Sung H, Ferlay J, Siegel RL, et al., 2021, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 71(3): 209–249. https://doi.org/10.3322/caac.21660

Thai AA, Solomon BJ, Sequist LV, et al., 2021, Lung cancer. Lancet, 398(10299): 535–554. https://doi.org/10.1016/S0140-6736(21)00312-3 

Goldstraw P, Chansky K, Crowley J, et al., 2016, 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. J Thorac Oncol, 11(1): 39–51. https://doi.org/10.1016/j.jtho.2015.09.009

Pantel K, Alix-Panabières C, 2017, Tumour microenvironment: Informing on minimal residual disease in solid tumours. Nat Rev Clin Oncol, 14(6): 325–326. https://doi.org/10.1038/nrclinonc.2017.53

Diaz LA Jr., Bardelli A, 2014, Liquid biopsies: Genotyping circulating tumor DNA. J Clin Oncol, 32(6): 579–586. https://doi.org/10.1200/JCO.2012.45.2011

Avanzini S, Kurtz DM, Chabon JJ, et al., 2020, A mathematical model of ctDNA shedding predicts tumor detection size. Sci Adv, 6(50): eabc4308. https://doi.org/10.1126/sciadv.abc4308

Jaiswal S, Fontanillas P, Flannick J, et al., 2014, Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med, 371(26): 2488–2498.

Siravegna G, Marsoni S, Siena S, et al., 2017, Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol, 14(9): 531–548. https://doi.org/10.1038/nrclinonc.2017.14

Zhao H, Chen KZ, Hui BG, et al., 2018, Role of circulating tumor DNA in the management of early-stage lung cancer. Thorac Cancer, 9(5): 509–515. https://doi.org/10.1111 / 1759-7714.12622

Mouliere F, Rosenfeld N, 2015, Circulating tumor-derived DNA is shorter than somatic DNA in plasma. Proc Natl Acad Sci U S A, 112(11): 3178–3179.

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

Chen KZ, Lou F, Yang F, et al., 2016, Circulating tumor DNA detection in early-stage non-small cell lung cancer patients by targeted sequencing. Sci Rep, 6: 31985. https://doi.org/10.1038/srep31985 

Jiao XD, Ding LR, Zhang CT, et al., 2021, Serum tumor markers for the prediction of concordance between genomic profiles from liquid and tissue biopsy in patients with advanced lung adenocarcinoma. Transl Lung Cancer Res, 10(7): 3236–3250. https://doi.org/10.21037/tlcr-21-543

Scherer F, 2020, Capturing tumor heterogeneity and clonal evolution by circulating tumor DNA profiling. Recent Results Cancer Res, 215: 213–230. https://doi.org/10.1007 / 978-3-030-26439-0_11

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

Chen K, Kang G, Zhao H, et al., 2019, Liquid biopsy in newly diagnosed patients with locoregional (I-IIIA) non-small cell lung cancer. Expert Rev Mol Diagn, 19(5): 419–427. https://doi.org/10.1080 / 14737159.2019.1599717

Spindler KL, Pallisgaard N, Vogelius I, et al., 2012, Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res, 18(4): 1177–1185. https://doi.org/10.1158 / 1078-0432.CCR-11-0564

Gormally E, Caboux E, Vineis P, et al., 2007, Circulating free DNA in plasma or serum as biomarker of carcinogenesis: Practical aspects and biological significance. Mutat Res, 635(2-3): 105–117. https://doi.org/10.1016/j.mrrev.2006.11.002

To EW, Chan KC, Leung SF, et al., 2003, Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of nasopharyngeal carcinoma. Clin Cancer Res, 9(9): 3254–3259.

