LAMPAD: An Integrated Circulating Tumor DNA-Based Model for Predicting Potential Cure in Patients With Resected NSCLC

Area of Science:

• Oncology
• Molecular Diagnostics
• Bioinformatics

Background:

• Postoperative molecular residual disease (MRD) assessment in non-small cell lung cancer (NSCLC) often uses circulating tumor DNA (ctDNA).
• Single-timepoint ctDNA analysis has a high false-negative rate (~70%), limiting its utility for guiding adjuvant therapy decisions within the narrow postoperative window.
• Accurate identification of MRD-negative patients is crucial for determining eligibility for curative treatment.

Purpose of the Study:

• To develop and validate a novel model (LAMPAD) for improved prognostic stratification of NSCLC patients after surgery.
• To refine the identification of truly disease-free patients among those with undetectable MRD at the standard postoperative timepoint.
• To enhance the utility of ctDNA analysis for guiding adjuvant therapy and patient management in NSCLC.

Main Methods:

• Introduction of LAMPAD, an XGBoost-Cox model integrating preoperative and postoperative ctDNA quantification.
• Utilizing Shapley Additive Explanations (SHAP) to identify key features: baseline ctDNA, TNM stage, landmark cfDNA, baseline cfDNA, and baseline ctDNA status.
• Training and validation on 163 stage I-III NSCLC patients with landmark undetectable MRD, across fixed-panel and personalized ctDNA-MRD approaches.

Main Results:

• The LAMPAD model significantly stratified patients into low-risk (2-year DFS: 97.8%) and high-risk (2-year DFS: 71.6%) groups (HR=0.11, p<0.001).
• Consistent performance observed in validation cohorts (pooled 2-year DFS: 94.3% vs 72.4%; HR=0.18, p<0.001).
• Preoperative ctDNA analysis and methylation analysis of cfDNA (immune- and lung-derived) provided significant prognostic value, suggesting immune system involvement.

Conclusions:

• The LAMPAD model surpasses single-timepoint postoperative ctDNA detection in accuracy.
• It reliably identifies truly MRD-negative NSCLC patients, distinguishing them from those with residual disease.
• LAMPAD offers a more dependable prognostic tool for identifying low-risk NSCLC patients with a higher likelihood of cure.