Ignite Creation Date:
2025-12-25 @ 12:00 AM
Ignite Modification Date:
2025-12-25 @ 9:57 PM
Study NCT ID:
NCT07257458
Status:
RECRUITING
Last Update Posted:
2025-12-02
First Post:
2025-11-17
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Application of Methylation Markers in Early Detection and MRD Monitoring of Lung Cancer
Sponsor:
Beijing Haidian Hospital
Organization:
Study Overview
Official Title:
Application of Methylation Markers in Early Detection and MRD Monitoring of Lung Cancer
Status:
RECRUITING
Status Verified Date:
2025-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study aims to evaluate the utility of combined plasma SHOX2 and PTGER4 gene methylation analysis as a dynamic biomarker for monitoring minimal residual disease (MRD) and predicting recurrence in postoperative non-small cell lung cancer (NSCLC) patients. The primary objective is to determine whether serial methylation assessment can guide personalized adjuvant therapy decisions by identifying high-risk individuals, thereby potentially reducing overtreatment or undertreatment.
Stage I-IV NSCLC patients undergoing surgical resection were enrolled. Peripheral blood was collected longitudinally for circulating tumor DNA (ctDNA) methylation testing: preoperatively, postoperatively at 3 days, 1, 3, 6, 9, 12, 18, and 24 months, and upon radiographic recurrence. The dynamic changes in SHOX2/PTGER4 methylation levels and conventional tumor marker positivity rates were analyzed.
Comprehensive statistical analyses were performed: Correlation between methylation levels and radiographic findings was assessed using Pearson/Spearman tests; predictive accuracy for recurrence was evaluated via ROC curve analysis; patients were stratified into methylation-based risk groups; survival differences were compared using Kaplan-Meier curves with log-rank testing; independent predictive value was determined through multivariate Cox regression adjusting for clinicopathological confounders. Final efficacy assessment integrated ctDNA positivity timing, disease-free survival (DFS), and overall survival (OS) metrics.
This prospective biomarker study seeks to validate a novel epigenetic approach for postoperative management, potentially establishing ctDNA methylation monitoring as a standardized tool for MRD detection and recurrence risk stratification in resected NSCLC.
Stage I-IV NSCLC patients undergoing surgical resection were enrolled. Peripheral blood was collected longitudinally for circulating tumor DNA (ctDNA) methylation testing: preoperatively, postoperatively at 3 days, 1, 3, 6, 9, 12, 18, and 24 months, and upon radiographic recurrence. The dynamic changes in SHOX2/PTGER4 methylation levels and conventional tumor marker positivity rates were analyzed.
Comprehensive statistical analyses were performed: Correlation between methylation levels and radiographic findings was assessed using Pearson/Spearman tests; predictive accuracy for recurrence was evaluated via ROC curve analysis; patients were stratified into methylation-based risk groups; survival differences were compared using Kaplan-Meier curves with log-rank testing; independent predictive value was determined through multivariate Cox regression adjusting for clinicopathological confounders. Final efficacy assessment integrated ctDNA positivity timing, disease-free survival (DFS), and overall survival (OS) metrics.
This prospective biomarker study seeks to validate a novel epigenetic approach for postoperative management, potentially establishing ctDNA methylation monitoring as a standardized tool for MRD detection and recurrence risk stratification in resected NSCLC.
Detailed Description:
Lung cancer has the highest global incidence and mortality among all malignancies. As a high-incidence country, China reported approximately 1.0606 million new cases and 733,300 deaths in 2022, accounting for 22.0% and 28.5% of all malignant tumors, respectively. While early surgery is the primary curative approach, the risk of postoperative recurrence is substantial, with 5-year recurrence rates of 19% for stage IA, 30% for stage IB, and 48.6% for stage II NSCLC. The 3-year recurrence rate for stage III patients is as high as 52%. Crucially, even when imaging confirms a "tumor-free status" (R0 resection), hidden minimal residual disease (MRD) often leads to recurrence.
Current MRD detection primarily analyzes mutations in circulating tumor DNA (ctDNA). However, high inter-patient mutational heterogeneity poses challenges for designing compact, broadly effective detection panels. The Tumor-informed approach, which designs patient-specific panels, is limited by its dependency on tumor tissue samples. In contrast, DNA methylation biomarkers for MRD analysis do not require prior knowledge of tumor-specific mutations. Their sensitivity is independent of high-frequency mutation burden, changes occur early in tumorigenesis, and they exhibit tissue and cancer type specificity. Furthermore, DNA methylation shows consistency across numerous genomic regions, enabling detection via multiple CpG sites.
