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. 2025 Feb 20:16:11-23.
doi: 10.2147/LCTT.S492825. eCollection 2025.

Genomic Profiling of Extensive Stage Small-Cell Lung Cancer Patients Identifies Molecular Factors Associated with Survival

Matteo Canale  1 , Milena Urbini  1 , Elisabetta Petracci  2 , Davide Angeli  2 , Gianluca Tedaldi  1 , Ilaria Priano  3 , Paola Cravero  4 , Michele Flospergher  4 , Kalliopi Andrikou  4 , Chiara Bennati  5 , Davide Tassinari  6 , Alessandra Dubini  7 , Giulio Rossi  8 , Riccardo Panzacchi  9 , Mirca Valli  10 , Giuseppe Bronte  11   12 , Lucio Crinò  4 , Angelo Delmonte  4 , Paola Ulivi  1
Affiliations

Genomic Profiling of Extensive Stage Small-Cell Lung Cancer Patients Identifies Molecular Factors Associated with Survival

Matteo Canale et al. Lung Cancer (Auckl). .

Abstract

Objective: Extensive stage Small-Cell Lung Cancer (ES-SCLC) is the most lethal lung cancer, and the addition of immunotherapy conferred a slight survival benefit for patients. Extensive molecular profiling of patients treated with chemotherapy (CT) or chemotherapy plus immunotherapy (CT+IO) would be able to identify molecular factors associated with patients' survival.

Material and methods: In this retrospective study, 99 ES-SCLC patients were considered. Of the 79 includible patients, 42 received CT (median age 71 y/o, I-IIIQ: 65-76), and 37 received CT+IO (median age 71 y/o, I-IIIQ 66-75). The FoundationOne CDx assay was performed on patients' tumor tissues.

Results: The most mutated genes were TP53 (99%), RB1 (78%), PTEN (23%) and MLL2 (20%), with no significant differences between the treatment groups. As a continuous variable, Tumor Mutation Burden (TMB) had an effect on patients' progression-free survival (PFS) by type of treatment (HR 1.81 (95%, CI: 0.99-3.31) and HR 0.84 (95%, CI: 0.56-1.26) for patients treated with CT and CT+IO, respectively). TMB was also computed and dichotomized using two different cut-offs: considering cut-offs of 10 mut/Mb and >16 mut/Mb, 45 patients (57%) and 68 patients (86.1%) had a low TMB, respectively. A high TMB (cut-off 10 mut/Mb) predicted worse PFS in patients treated with CT (p=0.046); even though not statistically significant, a high TMB (cut-off 16 mut/Mb) predicted a better survival in patients treated with CT+IO. Moreover, at univariate analysis, MLL2 mutations were associated with better prognosis in the overall case series (HRPFS = 0.51, 95% CI: 0.28-0.94), and overall survival (HROS = 0.52, 95% CI: 0.28-0.97).

Conclusion: In ES-SCLC, TMB is associated with worse survival in patients treated with CT alone, and with better survival in patients treated with CT+IO, whether considered as a continuous or a dichotomized variable, at different cut-offs. Alterations in epigenetic factors are also associated to better patient prognosis.

Keywords: immunotherapy; patients prognosis; predictive biomarkers; small-cell lung cancer; tumor mutation burden.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flow-chart of patients included in the study.
Figure 2
Figure 2
Kaplan–Meier curves for progression-free survival (A) and overall survival (B) by type of treatment.
Figure 3
Figure 3
Oncoprint of the most frequently altered genes in the overall samples, with the indication of type of mutation, first-line treatment and response, and tumor mutation burden using the 10 mut/Mb.
Figure 4
Figure 4
Kaplan–Meier curves for progression-free survival (A) and overall survival (B) by MLL2 mutational status.
See this image and copyright information in PMC

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