Patient-Specific MRD Liquid Biopsy in Resected NSCLC: Plasma and Bronchial Washing ctDNA (LUNG-MRDetect)
Development of a Patient-Specific MRD Liquid Biopsy Platform in Resected NSCLC: Combined Analysis of Plasma and Bronchial Washing ctDNA
This is a multicenter, prospective, observational pilot cohort study in patients with surgically resected non-small cell lung cancer (NSCLC, pathologic stage IA3-IIIA). Whole exome sequencing (WES) of each patient's resected tumor tissue and matched normal blood (buffy coat) is used to build a patient-specific (tumor-informed) minimal residual disease (MRD) panel, after excluding germline and clonal hematopoiesis variants. MRD is then assessed in paired plasma circulating tumor DNA (ctDNA) and bronchial washing fluid (BWF) ctDNA collected at 6, 12, 18 and 24 months after surgery. The study evaluates whether MRD positivity in plasma and/or BWF is associated with subsequent clinical or radiologic recurrence, compares MRD detection rates and quantitative values between plasma and BWF, and explores the lead time of MRD detection relative to standard surveillance with chest CT and serum CEA. MRD results are not used to confirm recurrence or to change treatment; all clinical decisions follow standard of care. Forty participants will be enrolled at three Severance hospitals in Korea.
Visão geral do estudo
Status
Descrição detalhada
Background. Postoperative recurrence is frequent in resected early-stage and locally advanced NSCLC (stage I-IIIA), most often within 2-3 years after surgery. Standard surveillance relies on chest CT and serum tumor markers such as CEA, which cannot detect molecular recurrence at the MRD stage before it appears on imaging. ctDNA-based MRD assessment is being actively investigated in several solid tumors. In early-stage lung cancer, however, plasma ctDNA levels after surgery are very low, which may limit detection sensitivity. Bronchial washing fluid reflects the local tumor environment of the lung, and prior studies suggest it may detect tumor-derived mutations with higher sensitivity than plasma. This study builds a patient-specific, tumor-informed MRD panel for each participant, instead of relying on a fixed generic gene panel, and evaluates plasma and BWF MRD in parallel.
Hypotheses. (1) A patient-specific MRD panel built from resected tumor tissue and normal control specimens can detect postoperative recurrence earlier than conventional imaging-based diagnosis. (2) BWF ctDNA, which reflects the local tumor environment, may show higher MRD detection sensitivity than plasma ctDNA.
Objectives. The primary objective is to evaluate whether MRD positivity in plasma and BWF is associated with subsequent clinical or radiologic recurrence in resected NSCLC. The secondary objectives are (a) to compare MRD detection rates and quantitative values between plasma and BWF and determine which specimen is more sensitive for detecting recurrence, and (b) to explore the lead time of MRD detection relative to recurrence confirmation and compare it with CT and CEA.
Design and procedures. At baseline (first outpatient visit within 1 month after surgery), unstained (10) and stained (1) slides of the surgical pathology specimen are obtained, together with blood for normal control and cfDNA. WES is performed on tumor tissue and buffy coat, and a patient-specific mutation panel is designed. At 6, 12, 18 and 24 months after surgery, 20 mL of blood and 20 mL of BWF (collected by bronchoscopy from the lobe or segment of the original lesion, using saline) are obtained for MRD analysis. Additional blood/BWF MRD assessments may be performed at unscheduled visits when recurrence is clinically suspected. MRD follow-up ends at 24 months, recurrence or death. After 24 months, participants are followed under standard practice (CT and CEA every 3 months) without additional MRD testing. All specimens are shipped under anonymized serial codes to an external laboratory (IMBDx) for analysis and are handled according to the participant's consent regarding retention and secondary use.
Statistical analysis. The main analysis set includes enrolled participants whose patient-specific panel was successfully built and who have at least one evaluable postoperative MRD result. Recurrence-free survival (RFS) of MRD-positive and MRD-negative groups is estimated by the Kaplan-Meier method and compared with the log-rank test. Hazard ratios with 95% confidence intervals are estimated by Cox regression as exploratory analyses. Paired plasma-BWF detection rates are compared with McNemar's test, and paired quantitative values (variant allele frequency) with the paired t-test or Wilcoxon signed-rank test. Sensitivity, specificity, PPV, NPV, ROC curve and AUC are computed exploratorily. Lead time is summarized descriptively. Missing data are not imputed. Because this is a pilot study of 40 participants, results are interpreted by effect sizes and confidence intervals rather than formal significance testing.
