The diagnosis of SMARCA4-altered pulmonary tumors primarily relies on the detection of protein loss by immunohistochemistry (IHC). However, the concordance between IHC and genetic testing results, as well as the clinical and biological differences caused by various mutation types, require further investigation. This study aimed to explore the clinicopathological, genomic characteristics, as well as the prognosis, of these tumors. A total of 18 consecutive cases of pulmonary tumor patients with SMARCA4 deficiency/mutation confirmed by IHC or genetic testing were retrospectively enrolled for clinical, genomic, and prognostic analysis. Based on the variant type, patients were categorized into Class 1 (protein loss or loss-of-function gene mutations, n=10) and Class 2 (missense mutation or other variants of unknown significance without protein loss, n=8) for intergroup comparison. Seventeen cases were diagnosed with non-small cell lung cancer (NSCLC) and one was diagnosed with thoracic SMARCA4-deficient undifferentiated tumor (SD-UT). Genotype-phenotype correlation analysis revealed that truncating mutations consistently led to protein loss, whereas missense mutations mostly did not. Two cases with protein loss but negative genetic testing results were identified. Class 1 alterations showed trends towards higher tumor mutational burden (TMB) (median 9.3 vs 4.7 Muts/Mb) and lower programmed cell death ligand 1 (PD-L1) expression (60.0% vs 25.0% with <1% expression) compared to Class 2, but the differences were not statistically significant (P>0.05). Two patients with co-occurring epidermal growth factor receptor (EGFR) L858R mutations showed poor initial response to third-generation EGFR-tyrosine kinase inhibitor monotherapy, but the efficacy was observed after combination with other therapies. Among stage IV patients, the median overall survival (OS) was 10.3 months for Class 1 and 19.9 months for Class 2 (P=0.967). Fourteen patients (77.8%) received immune checkpoint inhibitors (ICIs) combined with chemotherapy. Among them, 8 patients (57.1%) achieved an OS exceeding 12 months, and 7 patients (50.0%) exceeded 24 months. SMARCA4 gene mutations are not entirely consistent with IHC protein loss, necessitating combined interpretation. When SMARCA4 alterations co-exist with EGFR mutations, targeted monotherapy efficacy may be limited, and combination strategies should be considered. Classifying SMARCA4 alterations into Class 1 and Class 2 may have prognostic implications and could help predict the tumor immune microenvironment status (TMB and PD-L1). ICIs combined with chemotherapy is currently one of the main treatment options for patients with advanced SMARCA4-altered pulmonary tumors and showed potential efficacy in this study. 【中文题目：18例SMARCA4缺失或基因突变肺部肿瘤患者的临床病理与基因特征以及预后分析】 【中文摘要：背景与目的 SMARCA4变异肺部肿瘤的诊断主要依赖于免疫组化（immunohistochemistry, IHC）检测蛋白缺失，但其与基因检测结果的一致性以及不同突变类型所导致的临床与生物学差异仍有待进一步探索。本研究旨在探讨该类肿瘤的临床病理、基因特征及预后。方法 回顾性纳入18例经IHC或基因检测证实为SMARCA4缺失/基因突变的肺部肿瘤连续病例，进行临床基因特征和预后分析。根据变异类型分为1类（蛋白缺失或功能丧失性基因突变，n=10）和2类（错义突变或其他意义不明突变且蛋白非缺失，n=8），并进行组间比较。结果 17例为非小细胞肺癌（non-small cell lung cancer, NSCLC），1例为胸部SMARCA4缺失型未分化肿瘤（SMARCA4-deficient undifferentiated tumor, SD-UT）。基因型与表型分析显示：截短突变均导致蛋白缺失，错义突变多不引起缺失，2例蛋白缺失但基因检测阴性。1类较2类变异有更高的肿瘤突变负荷（tumor mutational burden, TMB）（中位数：9.3 vs 4.7 Muts/Mb）和更低的程序性死亡-配体1（programmed cell death ligand 1, PD-L1）表达（<1%者占比：60.0% vs 25.0%）趋势，但差异无统计学意义（P>0.05）。2例表皮生长因子受体（epidermal growth factor receptor, EGFR）L858R共突变患者初始第三代EGFR靶向单药疗效不佳，联合其他治疗见效。IV期患者中1类与2类变异的中位总生存期（overall survival, OS）分别为10.3和19.9个月（P=0.967）。14例（77.8%）患者接受了免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）联合化疗，其中8例（57.1%）OS超12个月，7例（50.0%）超24个月。结论 SMARCA4基因突变与蛋白缺失不完全一致，需联合判读。SMARCA4变异与EGFR突变共存时，单药靶向疗效可能有限，应考虑联合策略。将SMARCA4变异区分为1类与2类，可能具有预后提示价值，并有助于预测肿瘤的免疫微环境状态（TMB及PD-L1）。ICIs联合化疗的方案可能是目前SMARCA4变异晚期肺部肿瘤患者的主要治疗选择之一，在本研究中显示出潜在疗效。
】 【中文关键词：肺肿瘤；胸部SMARCA4缺失型未分化肿瘤；SMARCA4突变；SMARCA4 (BRG1)缺失；EGFR突变；靶向治疗；免疫检查点抑制剂；预后】.
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arXiv · 2025-02-24
arXiv · 2023-09-06