Predicting Non-small Cell Lung Cancer (NSCLC) Lymph Node Metastasis: Integrating Circulating Tumor DNA (ctDNA) Mutation/ Methylation Profiling With Positron Emission Tomography-computed Tomography (PET-CT) Scan

NCT06358222 | Recruiting

• 1 other identifier: LUNon-invasive
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single center, prospective and observational study conducted in three stages to predict the NSCLC lymph node metastasis based on ctDNA/specific methylation molecular features combined with PET-CT imaging features and intervention study.

Conditions

Carcinoma; Non-small Cell Lung Cancer

Keywords

Non-small Cell Lung Cancer; ctDNA; PET-CT; methylation; lymph node metastasis

Outcome Measures

Primary Outcomes (3)

• Negative prediction value (NPV) of lymph node metastasis rates

  The primary endpoint will be the negative prediction value (NPV) of LNM rates between groups using preoperative blood ctDNA/methylation alone or in combination with PET-CT. LNMs-specific ctDNA methylation signatures will be developed and the sensitivity and specificity of ctDNA mutation/methylation profiles alone or when combined with PET-CT scans for predicting LNMs will be assessed. Postoperative pathological results will serve as the reference standard for comparison.

  one day for each patient

• Disease-free survival (DFS)

  DFS is defined as the time from surgical resection to tumor recurrence or death due to tumor progression. DFS will be compared between the ctDNA-positive group and the ctDNA-negative group. DFS will be assessed in stage 3.

  Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.

• ctDNA-free interval (CFI)

  CFI is defined as the duration between a patient's transition from ctDNA negative to ctDNA positive status.

  Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.

Secondary Outcomes (1)

• Overall Survival (OS)

  Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years

Study Arms (3)

Blood ctDNA + methylation + PET-CT vs Postoperative pathology

Procedure: Blood ctDNA + methylation + PET-CT and Postoperative pathology

MRD+ methylation (or combined with PET-CT) vs Invasive mediastinoscopy /EBUS-TBNA

Procedure: MRD+ methylation (or combined with PET-CT) and Invasive mediastinoscopy /EBUS-TBNA

Lymph Node dissection vs no lymph node dissection

Procedure: Intraoperative lymph node dissection

Interventions

Blood ctDNA + methylation + PET-CT and Postoperative pathology PROCEDURE

A highly sensitive tumor-naïve MRD panel of ctDNA will be employed to detect preoperative blood. Some patients will undergo methylation profiling to prospectively establish LNMs-specific ctDNA methylation signatures.

Blood ctDNA + methylation + PET-CT vs Postoperative pathology

MRD+ methylation (or combined with PET-CT) and Invasive mediastinoscopy /EBUS-TBNA PROCEDURE

A certain number (depending on the Results of Stage 1) of patients requiring invasive mediastinoscopy or EBUS-TBNA, based on the clinical guidelines, will be included for blood ctDNA mutation/methylation profile (or combined PET-CT), and the detection rate of LNMs will be assessed in patients with negative preoperative blood ctDNA mutation/methylation (or combined PET-CT). The accuracy of predicting LNMs will be compared with that of patients with negative or positive preoperative blood ctDNA mutation/methylation (or combined PET-CT).

MRD+ methylation (or combined with PET-CT) vs Invasive mediastinoscopy /EBUS-TBNA

Intraoperative lymph node dissection PROCEDURE

For patients with negative preoperative blood negative testing (ctDNA mutation/methylation profiles alone or in combination with PET-CT), systematic lymph node sampling/dissection and no lymph node dissection will be grouped and compared. Regular follow-up is performed to investigate the impact on long-term MRD negative duration and prognosis.

Lymph Node dissection vs no lymph node dissection

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This program will be conducted in three stages. Stage 1: We will enroll 200 patients diagnosed with stage I-IIIB NSCLC who are scheduled for lobectomy and systematic lymph node dissection. Stage 2: A certain number (depending on the Results of Stage 1) of patients requiring invasive mediastinoscopy or EBUS-TBNA, based on the clinical guidelines, will be included for blood ctDNA mutation/methylation profile (or combined PET-CT), and the detection rate of LNMs will be assessed in patients with negative preoperative blood ctDNA mutation/methylation (or combined PET-CT). Stage 3: For patients with negative preoperative blood negative testing (ctDNA mutation/methylation profiles alone or in combination with PET-CT), systematic lymph node sampling/dissection and no lymph node dissection will be grouped and compared.

