ctDNA can detect minimal residual disease in curative treated non-small cell lung cancer patients using a tumor agnostic approach

doi:10.1016/j.lungcan.2025.108528

Multicenter Study

. 2025 May:203:108528.

doi: 10.1016/j.lungcan.2025.108528. Epub 2025 Apr 4.

ctDNA can detect minimal residual disease in curative treated non-small cell lung cancer patients using a tumor agnostic approach

Lærke Rosenlund¹, Kasper Guldbrandsen², Lise Barlebo Ahlborn³, Martin Bloch⁴, Kristin Skougaard⁵, Elisabeth Albrecht-Beste⁶, Hanne Marie Nellemann⁷, Martin Krakauer⁸, Peter Michael Gørtz⁹, Joan Fledelius¹⁰, Anne Lerberg Nielsen¹¹, Paw Christian Holdgaard¹², Søren Steen Nielsen¹³, Julie Marie Grüner¹⁴, Anette Højsgaard¹⁵, Rene Horsleben Petersen¹⁶, Lars Borgbjerg Møller¹⁷, Morten Dahl¹⁸, Malene Støchkel Frank¹⁹, Jeanette Haar Ehlers²⁰, Zaigham Saghir²¹, Mette Pøhl²², Svetlana Borissova²³, Lotte Holm Land²⁴, Charlotte Kristiansen²⁵, Tine McCulloch²⁶, Lise Saksø Mortensen²⁷, Malene Søby Christophersen²⁸, Ole Hilberg²⁹, Thor Lind Rasmussen³⁰, Signe Høyer Simonsen Schwaner³¹, Christian B Laursen³², Uffe Bodtger³³, Markus Nowak Lonsdale⁸, Christian Niels Meyer³⁴, Oke Gerke³⁵, Jann Mortensen⁶, Torben Riis Rasmussen³⁶, Karin Hjorthaug¹⁰, Klaus Richter Larsen³⁷, Peter Meldgaard³⁸, Barbara Malene Fischer⁶, Boe Sandahl Sorensen³⁹

Affiliations

¹ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
² Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
³ Department of Genomic Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁴ Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁵ Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Department of Oncology, University Hospital of Southern Denmark - Roskilde, Denmark.
⁶ Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Radiology, Aarhus University Hospital, Aarhus, Denmark.
⁸ Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
⁹ Department of Nuclear Medicine, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.
¹⁰ Department of Nuclear Medicine & PET-Centre, Aarhus University Hospital, Aarhus, Denmark.
¹¹ Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
¹² Department of Nuclear Medicine, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark.
¹³ Department of Nuclear Medicine, Aalborg University Hospital, Aalborg, Denmark.
¹⁴ Department of Clinical Physiology and Nuclear Medicine, Zealand University Hospital - Køge, Denmark.
¹⁵ Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
¹⁶ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁷ Department of Cardiothoracic Surgery, Aalborg University Hospital, Aalborg, Denmark.
¹⁸ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Zealand University Hospital - Køge, Denmark.
¹⁹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Denmark.
²⁰ Department of Oncology, University Hospital of Southern Denmark - Roskilde, Denmark; Medicin 2, Holbæk Hospital, Holbæk, Denmark.
²¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Section of Pulmonary Medicine, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.
²² Department of Oncology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
²³ Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.
²⁴ Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
²⁵ Department of Oncology, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark.
²⁶ Department of Oncology, Aalborg University Hospital, Aalborg Denmark; Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Aalborg, Denmark.
²⁷ Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
²⁸ Department of Respiratory Disease, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark; Department of Emergency Medicine, Regional Hospital Horsens, Horsens, Denmark.
²⁹ Department of Respiratory Disease, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
³⁰ Department of Respiratory Diseases, Aalborg University Hospital, Aalborg, Denmark.
³¹ Department of Respiratory Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
³² Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark; Odense Respiratory Research Unit (ODIN), Department of Clinical Medicine, University of Southern Denmark, Odense, Denmark.
³³ Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; Respiratory Research Unit PLUZ, Department of Respiratory Medicine, Zealand University Hospital - Næstved, Denmark.
³⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Zealand University Hospital - Roskilde, Denmark.
³⁵ Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³⁶ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Respiratory Medicine and Allergy, Aarhus University Hospital, Aarhus, Denmark.
³⁷ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Respiratory Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
³⁸ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
³⁹ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: boesoere@rm.dk.

PMID: 40220718
DOI: 10.1016/j.lungcan.2025.108528

Free article

Multicenter Study

ctDNA can detect minimal residual disease in curative treated non-small cell lung cancer patients using a tumor agnostic approach

Lærke Rosenlund et al. Lung Cancer. 2025 May.

Free article

. 2025 May:203:108528.

doi: 10.1016/j.lungcan.2025.108528. Epub 2025 Apr 4.

