Introduction

Minimal residual disease (MRD) detection using liquid biopsy is an emerging tool for risk stratification and monitoring for recurrence in resected early stage NSCLC. There is increasing need for clear guidance on its optimal clinical implementation.

Materials and Methods

The Asian Thoracic Oncology Research Group (ATORG) convened a multidisciplinary panel of 27 experts to develop a consensus statement on the clinical application of circulating tumor DNA–based MRD testing in early stage resected NSCLC, using a structured Delphi methodology. Statements were organized into the following broad thematic domains: assay validity and standardization; harmonization in research and trials; clinical application; challenges in implementation; consensus recommendations; infrastructure for regional MRD adoption; and roadmap for pragmatic trials.

Results

A total of 23 position statements were developed, of which all except one achieved strong consensus. The consensus highlighted the need to define minimum analytical performance thresholds for MRD assays, improve standardization of reporting metrics, and clear guidelines for pre-analytical handling. Harmonization of blood sampling time points and terminology across clinical trials is also essential to confirm the prognostic value of MRD assays. Although current MRD assays demonstrate high specificity and positive predictive value, variable sensitivity precludes routine use for adjuvant therapy deescalation outside clinical trials. Broader access, sustainable funding, ongoing consensus building, and collaborative real-world data generation are also critical to support clinical implementation and adoption. Future clinical trials must account for the distinct biology and changing standards of care associated with different driver genes.

Conclusion

These consensus recommendations provide a pragmatic framework to guide the responsible integration of MRD testing into clinical research and practice.

