Clinical Characteristics and Outcomes of SMARCA4-Mutated or Deficient Malignancies: A Systematic Review of Case...

Background/Objectives: SMARCA4-deficient or SMARCA4-mutated cancers are rare but highly aggressive tumors with poor differentiation, resistance to conventional treatments, and limited clinical guidance. While thoracic SMARCA4-deficient undifferentiated tumors are relatively well described, the full spectrum of SMARCA4-altered cancers across different organs and their therapeutic responses remains poorly understood. This study aimed to systematically review published case reports and case series to clarify the clinical characteristics, molecular features, treatment patterns, and survival outcomes of SMARCA4-altered malignancies. Methods: We conducted a systematic review of case reports and case series published between 2015 and 2025 using PubMed, Embase, and Web of Science. Eligible studies included adult patients with immunohistochemically or genetically confirmed SMARCA4-deficient or SMARCA4-mutated tumors. Key clinical, pathological, molecular, therapeutic, and outcome-related data were extracted. Descriptive statistics were used, and exploratory subgroup analyses were performed based on tumor type and treatment modality. The review protocol was registered in PROSPERO (CRD420251088805). Results: A total of 109 studies reporting 160 individual patients were included. Most tumors arose in the thorax (40.0%), followed by gastrointestinal (17.5%) and gynecologic sites (15.6%). The median age was 58 years, with a male predominance (70.0%) and frequent smoking history (44.4%). Platinum-based chemotherapy was administered in 62.5% of cases, and immune checkpoint inhibitors (ICIs) were used in 25.6%. Among ICI-treated patients, partial responses or stable disease were observed in 80.5%. The median progression-free survival (PFS) was 4.0 months, and the median overall survival (OS) was 5.0 months. Conclusions: SMARCA4-altered cancers are clinically and molecularly diverse but uniformly aggressive, with limited therapeutic benefit from conventional chemotherapy. Immune checkpoint inhibitors may offer improved outcomes in select patients, particularly those with thoracic tumors. Early molecular profiling, rare tumor registries, and biomarker-driven trials are crucial for guiding future treatment strategies.