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. 2025 Feb:52:102228.
doi: 10.1016/j.tranon.2024.102228. Epub 2024 Dec 21.

Clinical characteristics of EGFR-ctDNA shedders in EGFR-mutant NSCLC patients

Martina Ruglioni  1 , Iacopo Petrini  2 , Stefania Crucitta  1 , Andrea Sbrana  2 , Giovanna Irene Luculli  1 , Leila Sadeghi Gol  1 , Carola Forte  1 , Antonio Chella  2 , Christian Rolfo  3 , Romano Danesi  4 , Marzia Del Re  5
Affiliations

Clinical characteristics of EGFR-ctDNA shedders in EGFR-mutant NSCLC patients

Martina Ruglioni et al. Transl Oncol. 2025 Feb.

Abstract

Background: Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.

Methods: Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.

Results: A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA ("shedders"). Higher ECOG PS (p = 0.04), bilateral localization of primary tumor (p = 0.04), and the presence of intrathoracic/extrathoracic disease (p = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (p = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (p = 0.05).

Conclusion: Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.

Keywords: Circulating-tumor DNA; NSCLC; Predictive biomarkers; Tumor shedding; mEGFR.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Romano Danesi reports that financial support was provided by the Ministry of University and Research, Rome, Italy. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Associations between shedding status and clinical characteristics of patients.
Fig. 2
Fig. 2
Application of logistic regression estimating the predictive capability of clinical characteristics for shedding status in EGFR-mutated lung cancer patients at baseline (A), demonstration of specificity and sensitivity of shedding status combined with statistically significant clinical characteristics identified from the regression model (B) and median PFS of patients based on the clearance status. Univariate Cox regression analysis of the impact of shedding status and patients’ clinical characteristics on the PFS (C).
Fig. 3
Fig. 3
Median PFS of shedders compared to non-shedders (A), and shedders with AF% ≥0.38 (median cut-off), compared to shedders with AF% <0.38 (B).
Fig. 4
Fig. 4
Clinically and functionally relevant mechanisms of resistance identified at the progression of the disease (A), and the overall mutations (%) detectable in ctDNA at the clinical progression of the disease (B).
See this image and copyright information in PMC

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