Tan PX, et al. Dynamic circulating tumor DNA during chemoradiotherapy predicts clinical outcomes for locally advanced non-small cell lung cancer patients. Cancer Cell. 2023;41(10):1763-73. https://doi.org/10.1016/j.ccell.2023.09.007.
[19] Peng WW, Liu Y, Sha HH, Wen SD, Fang Y, Zhou GR. Relationship between plasma circulating cell-free DNA concentration and treatment outcomes including prognosis in patients with advanced non-small cell lung cancer. BMC Pulmonary Medicine. 2023;23(1):348. https://doi.org/10.1186/s12890-023-02586-2.
[20] Zhang JT, Liu SY, Gao W, Liu SY, Yan HH, Ji L, et al. Longitudinal undetectable molecular residual disease defines potentially cured population in localized non–small cell lung cancer. Cancer Discovery. 2022;12(7):1690-701. https://doi.org/10.1158/2159-8290.CD-21-1486.
[21] Chen K, Yang A, Carbone DP, Kanu N, Liu K, Wang R, et al. Spatiotemporal genomic analysis reveals distinct molecular features in recurrent stage I non-small cell lung cancers. Cell Reports. 2022;40(2). https://doi.org/10.1016/j.celrep.2022.111047.
[22] Provencio M, Serna-Blasco R, Nadal E, Insa A, García-Campelo MR, Rubio JC, et al. Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage IIIA non–small-cell lung cancer (NADIM phase II trial). Journal of Clinical Oncology. 2022;40(25):2924-33. https://doi.org/10.1200/JCO.21.02660.
 [23] Yue D, Liu W, Chen C, Zhang T, Ma Y, Cui L, et al. Circulating tumor DNA predicts neoadjuvant immunotherapy efficacy and recurrence-free survival in surgical non-small cell lung cancer patients. Translational lung cancer research. 2022;11(2):263-76. https://doi.org/10.21037/tlcr-22-106.
 [24] Li N, Wang BX, Li J, Shao Y, Li MT, Li JJ, et al. Perioperative circulating tumor DNA as a potential prognostic marker for operable stage I to IIIA non–small cell lung cancer. Cancer. 2022;128(4):708-18. https://doi.org/10.1002/cncr.33985.
[25] Gale D, Heider K, Ruiz-Valdepenas A, Hackinger S, Perry M, Marsico G, et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer. Annals of oncology. 2022;33(5):500-10. https://doi.org/10.1016/j.annonc.2022.02.007.
[26] Tan A, Lai G, Saw S, Chua K, Takano A, Ong B, et al. MA07. 06 circulating tumor DNA for monitoring minimal residual disease and early detection of recurrence in early stage lung cancer. Journal of Thoracic Oncology. 2021;16(10):S907. https://doi.org/10.1016/j.jtho.2021.08.144.
[27] Peng M, Huang Q, Yin W, Tan S, Chen C, Liu W, et al. Circulating tumor DNA as a prognostic biomarker in localized non-small cell lung cancer. Frontiers in oncology. 2020;10:561598. https://doi.org/10.3389/fonc.2020.561598.
[28] Faulkner LG, Howells LM, Pepper C, Shaw JA, Thomas AL. The utility of ctDNA in detecting minimal residual disease following curative surgery in colorectal cancer: a systematic review and meta-analysis. British journal of cancer. 2023;128(2):297-309. https://doi.org/10.1038/s41416-022-02017-9.
[29] Guo N, Lou F, Ma Y, Li J, Yang B, Chen W, et al. Circulating tumor DNA detection in lung cancer patients before and after surgery. Scientific reports. 2016;6(1):33519. https://doi.org/10.1038/srep33519.