Key contributors and trends in circulating tumor DNA research in lung cancer: A bibliometric analysis

Abstract

Lung cancer is one of the leading causes of cancer-related mortality, and liquid biopsy, particularly the detection of circulating tumor DNA (ctDNA), offers a promising non-invasive alternative for diagnosis. Despite significant research on ctDNA in lung cancer, a comprehensive bibliometric analysis on this topic is lacking in the literature. This study systematically reviews ctDNA research trends in lung cancer using bibliometric methods to identify leading contributors, emerging themes, and underexplored areas for future research. We conducted a search of the Web of Science Core Collection database for ctDNA-related lung cancer publications up to 2023. The bibliometric analysis was performed using VOSviewers, CiteSpace, and the R package “bibliometrix.” The results revealed a total of 2862 publications on ctDNA in lung cancer, comprising 1998 articles and 864 reviews. Between 2021 and 2023, the number of publications stabilized, with an average of approximately 360 publications per year. The countries with the highest number of published papers were China and the United States. The University of Texas MD Anderson Cancer Center was the leading institution in terms of publication output. Among journals, Cancers published the highest number of papers, while Clinical Cancer Research had the highest citation impact. Lanman RB was the leading author by publication count, and Newman was the most co-cited author. Current research on ctDNA in lung cancer primarily focuses on areas such as minimal residual disease, prognosis and recurrence monitoring, adjuvant therapy decision-making, epidermal growth factor receptor and targeted therapy, and immunotherapy. This bibliometric analysis highlights the impact of ctDNA in lung cancer, revealing key contributors and emerging research trends.

Keywords

Circulating tumor DNA / Lung cancer / Bibliometric analysis / Research trends / Key contributors

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. doi: 10.3322/caac.21834

[2] Campos-Balea B, de Castro Carpeño J, Massutí B, et al. Prognostic factors for survival in patients with metastatic lung adenocarcinoma: An analysis of the SEER database. Thorac Cancer. 2020; 11(11):3357-3364. doi: 10.1111/1759-7714.13681

[3] Reina C, Šabanović B, Lazzari C, Gregorc V, Heeschen C. Unlocking the future of cancer diagnosis - promises and challenges of ctDNA-based liquid biopsies in non-small cell lung cancer. Transl Res. 2024; 272:41-53. doi: 10.1016/j.trsl.2024.05.014

[4] Sundaresan TK, Sequist LV, Heymach JV, et al. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res. 2016; 22(5):1103-1110. doi: 10.1158/1078-0432.CCR-15-1031

[5] Lazzari C, Bulotta A, Cangi MG, et al. Next generation sequencing in non-small cell lung cancer: Pitfalls and opportunities. Diagnostics (Basel). 2020; 10(12):1092. doi: 10.3390/diagnostics10121092

[6] Li W, Liu JB, Hou LK, et al. Liquid biopsy in lung cancer: Significance in diagnostics, prediction, and treatment monitoring. Mol Cancer. 2022; 21(1):25. doi: 10.1186/s12943-022-01505-z

[7] Wan JCM, Massie C, Garcia-Corbacho J, et al. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017; 17(4):223-238. doi: 10.1038/nrc.2017.7

[8] Wen X, Pu H, Liu Q, Guo Z, Luo D. Circulating tumor DNA-A novel biomarker of tumor progression and its favorable detection techniques. Cancers (Basel). 2022; 14(24):6025. doi: 10.3390/cancers14246025

[9] Ji Z, Chen L, Yang Q, et al. Research trend of circulating tumor DNA associated with breast cancer from 2012 to 2021: A bibliometric analysis. Front Oncol. 2022; 12:1090503. doi: 10.3389/fonc.2022.1090503

[10] Wu F, Gao J, Kang J, et al. Knowledge mapping of exosomes in autoimmune diseases: A bibliometric analysis (2002- 2021). Front Immunol. 2022; 13:939433. doi: 10.3389/fimmu.2022.939433

[11] van Eck NJ, Waltman L. Software survey: VOSviewer, a computer program for bibliometric mapping. Scientometrics. 2010; 84(2):523-538. doi: 10.1007/s11192-009-0146-3

[12] Synnestvedt MB, Chen C, Holmes JH. CiteSpace II:Visualization and knowledge discovery in bibliographic databases. AMIA Annu Symp Proc. 2005; 2005:724-728.

[13] Aria M, Cuccurullo C. Bibliometrix: An R-tool for comprehensive science mapping analysis. J Informetrics. 2017; 11(4):959-975. doi: 10.1016/j.joi.2017.08.007

[14] Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001; 61(4):1659-1665.

[15] Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 2017; 7(12):1394-1403. doi: 10.1158/2159-8290.Cd-17-0716.

