Clinicopathological and molecular characteristics and treatment outcomes of SMARCA4-deficient thoracic tumors: A comprehensive analysis

Background SMARCA4-deficient thoracic tumors (SDTTs) mainly include SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-dUT) and SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC). Comparative studies between these subtypes remain limited, and no standardized therapeutic guidelines have been established. Materials and Methods This study retrospectively analyzed 102 patients with SDTT from January 2020 to May 2024. We evaluated the efficacy of different treatments for SDTT and compared the clinicopathological features and prognostic outcomes between SD-UT and SD-NSCLC. Results SDTT predominantly occurs in olderly male smokers. SMARCA4-dUT exhibits high NSE expression, higher risk of lymph node metastases, and lower rates of early diagnosis than SMARCA4-dNSCLC. SMARCA4-dNSCLC can be distinguished from SMARCA4-dUT by gland architecture and the diffuse expression of epithelial markers, whereas SMARCA4-dUT shows positive expression for Syn and stem cell markers. Common mutations include TP53, SMARCA4, KRAS, and STK11, with STK11/KRAS co-mutations associated with poorer prognosis. SMARCA4 protein loss was observed not only in class I mutations but also in class II mutations and wild-type cases. Both SMARCA4-dUT and SMARCA4-dNSCLC carry a high recurrence risk after radical treatment. Immune-based therapy significantly improved median progression-free survival (mPFS) and overall survival (mOS) compared with non-immunotherapy (mPFS, 8.6 vs. 3.3 months, P < 0.0001; mOS, 13.1 vs. 8.0 months, P = 0.048). Central nervous system metastasis, pleura metastasis, and primary tumor resection were independent factors for OS. Conclusion This study provides a comprehensive analysis of SDTT to date, based on a relatively large sample size. STK11/KRAS co-mutations are associated with poorer prognosis. SMARCA4-dNSCLC can be distinguished from SMARCA4-dUT by epithelial markers and stem cell markers. Immune-based therapy is the optimal option in the current treatment strategy.