Safety and monitoring. MRD results are not used alone to confirm recurrence or change adjuvant therapy. Adverse events related to blood sampling and bronchoscopy are recorded. An independent safety monitor, who is not a member of the study team, will perform two monitoring visits. Serious adverse events are reported according to each institution's IRB requirements. Data from all sites are de-identified, coded, and managed centrally.
Tipo de estudo
Inscrição (Estimado)
Contactos e Locais
Contato de estudo
- Nome: LEE Eunhye, Ph.D.Course of Medical Science
- Número de telefone: +82-10-4099-3780
- E-mail: hieunhye@yuhs.ac
Estude backup de contato
- Nome: SHIN Seonhye, Bachelor Degree, Nursing
- Número de telefone: +82-10-7767-3489
- E-mail: fresh@yuhs.ac
Locais de estudo
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Seoul, Coréia do Sul, 03722
- Ainda não está recrutando
- Severance Hospital
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Contato:
- SHIN Seonhye, Bachelor Degree, Nursing
- Número de telefone: +82-10-7767-3489
- E-mail: fresh@yuhs.ac
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Contato:
- YONG Seunghyun, Ph.D.Course of Medical Science
- Número de telefone: +82-10-6366-0213
- E-mail: roneirire@yuhs.ac
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Seoul, Coréia do Sul, 06229
- Ainda não está recrutando
- Gangnam Severance Hospital
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Contato:
- SHIN Seonhye, Bachelor Degree, Nursing
- Número de telefone: +82-10-7767-3489
- E-mail: fresh@yuhs.ac
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Contato:
- KIM Chiyoung, Ph.D.Course of Medical Science
- Número de telefone: +82-10-4182-1095
- E-mail: cykim@yuhs.ac
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Gyeonggi-do
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Yongin-si, Gyeonggi-do, Coréia do Sul, 16995
- Recrutamento
- Yongin Severance Hospital
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Contato:
- LEE Eunhye, Ph.D.Course of Medical Science
- Número de telefone: +82-10-4099-3780
- E-mail: hieunhye@yuhs.ac
-
Contato:
- SHIN Seonhye, Bachelor Degree, Nursing
- Número de telefone: +82-10-7767-3489
- E-mail: fresh@yuhs.ac
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Método de amostragem
População do estudo
Adult patients (aged 19 years or older) who underwent curative-intent (R0) surgical resection for pathologically confirmed non-small cell lung cancer (NSCLC) with a final pathologic stage of IA3 to IIIA, and who are followed at three tertiary referral hospitals in Korea (Severance Hospital, Gangnam Severance Hospital, and Yongin Severance Hospital). Eligible patients are identified through outpatient and inpatient medical record review and enrolled within 1 month after surgery. A total of 40 participants will be enrolled competitively across the three sites over 2 years.