1. Pignon, J. P., Tribodet, H., Scagliotti, G. V., et al. (2008). Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. Journal of Clinical Oncology, 26, 3552–3559.
2. Burdett, S., Rydzewska, L., Tierney, J., et al. (2016). Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database of Systematic Reviews, 2016(10), CD002142.
3. Le Péchoux, C., Dunant, A., Faivre-Finn, C., et al. (2015). Postoperative radiotherapy for pathologic N2 non-small-cell lung cancer treated with adjuvant chemotherapy: Need for randomized evidence. Journal of Clinical Oncology, 33, 2930–2931.
4. Wu, Y. L., Tsuboi, M., He, J., et al. (2020). Osimertinib in resected EGFR-mutated non-small-cell lung cancer. The New England Journal of Medicine, 383, 1711–1723.
5. Felip, E., Altorki, N., Zhou, C., et al. (2021). Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. The Lancet, 398, 1344–1357.
6. Wu, Y. L., Dziadziuszko, R., Ahn, J. S., et al. (2024). Alectinib in resected ALK-positive non-small-cell lung cancer. The New England Journal of Medicine, 390, 1265–1276.
7. O’Brien, M., Paz-Ares, L., Marreaud, S., et al. (2022). Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB–IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): An interim analysis of a randomised, triple-blind, phase 3 trial. The Lancet Oncology, 23, 1274–1286.
8. Spicer, J. D., Cascone, T., Wynes, M. W., et al. (2024). Neoadjuvant and adjuvant treatments for early-stage resectable NSCLC: Consensus recommendations from the International Association for the Study of Lung Cancer. Journal of Thoracic Oncology, 19, 1373–1414.
9. Tie, J., Cohen, J. D., Lahouel, K., et al. (2022). Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. The New England Journal of Medicine, 386, 2261–2272.
10. Kobayashi, S., Nakamura, Y., Hashimoto, T., et al. (2025). Japan Society of Clinical Oncology position paper on appropriate clinical use of molecular residual disease testing. International Journal of Clinical Oncology, 30, 605–654.
11. Abbosh, C., Birkbak, N. J., & Swanton, C. (2018). Early-stage NSCLC: Challenges to implementing ctDNA-based screening and MRD detection. Nature Reviews Clinical Oncology, 15, 577–586.
12. Boukouris, A. E., Michaelidou, K., Joosse, S. A., et al. (2025). A comprehensive overview of minimal residual disease in the management of early-stage and locally advanced non-small cell lung cancer. NPJ Precision Oncology, 9, 178.
13. Pascual, J., Attard, G., Bidard, F. C., et al. (2022). ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: A report from the ESMO Precision Medicine Working Group. Annals of Oncology, 33, 750–768.
14. Stetson, D., Labrousse, P., Russell, H., et al. (2024). Next-generation molecular residual disease assays: Do we have the tools to evaluate them properly? Journal of Clinical Oncology, 42, 2736–2740.
15. Aredo, J. V., Jamali, A., Zhu, J., et al. (2025). Liquid biopsy approaches for cancer characterization, residual disease detection, and therapy monitoring. American Society of Clinical Oncology Educational Book, 45, e481114.
16. Fusco, N., Venetis, K., Pepe, F., et al. (2025). International Society of Liquid Biopsy perspective on minimal requirements for ctDNA testing in solid tumors. Journal of Liquid Biopsy, 8, 100301.
17. van der Leest, P., & Schuuring, E. (2024). Critical factors in the analytical workflow of circulating tumor DNA-based molecular profiling. Clinical Chemistry, 70, 220–233.
18. Zhang, J. T., Liu, S. Y., Gao, X., et al. (2025). Follow-up analysis enhances understanding of molecular residual disease in localized non-small cell lung cancer. Clinical Cancer Research, 31, 1305–1314.
19. Zhang, J. T., Liu, S. Y., Gao, W., et al. (2022). Longitudinal undetectable molecular residual disease defines potentially cured population in localized non-small cell lung cancer. Cancer Discovery, 12, 1690–1701.
20. Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., et al. (2017). Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discovery, 7, 1394–1403.
21. Abbosh, C., Birkbak, N. J., Wilson, G. A., et al. (2017). Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature, 545, 446–451.
22. Ohara, S., Suda, K., Sakai, K., et al. (2020). Prognostic implications of preoperative versus postoperative circulating tumor DNA in surgically resected lung cancer patients: A pilot study. Translational Lung Cancer Research, 9, 1915–1923.
23. Kuang, P. P., Li, N., Liu, Z., et al. (2020). Circulating tumor DNA analyses as a potential marker of recurrence and effectiveness of adjuvant chemotherapy for resected non-small-cell lung cancer. Frontiers in Oncology, 10, 595650.
24. Xia, L., Mei, J., Kang, R., et al. (2022). Perioperative ctDNA-based molecular residual disease detection for non-small cell lung cancer: A prospective multicenter cohort study (LUNGCA-1). Clinical Cancer Research, 28, 3308–3317.
25. Tan, A. C., Lai, G. G. Y., Saw, S. P. L., et al. (2024). Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer. Cancer, 130, 1758–1765.
26. Gale, D., Heider, K., Ruiz-Valdepenas, A., et al. (2022). Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer. Annals of Oncology, 33, 500–510.
27. Chen, K., Yang, F., Shen, H., et al. (2023). Individualized tumor-informed circulating tumor DNA analysis for postoperative monitoring of non-small cell lung cancer. Cancer Cell, 41, 1749–1762.e6.
28. Tran, H. T., Heeke, S., Sujit, S., et al. (2024). Circulating tumor DNA and radiological tumor volume identify patients at risk for relapse with resected, early-stage non-small-cell lung cancer. Annals of Oncology, 35, 183–189.
