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Clinicopathological and molecular characteristics and treatment outcomes of SMARCA4-deficient thoracic tumors: a
Ying Liu1, Fangfang Liu1, Chengyan Wang1
1Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Objective:
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.
Design:
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 older 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 < .0001; mOS, 13.1 vs. 8.0 months, P = .048). Central nervous system metastasis, pleura metastasis, and primary tumor resection were independent factors for OS.
Conclusions:
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.
Insights
SMARCA4-deficient thoracic tumors (SDTTs) include undifferentiated (SMARCA4-dUT) and non-small cell lung cancer (SMARCA4-dNSCLC) subtypes. Immune-based therapy offers improved survival for SDTT patients, while STK11/KRAS co-mutations indicate a poorer prognosis.
Area of Science:
- Oncology
- Thoracic Oncology
- Molecular Pathology
Background:
- SMARCA4-deficient thoracic tumors (SDTTs) encompass SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-dUT) and SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC).
- Comparative data and therapeutic guidelines for these SDTT subtypes are limited.
Purpose of the Study:
- To compare clinicopathological features and prognostic outcomes between SMARCA4-dUT and SMARCA4-dNSCLC.
- To evaluate the efficacy of various treatments for SDTT.
Main Methods:
- Retrospective analysis of 102 SDTT patients (January 2020 - May 2024).
- Evaluation of treatment efficacy and comparison of clinicopathological features and prognostic outcomes between SMARCA4-dUT and SMARCA4-dNSCLC.
Main Results:
- SDTT is more prevalent in older male smokers. SMARCA4-dUT shows higher NSE, increased lymph node metastasis, and later diagnosis compared to SMARCA4-dNSCLC.
- Distinctive markers differentiate subtypes: SMARCA4-dNSCLC exhibits gland architecture and diffuse epithelial markers, while SMARCA4-dUT shows positive Syn and stem cell markers. Common mutations include TP53, SMARCA4, KRAS, and STK11; STK11/KRAS co-mutations correlate with worse prognosis.
- Immune-based therapy significantly improved progression-free survival (PFS) and overall survival (OS) compared to non-immunotherapy (mPFS: 8.6 vs. 3.3 months; mOS: 13.1 vs. 8.0 months). Central nervous system metastasis, pleural metastasis, and primary tumor resection were independent prognostic factors for OS.
Conclusions:
- Immune-based therapy represents the optimal treatment strategy for SDTT.
- STK11/KRAS co-mutations are associated with a poorer prognosis in SDTT.
- SMARCA4-dNSCLC and SMARCA4-dUT can be histologically distinguished using epithelial and stem cell markers.
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