小细胞肺癌（SCLC）是一种预后不良的侵袭性恶性肿瘤。有限期 (LS)-SCLC 仅占 SCLC 病例的三分之一，导致分子靶向治疗和治疗选择有限。尽管胸部和颅部放疗的进步导致了结果的改善，但仍有相当一部分患者出现脑转移 (BM)，这凸显了识别高危患者以制定量身定制的筛查和治疗策略的重要性。我们分析了 180 例 LS-SCLC 的基线肿瘤活检使用 474 基因泛癌组接受一线确定性放化疗 (dCRT) 的患者。将死亡评分作为竞争风险来计算 BM 的累积发生率。使用 Fine-Gray 模型确定了 BM 风险的独立预后因素。细胞周期途径的改变，特别是 RB1 突变，在 BM 患者中更常见，而 FLT4 突变在无 BM 患者中更常见（P=0.002 和 P =0.021，分别）。 BM 的重要危险因素包括吸烟（次分布风险比 [SHR]：1.73；95% 置信区间 [CI]：1.11-2.70；P=0.016）、RB1 突变（SHR：2.19；95% CI：1.27-3.81；P =0.005）和 BCL3 扩增（SHR：2.27；95% CI：1.09-4.71；P=0.028）。相反，预防性颅脑照射 (PCI)（SHR：0.39；95% CI：0.25-1.60；P<0.001）、FLT4 突变（SHR：0.26；95% CI：0.07-0.98；P=0.047）和 NOTCH 通路改变（SHR：0.65；95% CI：0.43-1.00；P=0.049）与 LS-SCLC 中较低的 BM 发生率相关。值得注意的是，巩固 PCI 治疗并没有降低基线 RB1 突变患者的 BM 风险，20 个月时 BM 发生概率为 34.7%，40 个月时为 62.6%。我们的研究对 LS-SCLC 患者的遗传特征产生了有价值的见解。无需 BM，有助于制定个性化治疗策略。在 dCRT 随后 PCI 的标准治疗方案中，识别与 BM 发生率和时间相关的风险因素可能有助于优化 LS-SCLC 的临床决策。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Small-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies.We analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model.Alterations in the cell cycle pathway, particularly RB1 mutations, were more common in patients with BM, while FLT4 mutations were more frequent in those without BM (P=0.002 and P=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11-2.70; P=0.016), RB1 mutations (SHR: 2.19; 95 % CI: 1.27-3.81; P=0.005), and BCL3 amplification (SHR: 2.27; 95 % CI: 1.09-4.71; P=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25-1.60; P<0.001), FLT4 mutations (SHR: 0.26; 95 % CI: 0.07-0.98; P=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43-1.00; P=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline RB1 mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months.Our study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.Copyright © 2024 Elsevier B.V. All rights reserved.