Descrição
Inclusion Criteria:
- Adults aged 19 years or older
- Pathologically confirmed non-small cell lung cancer who underwent curative-intent complete (R0) surgical resection
- Final pathologic stage IA3 (tumor size >2 cm) to IIIA after surgery
- Able to attend the first outpatient visit within 1 month after surgery, and agrees to research blood sampling, provision of surgical tissue slides, and long-term follow-up
- Provided voluntary written informed consent after adequate explanation of the study purpose and methods
Exclusion Criteria:
- Pathologic stage IA1 or IA2 (tumor size ≤2 cm), stage IV, or confirmed distant metastasis
- Incomplete resection (non-R0) or clear residual tumor after surgery
- History of other malignancy, including synchronous malignancy in another organ, that may confound interpretation of MRD results (cancers judged cured for more than 5 years may be included)
- Poor performance status or other conditions making repeated blood sampling or bronchoscopy difficult
- Unstable cardiopulmonary function, or high risk with sedation or additional procedures, in the judgment of the treating physician
- Unable to provide informed consent, or judged unable to comply with regular follow-up during the study period
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Modelos de observação: COHORT
- Perspectivas de Tempo: PROSPECTIVE
Coortes e Intervenções
Grupo / Coorte |
Intervenção / Tratamento |
|---|---|
|
Resected NSCLC (stage IA3-IIIA)
Adults who underwent curative-intent (R0) resection for pathologic stage IA3-IIIA NSCLC. Participants undergo patient-specific MRD panel construction and serial plasma and BWF MRD testing at 6, 12, 18 and 24 months after surgery. |
Teste de diagnostico: Patient-specific tumor-informed MRD assay (plasma and bronchial washing ctDNA)
WES of surgical tumor tissue and matched normal blood to design a patient-specific mutation panel, followed by MRD detection in plasma ctDNA and BWF ctDNA at 6, 12, 18 and 24 months after surgery and at unscheduled visits if recurrence is suspected. Results are not used for treatment decisions. Bronchoscopy performed by the treating pulmonologist, with 20 mL saline bronchial washing from the lobe or segment of the original tumor, at 6, 12, 18 and 24 months after surgery. |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Recurrence-free survival (RFS) according to MRD status in plasma and/or BWF ctDNA
Prazo: Up to 24 months after surgery
|
RFS of MRD-positive versus MRD-negative participants, defined as the time from surgery to first clinical or radiologic recurrence (or death, if applicable). Estimated by the Kaplan-Meier method and compared with the log-rank test. Hazard ratio with 95% confidence interval estimated exploratorily by Cox regression. |
Up to 24 months after surgery
|
Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
MRD detection rate in plasma ctDNA versus BWF ctDNA
Prazo: 6, 12, 18 and 24 months after surgery
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Proportion of MRD-positive results in paired plasma and BWF samples collected at the same time point, compared with McNemar's test. |
6, 12, 18 and 24 months after surgery
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|
Quantitative MRD value (variant allele frequency) in plasma versus BWF
Prazo: 6, 12, 18 and 24 months after surgery
|
ariant allele frequency of patient-specific variants in paired plasma and BWF samples, compared with the paired t-test or Wilcoxon signed-rank test. |
6, 12, 18 and 24 months after surgery
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Diagnostic performance of MRD for recurrence
Prazo: Up to 24 months after surgery
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Sensitivity, specificity, positive predictive value, negative predictive value, and area under the ROC curve (AUC) of plasma and BWF MRD for detecting recurrence, evaluated exploratorily and compared descriptively with CT and CEA. |
Up to 24 months after surgery
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Lead time of MRD positivity before recurrence confirmation
Prazo: Up to 24 months after surgery
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Interval (months) from first MRD positivity to recurrence confirmed by CT or clinical diagnosis, summarized as mean ± SD or median (IQR), range, and 95% confidence interval, and compared with CT and CEA. |
Up to 24 months after surgery
|
Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: LEE Eunhye, Ph.D.Course of Medical Science, Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine
Publicações e links úteis
Publicações Gerais
- Ohara S, Suda K, Sudhaman S, Hamada A, Chiba M, Shimoji M, Takemoto T, Kalashnikova E, Cheung SK, Krainock M, Feeney J, Sethi H, Liu MC, Soh J, Tsutani Y, Mitsudomi T. Clinical Significance of Perioperative Minimal Residual Disease Detected by Circulating Tumor DNA in Patients With Lung Cancer With a Long Follow-up Data: An Exploratory Study. JTO Clin Res Rep. 2024 Nov 12;6(3):100762. doi: 10.1016/j.jtocrr.2024.100762. eCollection 2025 Mar.
- Kim MH, Kim SH, Seong H, Eom JS. Enhanced Detection of Druggable Mutations in Non-Small Cell Lung Cancer Using Targeted Collection of Bronchial Washing Fluid Compared With Plasma and Tumor Tissue. JCO Precis Oncol. 2025 Aug;9:e2500299. doi: 10.1200/PO-25-00299. Epub 2025 Aug 1.
- Lee SH, Kim EY, Kim T, Chang YS. Compared to plasma, bronchial washing fluid shows higher diagnostic yields for detecting EGFR-TKI sensitizing mutations by ddPCR in lung cancer. Respir Res. 2020 Jun 9;21(1):142. doi: 10.1186/s12931-020-01408-x.