Keller L, Belloum Y, Wikman H, et al., 2021, Clinical relevance of blood-based ctDNA analysis: Mutation detection and beyond. Br J Cancer, 124(2): 345–358. https://doi.org/10.1038/s41416-020-01047-5

Adalsteinsson VA, Ha G, Freeman SS, et al., 2017, Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun, 8(1): 1324. https://doi.org/10.1038/s41467-017-00965-y

Redon R, Ishikawa S, Fitch KR, et al., 2006, Global variation in copy number in the human genome. Nature, 444(7118): 444–454. https://doi.org/10.1038/nature05329

Douville C, Springer S, Kinde I, et al., 2018, Detection of aneuploidy in patients with cancer through amplification of long interspersed nucleotide elements (LINEs). Proc Natl Acad Sci U S A, 115(8): 1871–1876. https://doi.org/10.1073/pnas.1717846115

Cristiano S, Leal A, Phallen J, et al., 2019, Genome-wide cell-free DNA fragmentation in patients with cancer. Nature, 570(7761): 385–389. https://doi.org/10.1038/s41586-019-1272-6

Ulz P, Perakis S, Zhou Q, et al., 2019, Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection. Nat Commun, 10(1): 4666. https://doi.org/10.1038/s41467-019-12714-4

Ansari J, Shackelford RE, El-Osta H, 2016, Epigenetics in non-small cell lung cancer: from basics to therapeutics. Transl Lung Cancer Res, 5(2): 155–171. https://doi.org/10.21037/tlcr.2016.02.02

Lu F, Zhang HT, 2011, DNA methylation and nonsmall cell lung cancer. Anat Rec (Hoboken), 294(11): 1787–1795. 

Bergman Y, Cedar H, 2013, DNA methylation dynamics in health and disease. Nat Struct Mol Biol, 20(3): 274–281. https://doi.org/10.1038/nsmb.2518

Lianidou E, 2021, Detection and relevance of epigenetic markers on ctDNA: Recent advances and future outlook. Mol Oncol, 15(6): 1683–1700. https://doi.org/10.1002 / 1878-0261.12978

Kurdyukov S, Bullock M, 2016, DNA methylation analysis: Choosing the right method. Biology (Basel), 5(1): 3. https://doi.org/10.3390/biology5010003

Li S, Tollefsbol TO, 2021, DNA methylation methods: Global DNA methylation and methylomic analyses. Methods, 187: 28–43. https://doi.org/10.1016/j.ymeth.2020.10.002

Bajbouj K, Al-Ali A, Ramakrishnan RK, et al., 2021, Histone modification in NSCLC: Molecular mechanisms and therapeutic targets. Int J Mol Sci, 22(21): 11701. https://doi.org/10.3390/ijms222111701

Friedman RC, Farh KK, Burge CB, et al., 2009, Most mammalian mRNAs are conserved targets of microRNAs. Genome Res, 19(1): 92–105. https://doi.org/10.1101/gr.082701.108

Vos PD, Leedman PJ, Filipovska A, et al., 2019, Modulation of miRNA function by natural and synthetic RNA-binding proteins in cancer. Cell Mol Life Sci, 76(19): 3745–3752. https://doi.org/10.1007/s00018-019-03163-9

Valihrach L, Androvic P, Kubista M, 2020, Circulating miRNA analysis for cancer diagnostics and therapy. Mol Aspects Med, 72: 100825. https://doi.org/10.1016/j.mam.2019.10.002 

Oudkerk M, Liu S, Heuvelmans MA, et al., 2021, Lung cancer LDCT screening and mortality reduction evidence, pitfalls and future perspectives. Nat Rev Clin Oncol, 18(3): 135–151. https://doi.org/10.1038/s41571-020-00432-6 

Aberle DR, Adams AM, Berg CD, et al., 2011, Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med, 365(5): 395–409.

de Koning HJ, van der Aalst CM, de Jong PA, et al., 2020, Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med, 382(6): 503–513. https://doi.org/10.1056/NEJMoa1911793 

Hoffman RM, Atallah RP, Struble RD, et al., 2020, Lung cancer screening with low-dose CT: A meta-analysis. J Gen Intern Med, 35(10): 3015–3025. https://doi.org/10.1007/s11606-020-05951-7

