Implementation of a Pilot Study to Analyze Circulating Tumor DNA in Early-Stage Lung Cancer

Authors

  • Joana Espiga de Macedo Medical Oncology Department. Centro Hospitalar de Entre o Douro e Vouga. Santa Maria da Feira. & Faculty of Medicine. Universidade do Porto. Porto. & Institute for Research and Innovation in Health (i3S). Universidade do Porto. Porto. https://orcid.org/0000-0002-9637-313X
  • Tiago Taveira-Gomes Faculty of Medicine. Universidade do Porto. Porto. & Department of Community Medicine. Information and Decision in Health (MEDCIDS). Faculdade de Medicina. Universidade do Porto. Porto. & Faculdade de Ciências Médicas. Universidade Fernando Pessoa. Porto.
  • José Carlos Machado Institute for Research and Innovation in Health (i3S). Universidade do Porto. Porto. & Institute of Molecular Pathology and Immunology (IPATIMUP). Universidade do Porto. Porto. & Department of Pulmonology. Hospital de São João. Porto. https://orcid.org/0000-0003-4741-8415
  • Venceslau Hespanhol Institute for Research and Innovation in Health (i3S). Universidade do Porto. Porto. & Institute of Molecular Pathology and Immunology (IPATIMUP). Universidade do Porto. Porto. & Department of Pulmonology. Hospital de São João. Porto. https://orcid.org/0000-0001-6577-0063

DOI:

https://doi.org/10.20344/amp.19487

Keywords:

Circulating Tumor DNA, Early Detection of Cancer/methods, High-Throughput Nucleotide Sequencing, Lung Neoplasms, Mutation, Neoplasm Staging

Abstract

Introduction: Liquid biopsies based on plasma circulating tumour deoxyribonucleic acid (ctDNA) have shown promise in monitoring lung cancer evolution. The expression of ctDNA across time, its relationship with clinicopathological parameters and its association with lung cancer progression through imaging allow us to weigh how useful ctDNA could be in monitoring surgically resectable lung cancer. The aim of this study was to assess the impact of ctDNA analysis implementation in early-stage lung cancer.
Methods: A cohort of 47 patients was sequentially recruited. Only 34 patients with early-stage lung cancer were included. All patients had a tissue specimen and five blood samples drawn: at the preoperative stage, from the pulmonary vein, at surgical discharge, at the first follow-up and at the last follow-up. All blood samples were evaluated for ctDNA expression.
Results: On average, the maximum yield of ctDNA was obtained in liquid biopsies at the surgical discharge of patients when compared with PO, PV, and F1 (p < 0.0001, p < 0.0001, p < 0.0001 respectively). No statistically significant differences were found when comparing the last follow-up to surgical discharge ctDNA expression (p = 0.851). The correlation between ctDNA concentration according to five-time points and the four clinicopathological characteristics showed that patients younger than 70 years had a statistically significant reduction of the concentration of ctDNA at the preoperative and surgical discharge time point [β = -16 734 (-27 707; - 5760); p = 0.003; β = -21 785 (-38 447; -5123); p = 0.010], as opposed to an increase of the concentration of ctDNA at the pulmonary vein and last follow-up time points [β = 8369 (0.359; 16 378); p = 0.041; β = 34 402 (12 549; 56 254); p = 0.002] all with a confidence level of 95%. In the cases where actionable mutations were identified in tissue biopsies, the expected mutation was found in five out of six patients plasma samples at the pre-operatory time point and in two out of six patients plasma samples at the pulmonary vein time point. Two out of six patients with actionable mutations had disease progression.
Conclusion: The results of this pilot study suggest that the maximum yield of ctDNA is obtained at the surgical discharge of the patients and that the pre-operatory timepoint is the one offering the highest sensitivity for the detection of actionable mutations in ctDNA in early-stage lung cancer.

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References

Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, regional, national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years from 29 cancer groups, 1990 to 2017. JAMA Oncol. 2019;5;1749-68.

GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific and cause-specific mortality for 24- causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117-71. DOI: https://doi.org/10.1016/S0140-6736(14)61682-2

World Health Organisation, International Agency for Research on Cancer. Globocan 2020. [cited 2022 Dec 17]. Available from: https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.

Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.

National Institute for Health and Care Excellence. NICE Clinical Guidelines. 2011 Update. [cited 2017 May 23]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22855970.

Früh M, Rolland E, Pignon J, Seymour L, Ding K, Tribodet H, et al. Pooled analysis of the effect of age on adjuvant cisplatin-based chemotherapy for completely resected non-small-cell lung cancer. J Clin Oncol. 2008;26:3573-81. DOI: https://doi.org/10.1200/JCO.2008.16.2727

Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-9. DOI: https://doi.org/10.1200/JCO.2007.13.9030

Shieh Y, Bohnenkamp M. Low- dose CT scan for lung cancer screening: clinical and coding considerations. Chest. 2017;152:204-9. DOI: https://doi.org/10.1016/j.chest.2017.03.019

Mandel P, Metais P. Les acides nucléiques du plasma sanguin chez l’homme. C R Seances Soc Biol Fil. 1948;142:241-3.

