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. 2025 Jun 19;44(1):178.
doi: 10.1186/s13046-025-03434-3.

Baseline levels and dynamic changes of cfDNA, tumor fraction and mutations to anticipate the clinical course of small cell lung cancer (SCLC) patients treated with first-line atezolizumab and chemotherapy: an hypothesis generating study (CATS/ML43257)

Giulia Pasello #  1   2 , Giulia Pigato #  3 , Daniela Scattolin  4   5 , Stefania Lando  4   6 , Sara Potente  7 , Chiara Romualdi  7 , Anna Roma  8 , Maria Vittoria Resi  9 , Stefano Frega  5 , Alessandra Ferro  5 , Alessandro Dal Maso  5 , Laura Bonanno  4   5 , Valentina Guarneri  4   5 , Elisabetta Lazzarini #  3 , Stefano Indraccolo #  4   3
Affiliations

Baseline levels and dynamic changes of cfDNA, tumor fraction and mutations to anticipate the clinical course of small cell lung cancer (SCLC) patients treated with first-line atezolizumab and chemotherapy: an hypothesis generating study (CATS/ML43257)

Giulia Pasello et al. J Exp Clin Cancer Res. .

Abstract

Background: Atezolizumab (A) plus carboplatin-etoposide (CE) represents the new first-line treatment in extensive stage (ES)-Small Cell Lung Cancer (SCLC) patients. This study aims at identifying the association of baseline and dynamic changes of cfDNA, Tumor Fraction (TF) and variant allele frequency (VAF) of tumor-related mutations with median (m) overall (OS) and progression free survival (PFS) in SCLC patients treated with ACE.

Materials and methods: This is a single-center prospective exploratory study including treatment-naive ES-SCLC patients eligible to first-line ACE. Liquid biopsies were longitudinally collected at baseline (T0), after cycle 1 (T1) and 2 (T2), at disease progression (T3). cfDNA Next Generation Sequencing (NGS) analysis was performed; genomic profiles and TF were inferred from shallow WGS (sWGS).

Results: Thirty-two patients were included; mPFS and mOS were 5.19 and 7.96 months, respectively. Higher T0 cfDNA (HR 1.44, 95% CI 1.17-1.77, p = 0.0006) and VAF (HR 2.6, 95% CI 1.36-4.93, p = 0.0039) were associated with risk of death; higher T0 cfDNA (HR 1.29, 95% CI 1.08-1.54, p = 0.0049), TF (HR 1.97, 95% CI 1.02-3.82, p = 0.044) and VAF (HR 2.32, 95% CI 1.22-4.42, p = 0.01) were predictors of risk of PD. Among the dynamic changes in the biomarkers under investigation, the association of 10-unit increase of VAF T0-T1 and T0-T2 with OS (HR 1.38, 95% CI 1.01-1.88, p = 0.043; HR 1.56, 95% CI 1.21-2.16, p = 0.008) and PFS (HR 1.69, 95% CI 1.18-2.43, p = 0.004; HR 1.81, 95% CI 1.22-2.70, p = 0.003) was estimated.

Conclusion: T0 and dynamic changes of cfDNA, TF and VAF may help physicians to stratify ES-SCLC patients receiving first-line ACE and to anticipate the clinical course of the disease.

Keywords: Atezolizumab; CfDNA; Chemoimmunotherapy; Liquid biopsy; SCLC.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study has been approved by Istituto Oncologico Veneto Ethical Committee (Cod. Int CESC IOV: 2021-85). All patients signed an informed consent form before enrollment. Consent for publication: All patient information has been anonymised and consent for publication of the current study was not required. All co-authors agreed for publication. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study design: T0: baseline; T1 after first cycle; T2: after second cycle; T3 at the time of disease progression
Fig. 2
Fig. 2
Swimmer plot showing association between baseline values of cfDNA, TF and VAF with PFS (A–C) and OS (D–F). The values reported on the Y axis between the patients’ ID and the plots are the T0 values of cfDNA (A, D), TF (B, E) and VAF (C, F)
Fig. 3
Fig. 3
Spaghetti plot showing dynamic changes of cfDNA (A), VAF (B) and TF (C) along different timepoints in each patient
Fig. 4
Fig. 4
Heatmap showing tumor-related mutations and specific VAF detected at T0
Fig. 5
Fig. 5
Random forest of covariates impact on OS (A) and PFS (B) and their relevance
See this image and copyright information in PMC

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