Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, PR China.
Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing 210000, Jiangsu, PR China.
Lung Cancer. 2024 Oct;196:107959. doi: 10.1016/j.lungcan.2024.107959. Epub 2024 Sep 19.
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.
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，预后较差。局限期（LS）-SCLC 仅占 SCLC 病例的三分之一，导致靶向治疗和治疗选择有限。尽管胸部和颅脑放疗的进展导致了更好的结果，但仍有相当一部分患者发生脑转移（BM），这突出表明需要确定高风险患者，以便制定个性化的筛查和治疗策略。
我们分析了 180 例接受一线根治性放化疗（dCRT）的 LS-SCLC 患者的基线肿瘤活检，使用了一个包含 474 个基因的泛癌面板。采用竞争风险模型计算 BM 的累积发生率。采用 Fine-Gray 模型确定 BM 风险的独立预后因素。
细胞周期通路的改变，特别是 RB1 突变，在发生 BM 的患者中更为常见，而 FLT4 突变在未发生 BM 的患者中更为常见（P=0.002 和 P=0.021）。发生 BM 的显著危险因素包括吸烟（亚分布危险比 [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 患者 BM 发生率较低相关。值得注意的是，在基线 RB1 突变患者中，巩固性 PCI 治疗并不能降低 BM 风险，20 个月时的 BM 发生率为 34.7%，40 个月时为 62.6%。
本研究深入了解了发生和未发生 BM 的 LS-SCLC 患者的基因特征，有助于制定个性化的治疗策略。确定与 dCRT 后序贯 PCI 方案中 BM 发生率和时间相关的危险因素，可能有助于优化 LS-SCLC 的临床决策。
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