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. 2022;33:500-10. DOI: https://doi.org/10.1016/j.annonc.2022.02.007

Hassanein M, Callison JC, Callaway-Lane C, Aldrich MC, Grogan EL, Massion PP, et al. The state of molecular biomarkers for the early detection of lung cancer. Cancer Prev Res. 2012;5:992-1006. DOI: https://doi.org/10.1158/1940-6207.CAPR-11-0441

Teixeira MR, Oliveira J, Borralho P, Fernandes OG, Almodovar T, Fernandes I, et al. Portuguese consensus recommendations for next-generation sequencing of lung cancer, rare tumors, and cancers of unknown primary origin in clinical practice. Acta Med Port. 2022;35:677-90. DOI: https://doi.org/10.20344/amp.17680

Diaz IM, Nocon A, Mehnert DH, Fredebohm J, Diehl F, Holtrup F, et al. Performance of streck cfDNA blood collection tubes for liquid biopsy testing. PLoS ONE. 2016;11:e0166354. DOI: https://doi.org/10.1371/journal.pone.0166354

Parpart-Li S, Bartlett B, Popoli M, Adleff V, Tucker L, Steinberg R, et al. The effect of preservative and temperature on the analysis of circulating tumor DNA. Clin Cancer Res. 2016;23:2471-7. DOI: https://doi.org/10.1158/1078-0432.CCR-16-1691

Toro PV, Erlanger B, Beaver JA, Cochran RL, VanDenBerg DA, Yakim E, et al. Comparison of cell stabilizing blood collection tubes for circulating plasma tumor DNA. Clin Biochem. 2015;48:993-8. DOI: https://doi.org/10.1016/j.clinbiochem.2015.07.097

Swinkels DW, Wiegerinck E, Steegers EA, Kok JK. Effects of blood-processing protocols on cell-free DNA quantification in plasma. Clin Chem. 2003;49:525-6. DOI: https://doi.org/10.1373/49.3.525

El Messaoudi S, Rolet F, Mouliere F, Thierry AR. Circulating cell free DNA: preanalytical considerations. Clin Chim Acta. 2013;424:222-30. DOI: https://doi.org/10.1016/j.cca.2013.05.022

Crowley E, Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472-84. DOI: https://doi.org/10.1038/nrclinonc.2013.110

Veldore VH, Choughule A, Routhu T, Mandloi N, Noronha V, Amit Joshi A, et al. Validation of liquid biopsy: plasma cell-free DNA testing in clinical management of advanced non-small cell lung cancer. Lung Cancer. 2018;9:1-11. DOI: https://doi.org/10.2147/LCTT.S147841

Gale D, Lawson AJ, Howarth K, Madi M, Durham B, Smalley S, et al. Development of a highly sensitive liquid biopsy platform to detect clinically relevant cancer mutations at low allele fractions in cell-free DNA. PLoS One. 2018;13:e0194630. DOI: https://doi.org/10.1371/journal.pone.0194630

Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545:446-51. DOI: https://doi.org/10.1038/nature22364

Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 2017;7:1394-403. DOI: https://doi.org/10.1158/2159-8290.CD-17-0716

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;128:708-18. DOI: https://doi.org/10.1002/cncr.33985

Zhang JT, Liu SY, Gao W, Liu SM, Yan HH, Ji L, et al. Longitudinal undetectable molecular residual disease defines potentially cured population in localized non–small cell lung cancer. Cancer Discov. 2022;12:1690-701. DOI: https://doi.org/10.1158/2159-8290.CD-21-1486

de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res. 2018;7:220-33. DOI: https://doi.org/10.21037/tlcr.2018.05.06

Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol. 2016;893:1-19. DOI: https://doi.org/10.1007/978-3-319-24223-1_1

Espiga de Macedo J, Manuela Machado M, Pereira MD, Machado FV, Amaral M. Will genetic testing be the answer to the definition of treatments in the era of precision therapies? Br J Cancer Res. 2020;3:1. DOI: https://doi.org/10.31488/bjcr.145

Li M, Hou X, Lin S, Zheng L, Liang J, Chen J, et al. Efficacy of adjuvant EGFR inhibitors and impact of clinical factors in resected EGFR-mutated non-small-cell lung cancer: a meta-analysis. Future Oncology. 2022;18:1159-69. DOI: https://doi.org/10.2217/fon-2021-0934

Moding EJ, Liu Y, Nabet BY, Chabon JJ, Chaudhuri AA, Hui AB, et al. Circulating tumour DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer. Nat Cancer. 2020;1:176-83. DOI: https://doi.org/10.1038/s43018-019-0011-0

Published

2023-07-25

How to Cite

1.
Espiga de Macedo J, Taveira-Gomes T, Machado JC, Hespanhol V. Implementation of a Pilot Study to Analyze Circulating Tumor DNA in Early-Stage Lung Cancer. Acta Med Port [Internet]. 2023 Jul. 25 [cited 2024 Jul. 25];37(1):10-9. Available from: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/19487

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