Authors

Affiliations

¹ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
² Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
³ Department of Genomic Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁴ Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁵ Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Department of Oncology, University Hospital of Southern Denmark - Roskilde, Denmark.
⁶ Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Radiology, Aarhus University Hospital, Aarhus, Denmark.
⁸ Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
⁹ Department of Nuclear Medicine, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.
¹⁰ Department of Nuclear Medicine & PET-Centre, Aarhus University Hospital, Aarhus, Denmark.
¹¹ Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
¹² Department of Nuclear Medicine, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark.
¹³ Department of Nuclear Medicine, Aalborg University Hospital, Aalborg, Denmark.
¹⁴ Department of Clinical Physiology and Nuclear Medicine, Zealand University Hospital - Køge, Denmark.
¹⁵ Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
¹⁶ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁷ Department of Cardiothoracic Surgery, Aalborg University Hospital, Aalborg, Denmark.
¹⁸ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Zealand University Hospital - Køge, Denmark.
¹⁹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Denmark.
²⁰ Department of Oncology, University Hospital of Southern Denmark - Roskilde, Denmark; Medicin 2, Holbæk Hospital, Holbæk, Denmark.
²¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Section of Pulmonary Medicine, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.
²² Department of Oncology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
²³ Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.
²⁴ Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
²⁵ Department of Oncology, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark.
²⁶ Department of Oncology, Aalborg University Hospital, Aalborg Denmark; Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Aalborg, Denmark.
²⁷ Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
²⁸ Department of Respiratory Disease, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark; Department of Emergency Medicine, Regional Hospital Horsens, Horsens, Denmark.
²⁹ Department of Respiratory Disease, University Hospital of Southern Denmark, Lillebaelt Hospital - Vejle, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
³⁰ Department of Respiratory Diseases, Aalborg University Hospital, Aalborg, Denmark.
³¹ Department of Respiratory Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
³² Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark; Odense Respiratory Research Unit (ODIN), Department of Clinical Medicine, University of Southern Denmark, Odense, Denmark.
³³ Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; Respiratory Research Unit PLUZ, Department of Respiratory Medicine, Zealand University Hospital - Næstved, Denmark.
³⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Zealand University Hospital - Roskilde, Denmark.
³⁵ Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³⁶ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Respiratory Medicine and Allergy, Aarhus University Hospital, Aarhus, Denmark.
³⁷ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Respiratory Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
³⁸ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
³⁹ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: boesoere@rm.dk.

PMID: 40220718
DOI: 10.1016/j.lungcan.2025.108528

Abstract

Background: Circulating tumor DNA (ctDNA) has the potential to become a reliable biomarker for identifying minimal residual disease (MRD) and predicting recurrence in patients with non-small cell lung cancer (NSCLC) following curative treatment. However, there is a lack of studies that investigate the clinical validity of ctDNA using a tumor-agnostic approach, which can provide significant clinical benefits.

Methods: We analyzed samples from 45 NSCLC patients recruited in a prospective national multicenter study, all of whom had undergone curative treatment. A total of 38 pre-treatment plasma samples and 76 post-treatment plasma samples were examined using a commercially available cancer personalized profiling by deep sequencing (CAPP-seq) strategy, and a tumor-agnostic approach. Post-treatment samples were collected at two distinct landmark time points: Follow-up 1 (0.5-4.5 months post-treatment) and Follow-up 2 (4.5-7.5 months post-treatment).

Results: Detectable ctDNA post-treatment was significantly associated with increased risk of tumor recurrence and shorter recurrence-free survival (RFS). Using only a single blood sample taken from Follow-up 2, we correctly identified MRD in 50% of the patients who later experienced recurrence. However, subgroup analysis further revealed that in patients treated with radiotherapy or chemoradiotherapy (CRT), ctDNA detection was significantly linked to shorter RFS in the MRD analysis from Follow-up 2, but not in the MRD analysis from Follow-up 1.

Conclusion: These findings suggest that post-treatment ctDNA, detected using a tumor-agnostic approach, is a reliable biomarker for predicting recurrence in NSCLC patients following curative treatment. However, the optimal timing for blood sampling to detect MRD appears to depend on the type of curative treatment received.

Keywords: Curative Therapy; Liquid Biopsy; MRD; NSCLC; Time Factors; Tumor-agnostic; ctDNA.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RHP: Speaker fee: Medtronic, AstraZeneca, Boehringer Ingelheim. Advisory board: AstraZeneca, BMS, Roche, MSD.

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Yang K, Noh JM, Kim YJ, Pyo H. Yang K, et al. Diagnostics (Basel). 2025 May 9;15(10):1198. doi: 10.3390/diagnostics15101198. Diagnostics (Basel). 2025. PMID: 40428191 Free PMC article.

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ctDNA can detect minimal residual disease in curative treated non-small cell lung cancer patients using a tumor agnostic approach

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ctDNA can detect minimal residual disease in curative treated non-small cell lung cancer patients using a tumor agnostic approach

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