The "Expert Consensus on Tumor DNA Methylation Biomarker Testing and Clinical Application (April 2024)" states that variations in DNA methylation levels are closely associated with tumor prognosis and can be used for MRD assessment and recurrence monitoring. Mounting evidence supports this: A 2023 BMC Medicine study of 195 NSCLC patients found that individualized methylation-based MRD monitoring signaled recurrence earlier than mutation-based monitoring. A 2023 JAMA Oncology study demonstrated that detecting ctDNA methylation of five genes could predict colorectal cancer recurrence up to 20 months earlier than imaging, with significantly higher recurrence risk in patients positive for ctDNA one month post-surgery (HR=17.5). Another prospective study (NCT00958737) in 805 colorectal cancer patients confirmed a significantly higher 2-year disease-free survival rate in the ctDNA methylation-negative group (82% vs 64%).
This study aims to investigate the role of plasma SHOX2 and PTGER4 gene methylation levels in monitoring MRD and evaluating efficacy in NSCLC patients post-surgery. The study will enroll patients with histopathologically/clinically diagnosed stage I-IV NSCLC undergoing surgical resection. Peripheral blood will be collected at multiple timepoints: pre-treatment, and post-treatment at 3 days, 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, and upon recurrence for ctDNA methylation analysis.
Statistical analyses will include: Assessing the correlation between methylation levels and radiological metrics using Pearson or Spearman coefficients; Evaluating the predictive power for recurrence using Receiver Operating Characteristic (ROC) curves; Stratifying patients into high-risk and low-risk groups based on methylation results; Plotting recurrence-free survival curves using the Kaplan-Meier method and comparing groups with the Log-rank test; Assessing the independent predictive value of SHOX2 and PTGER4 methylation for recurrence risk using multivariate Cox regression analysis, adjusting for confounders like age, gender, and tumor stage; Finally, evaluating individualized therapeutic efficacy based on the timing of ctDNA positivity, Disease-Free Survival (DFS), and Overall Survival (OS). The goal is to provide a scientific basis for predicting recurrence risk and guiding treatment decisions.
Current MRD detection primarily analyzes mutations in circulating tumor DNA (ctDNA). However, high inter-patient mutational heterogeneity poses challenges for designing compact, broadly effective detection panels. The Tumor-informed approach, which designs patient-specific panels, is limited by its dependency on tumor tissue samples. In contrast, DNA methylation biomarkers for MRD analysis do not require prior knowledge of tumor-specific mutations. Their sensitivity is independent of high-frequency mutation burden, changes occur early in tumorigenesis, and they exhibit tissue and cancer type specificity. Furthermore, DNA methylation shows consistency across numerous genomic regions, enabling detection via multiple CpG sites.
The "Expert Consensus on Tumor DNA Methylation Biomarker Testing and Clinical Application (April 2024)" states that variations in DNA methylation levels are closely associated with tumor prognosis and can be used for MRD assessment and recurrence monitoring. Mounting evidence supports this: A 2023 BMC Medicine study of 195 NSCLC patients found that individualized methylation-based MRD monitoring signaled recurrence earlier than mutation-based monitoring. A 2023 JAMA Oncology study demonstrated that detecting ctDNA methylation of five genes could predict colorectal cancer recurrence up to 20 months earlier than imaging, with significantly higher recurrence risk in patients positive for ctDNA one month post-surgery (HR=17.5). Another prospective study (NCT00958737) in 805 colorectal cancer patients confirmed a significantly higher 2-year disease-free survival rate in the ctDNA methylation-negative group (82% vs 64%).
This study aims to investigate the role of plasma SHOX2 and PTGER4 gene methylation levels in monitoring MRD and evaluating efficacy in NSCLC patients post-surgery. The study will enroll patients with histopathologically/clinically diagnosed stage I-IV NSCLC undergoing surgical resection. Peripheral blood will be collected at multiple timepoints: pre-treatment, and post-treatment at 3 days, 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, and upon recurrence for ctDNA methylation analysis.
Statistical analyses will include: Assessing the correlation between methylation levels and radiological metrics using Pearson or Spearman coefficients; Evaluating the predictive power for recurrence using Receiver Operating Characteristic (ROC) curves; Stratifying patients into high-risk and low-risk groups based on methylation results; Plotting recurrence-free survival curves using the Kaplan-Meier method and comparing groups with the Log-rank test; Assessing the independent predictive value of SHOX2 and PTGER4 methylation for recurrence risk using multivariate Cox regression analysis, adjusting for confounders like age, gender, and tumor stage; Finally, evaluating individualized therapeutic efficacy based on the timing of ctDNA positivity, Disease-Free Survival (DFS), and Overall Survival (OS). The goal is to provide a scientific basis for predicting recurrence risk and guiding treatment decisions.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: