| Sumario: | Background and objective The diagnosis of SMARCA4-altered pulmonary tumors primarily relies on the detection of protein loss by immunohistochemistry (IHC). However, the concordance between IHC and genetic testing results, as well as the clinical and biological differences caused by various mutation types, require further investigation. This study aimed to explore the clinicopathological, genomic characteristics, as well as the prognosis, of these tumors. Methods A total of 18 consecutive cases of pulmonary tumor patients with SMARCA4 deficiency/mutation confirmed by IHC or genetic testing were retrospectively enrolled for clinical, genomic, and prognostic analysis. Based on the variant type, patients were categorized into Class 1 (protein loss or loss-of-function gene mutations, n=10) and Class 2 (missense mutation or other variants of unknown significance without protein loss, n=8) for intergroup comparison. Results Seventeen cases were diagnosed with nonsmall cell lung cancer (NSCLC) and one was diagnosed with thoracic SMARCA4-deficient undifferentiated tumor (SD-UT). Genotype-phenotype correlation analysis revealed that truncating mutations consistently led to protein loss, whereas missense mutations mostly did not. Two cases with protein loss but negative genetic testing results were identified. Class 1 alterations showed trends towards higher tumor mutational burden (TMB) (median 9.3 vs 4.7 Muts/Mb) and lower programmed cell death ligand 1 (PD-L1) expression (60.0% vs 25.0% with <1% expression) compared to Class 2, but the differences were not statistically significant (P>0.05). Two patients with co-occurring epidermal growth factor receptor (EGFR) L858R mutations showed poor initial response to third-generation EGFR-tyrosine kinase inhibitor monotherapy, but the efficacy was observed after combination with other therapies. Among stage IV patients, the median overall survival (OS) was 10.3 months for Class 1 and 19.9 months for Class 2 (P=0.967). Fourteen patients (77.8%) received immune checkpoint inhibitors (ICIs) combined with chemotherapy. Among them, 8 patients (57.1%) achieved an OS exceeding 12 months, and 7 patients (50.0%) exceeded 24 months. Conclusion SMARCA4 gene mutations are not entirely consistent with IHC protein loss, necessitating combined interpretation. When SMARCA4 alterations co-exist with EGFR mutations, targeted monotherapy efficacy may be limited, and combination strategies should be considered. Classifying SMARCA4 alterations into Class 1 and Class 2 may have prognostic implications and could help predict the tumor immune microenvironment status (TMB and PD-L1). ICIs combined with chemotherapy is currently one of the main treatment options for patients with advanced SMARCA4-altered pulmonary tumors and showed potential efficacy in this study.
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