# Characterization of clinical risk factors for enhanced molecular residual disease monitoring in resected early-stage non-small cell lung cancer

## TL;DR

This study identifies clinical risk factors that help predict which early-stage lung cancer patients are at higher risk of cancer recurrence based on molecular residual disease monitoring.

## Contribution

A novel clinical risk factor (CRF) scoring system is developed to stratify patients by relapse risk using MRD and baseline clinical features.

## Key findings

- MRD-positive patients had significantly shorter disease-free survival compared to MRD-negative patients.
- A CRF score combining clinical staging, absence of driver mutations, and elevated CEA levels effectively stratified patients by relapse risk.
- The CRF score also predicted event-free survival, with CRF-low patients showing better outcomes.

## Abstract

Lung cancer is a leading cause of cancer mortality, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Standard treatment for early-stage NSCLC involves surgical resection, often complemented by adjuvant therapies. This study explores the dynamics of molecular residual disease (MRD) in early-stage NSCLC, emphasizing the prognostic value of baseline clinical characteristics.

We conducted a prospective study enrolling 78 patients with operable stage I-IIIA NSCLC. Serial blood samples were collected at various postoperative intervals to evaluate MRD via circulating tumor DNA (ctDNA) analysis. Clinical variables, such as tumor stage, driver mutations, carcinoembryonic antigen (CEA) levels, and histopathological characteristics, were assessed for their predictive capabilities for MRD positivity and disease relapse.

Among the 78 patients, 60.3% were diagnosed at stage IA, with a longitudinal MRD positivity rate of 20.5% (16/78). MRD-positive patients demonstrated shorter disease-free survival (DFS) compared to MRD-negative patients (hazard ratio = 171.4, P < 0.001). All nine patients with radiological relapse were MRD-positive, with a median lead time from MRD detection to relapse of 242.0 days. MRD + /DFS events were significantly associated with advanced clinical staging, absence of driver mutations, and elevated baseline CEA levels. A clinical risk factor (CRF) scoring system including the three factors effectively stratified patients by relapse risk, identifying those who could benefit from intensified postoperative treatment. The MRD + /DFS event rate was 36.3% for the CRF-high group compared to 0.0% for the CRF-low group (P < 0.001). The CRF score also stratified the patients by event-free survival, where CRF-low patients showed more favorable outcome compared to CRF-high patients (hazard ratio = 9.0, P < 0.001).

Our findings highlight the interplay between clinical risk factors and MRD dynamics in early-stage NSCLC, offering insights for risk stratification and personalized treatment approaches. The CRF score may help clinicians tailor adjuvant therapies, ultimately improving outcomes for high-risk patients.

The online version contains supplementary material available at 10.1186/s12885-025-15259-6.