Perisinakis K, Seimenis I, Tzedakis A, et al., 2018, Radiation burden and associated cancer risk for a typical population to be screened for lung cancer with low-dose CT: A phantom study. Eur Radiol, 28(10): 4370–4378. https://doi.org/10.1007/s00330-018-5373-7

Cohen JD, Li L, Wang Y, et al., 2018, Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science, 359(6378): 926–930. https://doi.org/10.1126/science.aar3247

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

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

Mathios D, Johansen JS, Cristiano S, et al., 2021, Detection and characterization of lung cancer using cell-free DNA fragmentomes. Nat Commun, 12(1): 5060. https://doi.org/10.1038/s41467-021-24994-w

Mouliere F, Chandrananda D, Piskorz AM, et al., 2018, Enhanced detection of circulating tumor DNA by fragment size analysis. Sci Transl Med, 10(466): eaat4921. https://doi.org/10.1126/scitranslmed.aat4921

Sun K, Jiang P, Cheng SH, et al., 2019, Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin. Genome Res, 29(3): 418–427. https://doi.org/10.1101/gr.242719.118

Snyder MW, Kircher M, Hill AJ, et al., 2016, Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell, 164(1-2): 57–68. https://doi.org/10.1016/j.cell.2015.11.050

Liu MC, Oxnard GR, Klein EA, et al., 2020, Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol, 31(6): 745–759. https://doi.org/10.1016/j.annonc.2020.02.011

Chen C, Huang X, Yin W, et al., 2020, Ultrasensitive DNA hypermethylation detection using plasma for early detection of NSCLC: A study in Chinese patients with very small nodules. Clin Epigenetics, 12(1): 39. https://doi.org/10.1186/s13148-020-00828-2

Shen SY, Singhania R, Fehringer G, et al., 2018, Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature, 563(7732): 579–583. https://doi.org/10.1038/s41586-018-0703-0

Qi J, Hong B, Tao R, et al., 2021, Prediction model for malignant pulmonary nodules based on cfMeDIP-seq and machine learning. Cancer Sci, 112(9): 3918–3923. https://doi.org/10.1111/cas.15052

Kumar S, Paiva B, Anderson KC, et al., 2016, International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol, 17(8): e328–e346. https://doi.org/10.1016/S1470-2045(16)30206-6

Cescon DW, Bratman SV, Chan SM, et al., 2020, Circulating tumor DNA and liquid biopsy in oncology. Nat Cancer, 1(3): 276–290. https://doi.org/10.1038/s43018-020-0043-5

Di Capua D, Bracken-Clarke D, Ronan K, et al., 2021, The liquid biopsy for lung cancer: state of the art, limitations and future developments. Cancers (Basel), 13(16): 3923. https://doi.org/10.3390/cancers13163923

Chin RI, Chen K, Usmani A, et al., 2019, Detection of solid tumor molecular residual disease (MRD) using circulating tumor DNA (ctDNA). Mol Diagn Ther, 23(3): 311–331. https://doi.org/10.1007/s40291-019-00390-5

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

Chen K, Sun J, Zhao H, et al., 2021, Non-invasive lung cancer diagnosis and prognosis based on multi-analyte liquid biopsy. Mol Cancer, 20(1): 23.https://doi.org/10.1186/s12943-021-01323-9

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

Henriksen TV, Tarazona N, Frydendahl A, et al., 2022, Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, toward assessment of adjuvant therapy efficacy and clinical behavior of recurrences. Clin Cancer Res, 28(3): 507–517.

Ettinger DS, Wood DE, Aisner DL, et al., 2021, NCCN guidelines insights: non-small cell lung cancer, version 2.2021. J Natl Compr Canc Netw, 19(3): 254–266. https://doi.org/10.6004/jnccn.2021.0013

Passiglia F, Bertaglia V, Reale ML, et al., 2021, Major breakthroughs in lung cancer adjuvant treatment: Looking beyond the horizon. Cancer Treat Rev, 101: 102308. https://doi.org/10.1016/j.ctrv.2021.102308

Wu YL, Zhou C, Liam CK, et al., 2015, First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol, 26(9): 1883–1889. https://doi.org/10.1093/annonc/mdv270

