Brief Report: Clinical Characteristics and Outcomes of Patients With Thoracic SMARCA4-Deficient Undifferentiated Tumors

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs) are a recently defined group of aggressive cancers in which the effectiveness of standard treatments for lung cancer is unknown.We collected clinical, pathologic, and demographic variables from five institutions for patients whose tumors met criteria for SMARCA4-UTs (undifferentiated phenotype and loss of SMARCA4 (BRG1) by immunohistochemistry).We identified 92 patients with SMARCA4-UTs; 58 (63%) had stage IV disease at diagnosis and 16 (17%) developed recurrent or metastatic disease after initial diagnosis. Median overall survival from metastatic diagnosis was 7.3 (95% confidence interval [CI]: 4.6–12.8) months. Of patients with metastatic disease, 58 (78%) received first-line systemic treatment. Most often, patients received chemo and immunotherapy combination (41%), chemotherapy alone (33%), or immunotherapy alone (16%). Median progression-free survival from start of systemic therapy was 1.9 (95% CI: 1.4–14.5) months for chemo and immunotherapy, 1.6 (95% CI: 1.1–5.8) months for chemotherapy, and 3.3 (95% CI: 1.2–undefined) months for immunotherapy alone. Five patients had durable responses (≥2 y); all received immunotherapy as part of first-line regimens. Nine (16%) of 55 tumor samples tested had programmed death-ligand 1 expression more than or equal to 50%, with 24 (44%) negative samples. Tumor mutational burden was available in 48 cases (52%), and median was 10.5 (range: 2–48) mutations per megabase.This multi-institution retrospective cohort analysis revealed a population of patients with short progression-free survival to standard therapies and poor overall survival. A few patients had remarkable response to regimens including immunotherapy. Prospective clinical studies are urgently needed to identify better therapeutic approaches to treat this aggressive malignancy, and this analysis may serve as a benchmark for future clinical trial design.

胸腺瘤SMARCA4缺陷未分化肿瘤（SMARCA4 - UTs）是最近定义的一组侵袭性癌症，其中肺癌标准治疗的有效性尚不清楚。我们从五家机构收集了肿瘤符合SMARCA4 - UTs标准（免疫组化显示未分化表型且SMARCA4（BRG1）缺失）的患者的临床、病理和人口统计学变量。我们确定了92例SMARCA4 - UTs患者；58例（63%）在诊断时为IV期疾病，16例（17%）在初次诊断后出现复发或转移性疾病。从转移性诊断开始的中位总生存期为7.3个月（95%置信区间[CI]：4.6 - 12.8个月）。在转移性疾病患者中，58例（78%）接受了一线全身治疗。最常见的是，患者接受化疗和免疫治疗联合（41%）、单纯化疗（33%）或单纯免疫治疗（16%）。从开始全身治疗起，化疗和免疫治疗的中位无进展生存期为1.9个月（95% CI：1.4 - 14.5个月），化疗为1.6个月（95% CI：1.1 - 5.8个月），单纯免疫治疗为3.3个月（95% CI：1.2 - 未定义）。5例患者有持久应答（≥2年）；所有患者在一线治疗方案中都接受了免疫治疗。在检测的55个肿瘤样本中，9例（16%）的程序性死亡配体1表达≥50%，24例（44%）为阴性样本。48例（52%）有肿瘤突变负荷数据，中位值为每兆碱基10.5个突变（范围：2 - 48个）。这项多机构回顾性队列分析揭示了一组患者对标准疗法的无进展生存期短且总生存期差。少数患者对包括免疫治疗在内的方案有显著应答。迫切需要前瞻性临床研究来确定治疗这种侵袭性恶性肿瘤的更好治疗方法，并且该分析可作为未来临床试验设计的基准。