- Wang Y, Shao W, Li H, Zhao P, Tian L, Zhang L, Lan S, Zhong R, Zhang S, Cheng Y. Clinical application of minimal residual disease detection by ctDNA testing in non-small cell lung cancer: a narrative review. Transl Lung Cancer Res. 2025 Mar 31;14(3):1007-1020. doi: 10.21037/tlcr-24-942. Epub 2025 Mar 27.
- Lu D, Lin N, Li S, Jing Q, Yin JC, Shi L, Zhang Z, Chen Z, Wang Z, Tong Y, Zhai J, Feng S, Cai K. Predictive Effectiveness of Circulating Tumor DNA in Recurrent Early-Stage Non-Small Cell Lung Cancer: An Updated Meta-Analysis. JCO Precis Oncol. 2025 Oct;9:e2500489. doi: 10.1200/PO-25-00489. Epub 2025 Oct 9.
- Kim KY, Kim HC, Kim TJ, Kim HK, Moon MH, Beck KS, Suh YG, Song CH, Ahn JS, Lee JE, Jeon JH, Jung CY, Cho JS, Choi YD, Hwang SS, Choi CM, Jang SH, Lim JU; Korean Association for Lung Cancer, Korea Central Cancer Registry. Factors Associated with Postoperative Recurrence in Stage I to IIIA Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation: Analysis of Korean National Population Data. Cancer Res Treat. 2025 Jan;57(1):83-94. doi: 10.4143/crt.2024.073. Epub 2024 Jul 10.
- Ahn JH, Choi SH, Park SH, Kim I, Park JH, Kim JY, Kim TH, Lee T, Cho HK, Jeong JH, Yang JW, Park JE, Kim TH, Lee HK, Lee HY, Jung HJ, Kim J, Son J, Eom JS. Longitudinal Analysis of Recurrence and Risk Factors of Early-Stage Resected Adenocarcinoma With Common EGFR Mutations: A Multicenter Retrospective Cohort Study in South Korea. Clin Lung Cancer. 2025 Jun;26(4):314-323.e6. doi: 10.1016/j.cllc.2025.02.016. Epub 2025 Mar 7.
- Rajaram R, Huang Q, Li RZ, Chandran U, Zhang Y, Amos TB, Wright GWJ, Ferko NC, Kalsekar I. Recurrence-Free Survival in Patients With Surgically Resected Non-Small Cell Lung Cancer: A Systematic Literature Review and Meta-Analysis. Chest. 2024 May;165(5):1260-1270. doi: 10.1016/j.chest.2023.11.042. Epub 2023 Dec 6.
Datas de registro do estudo
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Conclusão do estudo (Estimado)
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Enviado pela primeira vez que atendeu aos critérios de CQ
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Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Processos Patológicos
- Neoplasias por local
- Neoplasias
- Doenças Respiratórias
- Doenças pulmonares
- Neoplasias do Trato Respiratório
- Neoplasias Torácicas
- Processos Neoplásicos
- Neoplasias Pulmonares
- Carcinoma Broncogênico
- Neoplasias Brônquicas
- Condições Patológicas, Sinais e Sintomas
- Neoplasia Residual
- Carcinoma pulmonar de células não pequenas
- Técnicas de investigação
- Técnicas e procedimentos de diagnóstico
- Diagnóstico
- Procedimentos cirúrgicos, operatórios
- Procedimentos cirúrgicos minimamente invasivos
- Técnicas de diagnóstico, cirúrgico
- Endoscopia
- Técnicas de diagnóstico, sistema respiratório
- Procedimentos cirúrgicos torácicos
- Irrigação terapêutica
- Procedimentos cirúrgicos pulmonares
- Lavagem Broncoalveolar
- Broncoscopia
- Líquido de Lavagem Broncoalveolar
Outros números de identificação do estudo
- 9-2026-0153
Plano para dados de participantes individuais (IPD)
Planeja compartilhar dados de participantes individuais (IPD)?
Descrição do plano IPD
Data will be de-identified and managed centrally; individual participant data are not planned to be shared at this time.
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