WCLC 2025 - Posters & ePosters-P3.03.44 High Frequency of SMARCA4 Inactivating Mutations in Advanced NSCLC and Their Association With Low PD-L1 Expression

P3.03.44 High Frequency of SMARCA4 Inactivating Mutations in Advanced NSCLC and Their Association With Low PD-L1 Expression

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This study investigates the genomic and molecular features influencing immunogenicity in advanced non-small cell lung cancer (NSCLC), focusing on the role of SMARCA4 mutations and their relationship with PD-L1 expression and response to immune checkpoint inhibitors (ICI). A cohort of 48 NSCLC patients treated with ICI-based therapies at the Catalan Institute of Oncology was prospectively enrolled, with tumor samples analyzed using immunohistochemistry for PD-L1 and comprehensive genomic profiling via whole-exome and RNA sequencing on 29 samples.<br /><br />Key findings reveal a notably high frequency (17%) of truncating inactivating mutations in the SMARCA4 gene, an essential component of the chromatin remodeling complex linked to poor cancer prognosis. Tumors harboring SMARCA4 mutations exhibited significantly lower PD-L1 expression compared to non-mutated tumors (mean 8% vs. 27%, p=0.06), with none of the SMARCA4-mutated tumors showing high PD-L1 (≥50%) expression. Additionally, these mutations correlated with downregulation of interferon-gamma (IFNγ) related genes, suggesting compromised anti-tumor immune responses.<br /><br />Clinically, higher PD-L1 expression (≥50%) was associated with a trend toward improved median overall survival (30.9 months) compared to tumors with lower PD-L1 (14.5 months), although this did not reach statistical significance (p=0.37). The study highlights the genomic heterogeneity of NSCLC and posits that alterations in chromatin remodeling genes like SMARCA4 may impact the efficacy of ICI by modulating tumor immune environment.<br /><br />In conclusion, SMARCA4 mutations represent a frequent alteration in advanced NSCLC that associates with reduced PD-L1 expression and impaired IFNγ signaling, potentially contributing to resistance against immunotherapy. These findings underscore the potential of SMARCA4 and related chromatin remodeling gene alterations as predictive biomarkers for ICI response, warranting further investigation for personalized NSCLC treatment strategies.

Asset Subtitle

Maria Saigí Morguí

Meta Tag

Speaker Maria Saigí Morguí

Topic Tumor Biology – Translational Biology

Keywords

SMARCA4 mutations

non-small cell lung cancer

NSCLC

immune checkpoint inhibitors

PD-L1 expression

chromatin remodeling

interferon-gamma signaling

immunotherapy resistance

genomic profiling

personalized cancer treatment