Prognostic performance of a novel multiplex circulating tumor DNA assay for lung cancer outcomes

Abstract

Background: Lung cancer is a heterogeneous disease with unpredictable trajectories. Risk stratification in lung cancer remains imprecise within tumor-node-metastasis (TNM) stages. Objectives: This work aims to evaluate whether methylated circulating tumor DNA (ctDNA) can improve prognostication at the time of diagnosis. Methods: We enrolled 213 participants with recently diagnosed lung cancer, of whom 100 underwent curative treatment and 113 underwent palliative treatment. All blood samples were collected prior to lung cancer diagnosis and analyzed using multiplex methylation-specific digital droplet polymerase chain reaction targeting five methylated ctDNA markers. ctDNA output was interpreted in two models: a three-tiered (negative/Low-level/High-level ctDNA) and a binary (negative/positive). Results: We observed significantly increased overall survival (OS) among all participants with negative or low-level ctDNA results compared with those with high-level ctDNA. The adjusted hazard ratio (HR) for OS was higher when comparing high-level ctDNA to negative results (HR = 1.96, 95% confidence interval (CI): 1.09–3.51; p = 0.024). In the palliative treatment subgroup, HR for progression-free survival was higher comparing high-level ctDNA to negative results (adjusted HR = 2.32, 95% CI: 1.10–4.92; p = 0.028). In the curative treatment subgroup, the association between ctDNA levels and recurrence-free survival was not statistically significant (adjusted HR = 1.81, 95% CI: 0.73–4.48; p = 0.200). Conclusion: Detection of, and risk stratification based on, levels of methylated ctDNA at diagnosis appears to provide valuable prognostic information in lung cancer, both in early and late stages of the disease. Such information may have implications for the choice of follow-up regimens and treatment strategies. Design: Retrospective observational cohort study using prospectively collected blood samples.