29. He, J., Tsuboi, M., Weder, W., et al. (2025). Neoadjuvant osimertinib for resectable EGFR-mutated non-small cell lung cancer. Journal of Clinical Oncology, 43, 2875–2887.
30. Forde, P. M., Spicer, J. D., Provencio, M., et al. (2025). Overall survival with neoadjuvant nivolumab plus chemotherapy in lung cancer. The New England Journal of Medicine, 393, 741–752.
31. Reck, M., Gale, D., Zhu, Z., et al. (2025). Association of post-surgical MRD status with neoadjuvant ctDNA dynamics, genomic mutations, and clinical outcomes in patients with resectable NSCLC from the phase 3 AEGEAN trial. Journal of Clinical Oncology, 43, 8009.
32. Felip, E., Srivastava, M., Reck, M., et al. (2022). IMpower010: ctDNA status in patients with resected NSCLC who received adjuvant chemotherapy followed by atezolizumab or best supportive care. Immuno-Oncology Technology, 16, 100106.
33. Tie, J., Wang, Y., Loree, J. M., et al. (2025). ctDNA-guided adjuvant chemotherapy escalation in stage III colon cancer: Primary analysis of the ctDNA-positive cohort from the randomized AGITG DYNAMIC-III trial. Journal of Clinical Oncology, 43, 3503.
34. Heitzer, E., Haque, I. S., Roberts, C. E. S., et al. (2019). Current and future perspectives of liquid biopsies in genomics-driven oncology. Nature Reviews Genetics, 20, 71–88.
35. Smeltzer, M. P., King, J. C., Connolly, C., et al. (2025). The 2024 International Association for the Study of Lung Cancer global survey on biomarker testing. Journal of Thoracic Oncology, 20, 1801–1813.
36. Tan, O., Shrestha, R., Cunich, M., et al. (2018). Application of next-generation sequencing to improve cancer management: A review of the clinical effectiveness and cost-effectiveness. Clinical Genetics, 93, 533–544.
37. Schneider, B. J., Ismaila, N., Aerts, J., et al. (2020). Lung cancer surveillance after definitive curative-intent therapy: ASCO guideline. Journal of Clinical Oncology, 38, 753–766.
38. Benson, A. B., Venook, A. P., Adam, M., et al. (2024). Colon cancer, version 3.2024, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, 22, e240029.
39. Benson, A. B., Venook, A. P., Adam, M., et al. (2024). NCCN Guidelines insights: Rectal cancer, version 3.2024. Journal of the National Comprehensive Cancer Network, 22, 366–375.
40. Schmults, C. D., Blitzblau, R., Aasi, S. Z., et al. (2024). NCCN Guidelines insights: Merkel cell carcinoma, version 1.2024. Journal of the National Comprehensive Cancer Network, 22, e240002.
41. Chakravarty, D., Johnson, A., Sklar, J., et al. (2022). Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion. Journal of Clinical Oncology, 40, 1231–1258.
42. Rolfo, C., Mack, P., Scagliotti, G. V., et al. (2021). Liquid biopsy for advanced NSCLC: A consensus statement from the International Association for the Study of Lung Cancer. Journal of Thoracic Oncology, 16, 1647–1662.
43. Riely, G. J., Wood, D. E., Ettinger, D. S., et al. (2024). Non-small cell lung cancer, version 4.2024, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, 22, 249–274.
44. Noronha, V., Budukh, A., Chaturvedi, P., et al. (2024). Uniqueness of lung cancer in Southeast Asia. The Lancet Regional Health—Southeast Asia, 27, 100430.
45. Barta, J. A., Powell, C. A., & Wisnivesky, J. P. (2019). Global epidemiology of lung cancer. Annals of Global Health, 85, 8.
46. Centers for Medicare & Medicaid Services. (2025). Local coverage determination: MolDX: Minimal residual disease testing for cancer. https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=38779&ver=4
47. Senter, L., Veney, D., Surplus, T., et al. (2023). Patient understanding of tumor genomic testing: A quality improvement effort. JCO Oncology Practice, 19, e8–e14.
48. Pantel, K., & Alix-Panabières, C. (2019). Liquid biopsy and minimal residual disease: Latest advances and implications for cure. Nature Reviews Clinical Oncology, 16, 409–424.
49. Normanno, N., Morabito, A., Rachiglio, A. M., et al. (2025). Circulating tumour DNA in early-stage and locally advanced NSCLC: Ready for clinical implementation? Nature Reviews Clinical Oncology, 22, 215–231.
50. Moding, E. J., Nabet, B. Y., Alizadeh, A. A., et al. (2021). Detecting liquid remnants of solid tumors: Circulating tumor DNA minimal residual disease. Cancer Discovery, 11, 2968–2986.
51. Zhang, J. T., Dong, S., Gu, W. Q., et al. (2024). Adjuvant therapy-free strategy for stage IB to IIIA non-small-cell lung cancer patients after radical resection based on longitudinal undetectable molecular residual disease: Prospective, multicenter, single-arm study (CTONG 2201). Clinical Lung Cancer, 25, e1–e4.
52. Wakelee, H., Liberman, M., Kato, T., et al. (2023). Perioperative pembrolizumab for early-stage non-small-cell lung cancer. The New England Journal of Medicine, 389, 491–503.
53. Cascone, T., Awad, M. M., Spicer, J. D., et al. (2024). Perioperative nivolumab in resectable lung cancer. The New England Journal of Medicine, 390, 1756–1769.
54. Tsuboi, M., Herbst, R. S., John, T., et al. (2023). Overall survival with osimertinib in resected EGFR-mutated NSCLC. The New England Journal of Medicine, 389, 137–147.
55. Lam, V. K., Zhang, J., Wu, C. C., et al. (2021). Genotype-specific differences in circulating tumor DNA levels in advanced NSCLC. Journal of Thoracic Oncology, 16, 601–609.
56. Jung, H. A., Ku, B. M., Kim, Y. J., et al. (2023). Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stages I to IIIA EGFR-mutant non-small cell lung cancer. Journal of Thoracic Oncology, 18, 1199–1208.
57. Herbst, R. S., John, T., Grohé, C., et al. (2025). Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB–IIIA non-small-cell lung cancer. Nature Medicine, 31, 1958–1968.