Clinicopathological and Genomic Analysis of SMARCA4-Deficient Non-Small Cell Lung Cancer: A Retrospective Cohort Study

Dongmei Chen,1,* Heng Zhang,1,2,* Diming Wang,1 Wei Ye,1,3 Hongfei Zhao,1 Chi Zhang,1 Sihan Wu,1 Qingming Shi1 1Department of Oncology, Anhui Chest Hospital, Hefei, Anhui, 230022, People’s Republic of China; 2Department of Thoracic Surgery II, Anhui Chest Hospital, Hefei, Anhui, 230022, People’s Republic of China; 3Department of Pathology, Anhui Chest Hospital, Hefei, Anhui, 230022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingming Shi, Email [email protected]: SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) is a rare, aggressive subtype with limited treatment options. This study analyzed clinical, pathological, molecular, and prognostic features to improve recognition and identify survival determinants.Methods: This retrospective cohort study included 47 patients with pathologically confirmed SMARCA4-dNSCLC diagnosed at Anhui Chest Hospital between July 2022 and January 2024. SMARCA4 deficiency was defined as loss of BRG1 expression by immunohistochemistry. Clinical data, imaging findings, histopathology, molecular profiles, treatment modalities, and follow-up outcomes were reviewed. Overall survival (OS) was analyzed using Kaplan-Meier curves and Cox proportional hazards regression models to determine independent prognostic factors.Results: The cohort was predominantly older male smokers (median age 66; 87% male) with advanced disease (47% with distant metastasis at diagnosis). Imaging typically showed large, necrotic masses with ill-defined borders. Adenocarcinoma was the most common subtype (60%). Immunohistochemistry revealed BRG1 loss (91%), frequent TTF-1 negativity, and high Ki-67 expression. Common genetic alterations included TP53, KRAS, and STK11 mutations, while EGFR mutations were rare. Median overall survival was not reached in the treated group (median follow-up: 12.3 months; IQR: 8.5– 15.1 months), compared with 3 months in the untreated group (median follow-up: 4.2 months; IQR: 2.8– 5.6 months). Advanced TNM stage, distant metastasis, and absence of treatment were independent adverse prognostic factors (p< 0.05).Conclusion: SMARCA4-dNSCLC represents a distinct clinicopathologic entity with poor outcomes. Given the aggressive nature and poor prognosis of untreated SMARCA4-dNSCLC, timely diagnosis and multimodal treatment are essential to improving survival. Further prospective studies are needed to optimize management strategies.Keywords: SMARCA4-deficient lung cancer, BRG1 loss, immunohistochemistry, prognosis, treatment outcome, molecular profiling