Goss G, Tsai CM, Shepherd FA, et al., 2016, Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol, 17(12): 1643–1652. https://doi.org/10.1016/S1470-2045(16)30508-3

Nabet BY, Esfahani MS, Moding EJ, et al., 2020, Noninvasive early identification of therapeutic benefit from immune checkpoint inhibition. Cell, 183(2): 363–376.e13. https://doi.org/10.1016/j.cell.2020.09.001

Moding EJ, Liu Y, Nabet BY, et al., 2020, Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small cell lung cancer. Nat Cancer, 1(2): 176–183. https://doi.org/10.1038/s43018-019-0011-0

Phase III study to determine the efficacy of durvalumab in combination with chemotherapy in completely resected stage II-III non-small cell lung cancer (NSCLC) (the MERMAID-1 Trial). Available from: https://wwwclinicaltrialsgov/ct2/ show/NCT04385368 [Last accessed on 2021 Jun 30].

Phase III study to determine efficacy of durvalumab in stage II-III non-small cell lung cancer (NSCLC) after curative intent therapy (the MERMAID-2 Trial). Available from: https://wwwclinicaltrialsgov/ct2/show/NCT04642469 [Last accessed on 2021 Jun 30].

Adjuvant treatment with cisplatin-based chemotherapy plus concomitant Atezolizumab in patients with stage I (Tumors ≥ 4cm), IIA, IIB, and select IIIA (T3N1-2, T4N0-2) resected non-small cell lung cancer (NSCLC) and the clearance of circulating tumor DNA (ctDNA) (the BTCRC-LUN19-396 Trial). Available from: https://www.clinicaltrials.gov/ct2/ show/NCT04367311. [Last accessed on 2021 Jun 30].

Adjuvant durvalumab for early stage NSCLC patients with ctDNA minimal residual disease. Available from: https:// www.clinicaltrials.gov/ct2/show/NCT04585477 [Last accessed on 2021 Jun 30].

Personalized escalation of consolidation treatment following chemoradiotherapy and immunotherapy in stage III NSCLC in stage III NSCLC. Available from: https://www. clinicaltrials.gov/ct2/show/NCT04585490 [Last accessed on 2021 Jun 30].

Circulating tumor DNA (ctDNA) for early treatment response assessment of solid tumors. Available from: https:// www.clinicaltrials.gov/ct2/show/NCT04354064 [Last accessed on 2021 Jun 30].

A study of the efficacy and safety of RO7198457 in combination with atezolizumab versus atezolizumab alone following adjuvant platinum-doublet chemotherapy in participants who are ctDNA positive after surgical resection of stage II-III non-small cell lung cancer. Available from: https://www.clinicaltrials.gov/ct2/show/record/ NCT04267237 [Last accessed on 2021 Jun 30].

A study evaluating the efficacy and safety of adjuvant platinum-doublet chemotherapy, with or without atezolizumab, in patients who are ctDNA positive after complete surgical resection of stage IB to select IIIB non-small cell lung cancer (CATHAYA). Available from: https:// www.clinicaltrials.gov/ct2/show/record/NCT04611776 [Last accessed on 2021 Jun 30].

Horn L, Whisenant JG, Wakelee H, et al., 2019, Monitoring therapeutic response and resistance: Analysis of circulating tumor DNA in patients with ALK+ lung cancer. J Thorac Oncol, 14(11): 1901–1911. https://doi.org/10.1016/j.jtho.2019.08.003

Gao Z, Shang Y, Wang X, et al., 2019, Application of circulating tumor DNA for dynamic monitoring of advanced non-small cell lung cancer treatment response: An open-label, multicenter, prospective, observational study protocol. Thorac Cancer, 10(5): 1310–1315. https://doi.org/10.1111 / 1759-7714.13031

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

Kang G, Chen K, Yang F, et al., 2019, Monitoring of circulating tumor DNA and its aberrant methylation in the surveillance of surgical lung Cancer patients: Protocol for a prospective observational study. BMC Cancer,19(1): 579.