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Rare SMARCA4-deficient thoracic tumor: Insights into molecular characterization and optimal therapeutics methods
Mengting Shi1, Lanlan Pang1, Huaqiang Zhou1
1Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Introductions:
The 2021 WHO Classification of Thoracic Tumors recognized SMARCA4-deficient undifferentiated thoracic tumors (SMARCA4-dUT) as a distinct entity that shows a striking overlap in demographic and molecular profiles with SMARCA4-deficient non-small lung cancer (SMARCA4-dNSCLC). The implications of SMARCA4 deficiency based on immunohistochemistry remain unclear. We aimed to investigate molecular characteristics of SMARCA4-deficient thoracic tumors (SDTT) and explore optimal therapeutics.
Methods:
From June.15, 2018, to Nov.15, 2023, a large cohort including patients diagnosed with SMARCA4-deficient (N = 196) and SMARCA4-intact (N = 438) thoracic tumors confirmed by immunohistochemistry at SYSUCC were screened. Clinicopathologic and molecular characteristics were identified and compared. External SRRSH cohort (N = 34) was combined into a pooled cohort to compare clinical outcome of first-line therapy efficacy.
Results:
SDTT is male predominance with smoking history, high tumor burden, and adrenal metastases. The relationship between SMARCA4 mutation and protein expression is not completely parallel. The majority of SMARCA4-deficient patients harbor truncating (Class-I) SMARCA4 mutations, whereas class-II alterations and wild-type also exist. Compared with SMARCA4-intact thoracic tumors, patients with SDTT displayed a higher tumor mutation burden (TMB) and associated with a shorter median OS (16.8 months vs. Not reached; P < 0.001). Notably, SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in these differences. SDTT is generally resistant to chemotherapy, while sensitive to chemoimmunotherapy (median PFS: 7.5 vs. 3.5 months, P < 0.001). In particular, patients with SMARCA4 deficient thoracic tumors treated with paclitaxel-based chemoimmunotherapy achieved a longer median PFS than those with pemetrexed-based chemoimmunotherapy (10.0 vs. 7.3 months, P = 0.028).
Conclusions:
SMARCA4 protein deficiency, rather than genetic mutations, played a decisive role in its characteristics of higher TMB and poor prognosis. Chemoimmunotherapy serves as the optimal option in the current treatment regimen. Paclitaxel-based chemoimmunotherapy performed better than those with pemetrexed-based chemoimmunotherapy.
Insights
SMARCA4 protein deficiency, not mutations, drives higher tumor mutation burden and poor prognosis in thoracic tumors. Chemoimmunotherapy, particularly paclitaxel-based, is the optimal treatment for these patients.
Area of Science:
- Oncology
- Thoracic Oncology
- Molecular Pathology
Background:
- The 2021 WHO Classification recognized SMARCA4-deficient undifferentiated thoracic tumors (SMARCA4-dUT) with overlapping profiles to SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC).
- The clinical implications of SMARCA4 deficiency, particularly as assessed by immunohistochemistry, require further elucidation.
- This study investigates the molecular characteristics of SMARCA4-deficient thoracic tumors (SDTT) to identify optimal therapeutic strategies.
Purpose of the Study:
- To investigate the clinicopathologic and molecular characteristics of SMARCA4-deficient thoracic tumors (SDTT).
- To compare these characteristics with SMARCA4-intact thoracic tumors.
- To evaluate the efficacy of different therapeutic strategies for SDTT.
Main Methods:
- Screened a cohort of 196 SMARCA4-deficient and 438 SMARCA4-intact thoracic tumors diagnosed via immunohistochemistry.
- Analyzed clinicopathologic and molecular features, including tumor mutation burden (TMB).
- Combined external data to compare the clinical outcomes of first-line therapies.
Main Results:
- SMARCA4-deficient thoracic tumors (SDTT) exhibit male predominance, smoking history, high tumor burden, and adrenal metastases.
- SMARCA4 protein deficiency, not genetic mutations, was associated with higher TMB and poorer overall survival (OS) compared to SMARCA4-intact tumors (16.8 months vs. Not reached; P < 0.001).
- SDTT showed resistance to chemotherapy but sensitivity to chemoimmunotherapy (median progression-free survival [PFS]: 7.5 vs. 3.5 months; P < 0.001), with paclitaxel-based regimens outperforming pemetrexed-based ones (10.0 vs. 7.3 months; P = 0.028).
Conclusions:
- SMARCA4 protein deficiency is a key determinant of higher TMB and poor prognosis in thoracic tumors.
- Chemoimmunotherapy represents the optimal therapeutic approach for SDTT.
- Paclitaxel-based chemoimmunotherapy demonstrates superior efficacy compared to pemetrexed-based regimens in this patient group.
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