You may qualify if:

• Provision of informed consent prior to study initiation.
• Age between 18 and 75 years.
• Preoperative clinical evaluation indicating non-small cell lung cancer (NSCLC) stage I-IIIB (without initial treatment sought).
• Newly treated patients who have consented to undergo surgery.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.

You may not qualify if:

• Non-small cell lung cancer (NSCLC) histopathologically determined to be other than stage I-IIIB following surgical evaluation.
• Presence of other active malignant tumor diseases.
• History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid therapy, or any indication of clinically active ILD.
• Patients considered by the investigator to be unable to comply with the study protocol, restrictions, and requirements, or those facing circumstances at the investigator's discretion that would impede their participation in the study.

Sponsors & Collaborators

• Shanghai Chest Hospital: lead

Study Sites (1)

Shanghai Chest Hospital

Shanghai, China

RECRUITING

Related Publications (6)

• Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Gronroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts HJWL, Hackshaw A, Shaw JA, Zimmermann BG; TRACERx consortium; PEACE consortium; Swanton C. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017 Apr 26;545(7655):446-451. doi: 10.1038/nature22364.

  PMID: 28445469 BACKGROUND

• Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, Khodadoust MS, Esfahani MS, Liu CL, Zhou L, Scherer F, Kurtz DM, Say C, Carter JN, Merriott DJ, Dudley JC, Binkley MS, Modlin L, Padda SK, Gensheimer MF, West RB, Shrager JB, Neal JW, Wakelee HA, Loo BW Jr, Alizadeh AA, Diehn M. Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling. Cancer Discov. 2017 Dec;7(12):1394-1403. doi: 10.1158/2159-8290.CD-17-0716. Epub 2017 Sep 24.

  PMID: 28899864 BACKGROUND

• Chen K, Zhao H, Shi Y, Yang F, Wang LT, Kang G, Nie Y, Wang J. Perioperative Dynamic Changes in Circulating Tumor DNA in Patients with Lung Cancer (DYNAMIC). Clin Cancer Res. 2019 Dec 1;25(23):7058-7067. doi: 10.1158/1078-0432.CCR-19-1213. Epub 2019 Aug 22.

  PMID: 31439586 BACKGROUND

• Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I; WHO Panel. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015 Sep;10(9):1243-1260. doi: 10.1097/JTO.0000000000000630.

  PMID: 26291008 BACKGROUND

• Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC - challenges to implementing ctDNA-based screening and MRD detection. Nat Rev Clin Oncol. 2018 Sep;15(9):577-586. doi: 10.1038/s41571-018-0058-3.

  PMID: 29968853 BACKGROUND

• Yang H, Gu X, Wang Z, Liu G, Niu Y, Pan X, Yao F. Predicting non-small cell lung cancer lymph node metastasis: integrating ctDNA mutation/methylation profiling with positron emission tomography-computed tomography (PET-CT) scan: protocol for a prospective clinical trial (LUNon-invasive Study). J Thorac Dis. 2024 Sep 30;16(9):6272-6285. doi: 10.21037/jtd-24-1033. Epub 2024 Sep 26.

  PMID: 39444874 DERIVED

MeSH Terms

Conditions

Carcinoma; Carcinoma, Non-Small-Cell Lung; Lymphatic Metastasis

Interventions

Methylation

Condition Hierarchy (Ancestors)

Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Neoplasm Metastasis; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Alkylation; Biochemical Phenomena; Chemical Phenomena; Organic Chemistry Phenomena; Metabolism

Central Study Contacts

Feng Yao, PhD

CONTACT

021-2220000; yaofeng@shsmu.edu.cn

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 28, 2024
• First Posted: April 10, 2024
• Study Start: December 15, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: May 18, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)