[16] Wang H, Zhang Y, Zhang H, et al. Liquid biopsy for human cancer: Cancer screening, monitoring, and treatment. MedComm (2020). 2024; 5(6):e564. doi: 10.1002/mco2.564

[17] Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014; 6(224):224ra224. doi: 10.1126/scitranslmed.3007094

[18] Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014; 20(5):548-554. doi: 10.1038/nm.3519

[19] Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008; 14(9):985-990. doi: 10.1038/nm.1789

[20] Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017; 545(7655):446-451. doi: 10.1038/nature22364

[21] Bardelli A. Liquid biopsies: Genotyping circulating tumor DNA. J Clin Oncol. 2014; 32(6):579-586. doi: 10.1200/jco.2012.45.2011

[22] Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013; 368(13):1199-1209. doi: 10.1056/NEJMoa1213261

[23] Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014; 20(6):1698-1705. doi: 10.1158/1078-0432.Ccr-13-2482

[24] Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013; 497(7447):108-112. doi: 10.1038/nature12065

[25] Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol. 2016; 34(28):3375-3382. doi: 10.1200/jco.2016.66.7162

[26] Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977; 37(3):646-650.

[27] Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-957. doi: 10.1056/NEJMoa0810699

[28] Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011; 11(6):426-437. doi: 10.1038/nrc3066

[29] Mok T, Wu YL, Lee JS, et al. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated erlotinib and chemotherapy. Clin Cancer Res. 2015; 21(14):3196-3203. doi: 10.1158/1078-0432.Ccr-14-2594

[30] Forshew T, Murtaza M, Parkinson C, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012; 4(136):136ra168. doi: 10.1126/scitranslmed.3003726

[31] Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016; 34(5):547-555. doi: 10.1038/nbt.3520

[32] Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13(3):239-246. doi: 10.1016/s1470-2045(11)70393-x

[33] Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: Monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013; 10(8):472-484. doi: 10.1038/nrclinonc.2013.110

[34] Galant N, Nicoś M, Kuźnar-Kamińska B, Krawczyk P. Variant allele frequency analysis of circulating tumor DNA as a promising tool in assessing the effectiveness of treatment in non-small cell lung carcinoma patients. Cancers (Basel). 2024; 16(4):782. doi: 10.3390/cancers16040782

[35] Douillard JY, Ostoros G, Cobo M, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: Circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol. 2014; 9(9):1345-1353. doi: 10.1097/jto.0000000000000263

[36] Thress KS, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer. 2015; 90(3):509-515. doi: 10.1016/j.lungcan.2015.10.004

[37] Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016; 8(346):346ra392. doi: 10.1126/scitranslmed.aaf6219

[38] Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018; 24(9):1441-1448. doi: 10.1038/s41591-018-0134-3

[39] Leighl NB, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer. Clin Cancer Res. 2019; 25(15):4691-4700. doi: 10.1158/1078-0432.Ccr-19-0624

[40] Chabon JJ, Hamilton EG, Kurtz DM, et al. Integrating genomic features for non-invasive early lung cancer detection. Nature. 2020; 580(7802):245-251. doi: 10.1038/s41586-020-2140-0

[41] Lanman RB, Mortimer SA, Zill OA, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One. 2015; 10(10):e0140712. doi: 10.1371/journal.pone.0140712

[42] Iwahashi N, Sakai K, Noguchi T, et al. Liquid biopsy-based comprehensive gene mutation profiling for gynecological cancer using CAncer Personalized Profiling by deep Sequencing. Sci Rep. 2019; 9(1):10426. doi: 10.1038/s41598-019-47030-w

[43] Kaneko A, Kanemaru H, Kajihara I, et al. Liquid biopsy-based analysis by ddPCR and CAPP-Seq in melanoma patients. J Dermatol Sci. 2021; 102(3):158-166. doi: 10.1016/j.jdermsci.2021.04.006

[44] Chen C. CiteSpace II: Detecting and visualizing emerging trends and transient patterns in scientific literature. J Assoc Inf Sci Technol. 2006; 57:359-377. doi: 10.1002/asi.20317

[45] Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17(8):e328-e346. doi: 10.1016/s1470-2045(16)30206-6

[46] Mohan M, Kendrick S, Szabo A, et al. Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma. Blood Adv. 2022; 6(3):808-817. doi: 10.1182/bloodadvances.2021005822

[47] Pierce E, Mautner B, Mort J, et al. MRD in ALL: Optimization and innovations. Curr Hematol Malig Rep. 2022; 17(4):69-81. doi: 10.1007/s11899-022-00664-6

[48] Xie W, Suryaprakash S, Wu C, Rodriguez A, Fraterman S. Trends in the use of liquid biopsy in oncology. Nat Rev Drug Discov. 2023; 22(8):612-613. doi: 10.1038/d41573-023-00111-y

