Circulating cell-free and extracellular vesicles-derived microRNA as prognostic biomarkers in patients with early-stage NSCLC: results from RESTING study

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2024年8月22日

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Elisabetta Petracci,
Luigi Pasini,
Milena Urbini,
Enriqueta Felip,
Franco Stella,
Fabio Davoli,
Maurizio Salvi,
Michele Beau-Faller,
Michela Tebaldi,
Irene Azzali,
Matteo Canale,
Piergiorgio Solli,
Giulia Lai,
Ramon Amat,
Caterina Carbonell,
Pierre-Emmanuel Falcoz,
Alex Martinez-Marti,
Erwan Pencreach,
Angelo Delmonte,
Lucio Crinò,
Paola Ulivi

摘要

Background

Factors to accurately stratify patients with early-stage non-small cell lung cancer (NSCLC) in different prognostic groups are still needed. This study aims to investigate 1) the prognostic potential of circulating cell-free (CF) and extracellular vesicles (EVs)-derived microRNA (miRNAs), and 2) their added value with respect to known prognostic factors (PFs).

Methods

The RESTING study is a multicentre prospective observational cohort study on resected stage IA-IIIA patients with NSCLC. The primary end-point was disease-free survival (DFS), and the main analyses were carried out separately for CF- and EV-miRNAs. CF- and EV-miRNAs were isolated from plasma, and miRNA-specific libraries were prepared and sequenced. To reach the study aims, three statistical models were specified: one using the miRNA data only (Model 1); one using both miRNAs and known PFs (age, gender, and pathological stage) (Model 2), and one using the PFs alone (Model 3). Five-fold cross-validation (CV) was used to assess the predictive performance of each. Standard Cox regression and elastic net regularized Cox regression were used.

Results

A total of 222 patients were enrolled. The median follow-up time was 26.3 (95% CI 25.4–27.6) months. From Model 1, three CF-miRNAs and 21 EV-miRNAs were associated with DFS. In Model 2, two CF-miRNAs (miR-29c-3p and miR-877-3p) and five EV-miRNAs (miR-181a-2-3p, miR-182-5p, miR-192-5p, miR-532-3p and miR-589-5p) remained associated with DFS. From pathway enrichment analysis, TGF-beta and NOTCH were the most involved pathways.

Conclusion

This study identified promising prognostic CF- and EV-miRNAs that could be used as a non-invasive, cost-effective tool to aid clinical decision-making. However, further evaluation of the obtained miRNAs in an external cohort of patients is warranted.