Monitoring of circulating tumor DNA and its aberrant methylation in the surveillance of surgical lung Cancer patients: protocol for a prospective observational study

Guannan Kang, Kezhong Chen, Fan Yang, Shannon Chuai, Heng Zhao, Kai Zhang, Bingsi Li, Zhihong Zhang, Jun Wang, Guannan Kang, Kezhong Chen, Fan Yang, Shannon Chuai, Heng Zhao, Kai Zhang, Bingsi Li, Zhihong Zhang, Jun Wang

Abstract

Background: Detection of circulating tumor DNA (ctDNA) is a promising method for postoperative surveillance of lung cancer. However, relatively low positive rate in early stage patients restricts its application. Aberrant methylation of ctDNA can be detected in blood samples, and may provide a more sensitive method. This study is designed to systematically evaluate and compare the detection of aberrant methylation and mutations in ctDNA among surgical non-small cell lung cancer (NSCLC) patients, aiming to investigate the feasibility of ctDNA detection as a means of lung cancer surveillance.

Methods: This is a prospective observational study. Consecutive surgical NSCLC patients will be recruited. Blood samples will be collected both before and after surgery (during the follow-up period), while matching tumor tissues and tumor-adjacent normal tissues will be collected during surgery. Quantitative analysis of aberrant methylation and mutations of ctDNA will be conducted in combination with a three-year follow-up data.

Discussion: This is the first registered prospective study designed to investigate the feasibility of ctDNA methylation detection as a means of postoperative lung cancer surveillance. We will systematically evaluate and compare the quantitative detection of ctDNA mutations and ctDNA methylation in surgical NSCLC patients, combining with the follow-up information. By integrating genetic and epigenetic information of ctDNA, more effective strategies for postoperative surveillance may be defined.

Trial registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826; Pre-results).

Keywords: Circulating tumor DNA; DNA methylation; Lung cancer.

Conflict of interest statement

SC, BL and ZZ are employed by Burning Rock Biotech. The study is sponsored by Burning Rock Biotech, which will participate in the detection of the samples and has reviewed the manuscript and approved for publication. Other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of patient recruitment, sample collection and follow-up
Fig. 2
Fig. 2
Strategy for DNA library preparation and sequencing

References

    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.
    1. Hoffman PC, Mauer AM, Vokes EE. Lung cancer. Lancet. 2000;355(9202):479–485. doi: 10.1016/S0140-6736(00)82038-3.
    1. Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung Cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15(4):504–535. doi: 10.6004/jnccn.2017.0050.
    1. Ignatiadis M, Lee M, Jeffrey SS. Circulating tumor cells and circulating tumor DNA: challenges and opportunities on the path to clinical utility. Clin Cancer Res. 2015;21(21):4786–4800. doi: 10.1158/1078-0432.CCR-14-1190.
    1. 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. 2017;11(2):117–118.
    1. Xu RH, Wei W, Krawczyk M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater. 2017;16(11):1155–1161. doi: 10.1038/nmat4997.
    1. Garcia-Murillas I, Schiavon G, Weigelt B, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133. doi: 10.1126/scitranslmed.aab0021.
    1. Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985. doi: 10.1038/nm.1789.
    1. Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem. 2015;61(1):112–123. doi: 10.1373/clinchem.2014.222679.
    1. Diaz LA, Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579–586. doi: 10.1200/JCO.2012.45.2011.
    1. Chen KZ, Lou F, Yang F, et al. Circulating tumor DNA detection in early-stage non-small cell lung Cancer patients by targeted sequencing. Sci Rep. 2016;6(31985).
    1. Chen K, Zhang J, Guan T, et al. Comparison of plasma to tissue DNA mutations in surgical patients with non-small cell lung cancer. J Thorac Cardiovasc Surg. 2017;154(3):1123–31 e2. doi: 10.1016/j.jtcvs.2017.04.073.
    1. Wang Z, Cheng Y, An T, et al. Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial. Lancet Respir Med. 2018;6(9):681–690. doi: 10.1016/S2213-2600(18)30264-9.
    1. 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.
    1. 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.
    1. 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/-17-0716.
    1. Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the evolution of non-small-cell lung Cancer. N Engl J Med. 2017;376(22):2109–2121. doi: 10.1056/NEJMoa1616288.
    1. Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC - challenges to implementing ctDNA-based screening and MRD detection. Nat Rev Clin Oncol. 2018;15(9):577–586. doi: 10.1038/s41571-018-0058-3.
    1. Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001;134(7):573. doi: 10.7326/0003-4819-134-7-200104030-00011.
    1. Brock MV, Hooker CM, Otamachida E, et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med. 2008;358(11):1118–1128. doi: 10.1056/NEJMoa0706550.
    1. Ooki A, Maleki Z, Tsay JJ, et al. A panel of novel detection and prognostic methylated DNA markers in primary non-small cell lung Cancer and serum DNA. Clin Cancer Res. 2017;23(22):7141–7152. doi: 10.1158/1078-0432.CCR-17-1222.
    1. Chen K, Zhao H, Yang F, et al. Dynamic changes of circulating tumour DNA in surgical lung cancer patients: protocol for a prospective observational study. BMJ Open. 2018;8(2):e019012. doi: 10.1136/bmjopen-2017-019012.
    1. Chen K, Kang G, Zhao H, et al. Liquid biopsy in newly diagnosed patients with locoregional (I-IIIA) non-small cell lung cancer. Expert Rev Mol Diagn. 2019;19(5):419–427. doi: 10.1080/14737159.2019.1599717.

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