[49] MRD may predict relapse in NSCLC. Cancer Discov. 2020; 10(7):Of7. doi: 10.1158/2159-8290.Cd-nd2020-010

[50] Kanayama M, Kuwata T, Mori M, et al. Prognostic impact of circulating tumor cells detected with the microfluidic “universal CTC-chip” for primary lung cancer. Cancer Sci. 2022; 113(3):1028-1037. doi: 10.1111/cas.15255

[51] Lam VK, Zhang J, Wu CC, et al. Genotype-specific differences in circulating tumor DNA levels in advanced NSCLC. J Thorac Oncol. 2021; 16(4):601-609. doi: 10.1016/j.jtho.2020.12.011

[52] Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. doi: 10.1038/nature12213

[53] Li T, Liu J, Zhou Y, et al. Clinical relevance of somatic mutations in Chinese lung adenocarcinoma and their prognostic implications for survival. Cancer Med. 2024; 13(10):e7227. doi: 10.1002/cam4.7227

[54] Zhong J, Bai H, Wang Z, et al. Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions. Front Med. 2023; 17(1):18-42. doi: 10.1007/s11684-022-0976-4

[55] Lyu M, Zhou J, Ning K, Ying B. The diagnostic value of circulating tumor cells and ctDNA for gene mutations in lung cancer. Onco Targets Ther. 2019; 12:2539-2552. doi: 10.2147/ott.S195342

[56] Razavi P, Li BT, Brown DN, et al. High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat Med. 2019; 25(12):1928-1937. doi: 10.1038/s41591-019-0652-7

[57] Abbosh C, Frankell A, Garnett A, et al. Abstract CT023: Phylogenetic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study. Cancer Res. 2020; 80(16 Suppl):CT023-CT023. doi: 10.1158/1538-7445.AM2020-CT023

[58] Abbosh C, Frankell AM, Harrison T, et al. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature. 2023; 616(7957):553-562. doi: 10.1038/s41586-023-05776-4

[59] Chen K, Zhao H, Shi Y, et al. Perioperative dynamic changes in circulating tumor DNA in patients with lung cancer (DYNAMIC). Clin Cancer Res. 2019; 25(23):7058-7067. doi: 10.1158/1078-0432.CCR-19-1213

[60] Zviran A, Schulman RC, Shah M, et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med. 2020; 26(7):1114-1124. doi: 10.1038/s41591-020-0915-3

[61] Qiu B, Guo W, Zhang F, et al. Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun. 2021; 12(1):6770. doi: 10.1038/s41467-021-27022-z

[62] Xia L, Mei J, Kang R, et al. Perioperative ctDNA-based molecular residual disease detection for non-small cell lung cancer: A prospective multicenter cohort study (LUNGCA-1). Clin Cancer Res. 2022; 28(15):3308-3317. doi: 10.1158/1078-0432.CCR-21-3044

[63] Jänne PA, Kobayashi K, Robichaux J, et al. Abstract CT017: FLAURA2: Exploratory analysis of baseline (BL) and on-treatment plasma EGFRm dynamics in patients (pts) with EGFRm advanced NSCLC treated with first-line (1L) osimertinib (osi)±platinum-pemetrexed. Cancer Res. 2024; 84(7 Suppl):CT017. doi: 10.1158/1538-7445.AM2024-CT017

[64] Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020; 382(1):41-50. doi: 10.1056/NEJMoa1913662

[65] Dong S, Wang Z, Zhang JT, et al. Circulating tumor DNA-guided de-escalation targeted therapy for advanced non-small cell lung cancer: A nonrandomized controlled trial. JAMA Oncol. 2024; 10(7):932-940. doi: 10.1001/jamaoncol.2024.1779

[66] Anagnostou V, Ho C, Nicholas G, et al. ctDNA response after pembrolizumab in non-small cell lung cancer: Phase 2 adaptive trial results. Nat Med. 2023; 29(10):2559-2569. doi: 10.1038/s41591-023-02598-9

[67] Lu S, Wang J, Sun M, et al. Abstract LB289: Longitudinal ctDNA levels and clinical outcomes of first-line (1L) tislelizumab (TIS) + chemotherapy (chemo) treatment for advanced non-small cell lung cancer (NSCLC) in the RATIONALE-304 and 307 studies. Cancer Res. 2023; 83(8 Suppl):LB289. doi: 10.1158/1538-7445.AM2023-LB289

[68] Lu S, Wang J, Yu Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): A randomized phase 3 trial. J Thorac Oncol. 2021; 16(9):1512-1522. doi: 10.1016/j.jtho.2021.05.005

[69] Wang J, Lu S, Yu X, et al. Tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for advanced squamous non-small-cell lung cancer: A phase 3 randomized clinical trial. JAMA Oncol. 2021; 7(5):709-717. doi: 10.1001/jamaoncol.2021.0366