Abstract
BACKGROUND: SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) encodes the BRG1 (Brahma-related gene 1) protein, which regulates chromatin remodeling and gene expression; its loss leads to chromatin reorganization and aberrant expression of tumor-related genes, and it has been detected in multiple aggressive malignancies. SMARCA4-deficient thoracic tumors (SMARCA4-dTTs) mainly include the highly malignant SMARCA4-deficient undifferentiated tumor [SMARCA4-dUT, recognized as a distinct entity in the 2021 World Health Organization (WHO) classification] and SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC). Currently, there is no standard treatment plan for SMARCA4-dTTs. platinum-based chemotherapy, targeted therapy, and immunotherapy have limited efficacy, underscoring the need for further investigation. This study aims to remind the clinicians and pathologists that they should raise their awareness of the existence of these rare subtypes of lung cancer, proactively conduct differential diagnosis to avoid misdiagnosis, and look for effective treatment options. METHODS: This retrospective observational clinical study included 22 patients who diagnosed with SMARCA4-dTTs and attended in Xijing Hospital from January 2022 to June 2024. The clinical data of the patients were collected, including gender, age, smoking history, family history of tumors, symptoms, Eastern Cooperative Oncology Group performance status (ECOG-PS) score, programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS), distant metastasis status, treatment regimens, and survival. All the patients were pathologically diagnosed according to the WHO Classification of Thoracic Tumors (5th edition) and staged according to the Tumor-Node-Metastasis (TNM) Staging System for Lung Cancer (8th edition). The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used to compare survival differences between groups. RESULTS: Among the 22 patients, 15 were diagnosed with SMARCA4-dNSCLC, and seven with SMARCA4-dUT. Most patients were male (95.5%) and smokers (90.9%), with mediastinal lymph node metastasis (81.8%) and distant metastasis (68.2%). The histopathological and immunohistochemical results showed significant tumor cell atypia, SMARCA4 expression loss, and high Ki-67 expression. The median overall survival (OS) of the 22 patients was 4 months. The main factors affecting survival were tumor staging (median OS, non-stage IV patients 12 months, stage IV patients 3 months, P<0.01) and undergoing treatment (median OS, treated patients 7 months, untreated patients 1 month, P<0.01). No significant survival differences were found among various drugs and combined treatment regimens. CONCLUSIONS: SMARCA4-dTTs are a rare, highly malignant group of tumors with an extremely poor prognosis. There is currently no standard drug treatment regimen for SMARCA4-dTTs, but patients who receive treatment derive some survival benefits. Future research is needed to explore more effective treatment strategies.