小细胞肺癌中脑转移风险及预防性颅脑照射疗效的生物标志物探索

A biomarker exploration in small-cell lung cancer for brain metastases risk and prophylactic cranial irradiation therapy efficacy

LUNG CANCER

影响因子:4.4

分区:医学2区 / 肿瘤学3区呼吸系统3区

发表日期:2024 Oct

作者: Li Li, Ning Liu, Tao Zhou, Xueting Qin, Xiaoyu Song, Song Wang, Jiaohui Pang, Qiuxiang Ou, Yong Wang, Dexian Zhang, Jiaran Li, Fuhao Xu, Shuming Shi, Jinming Yu, Shuanghu Yuan

DOI: 10.1016/j.lungcan.2024.107959

摘要

小细胞肺癌（SCLC）是一种侵袭性极强的恶性肿瘤，预后较差。限期（LS）-SCLC仅占全部SCLC病例的三分之一，导致分子靶向治疗和治疗方案有限。尽管胸部和颅脑照射技术的进步带来了预后改善，但大量患者仍发生脑转移（BM），突显出识别高风险患者以制定个性化筛查和治疗策略的重要性。我们分析了180例接受一线确切性放化疗（dCRT）的LS-SCLC患者的基线肿瘤活检样本，采用474基因全癌症面板。通过将死亡作为竞争风险，计算了脑转移的累积发生率。使用Fine-Gray模型识别了BM风险的独立预后因素。在细胞周期途径的改变中，尤其是RB1突变，在有BM的患者中更为常见，而FLT4突变在无BM患者中更频繁（P=0.002 和 P=0.021）。BM的显著风险因素包括吸烟（亚风险比[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）以及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）以及Notch通路的改变（SHR：0.65；95%CI：0.43-1.00；P=0.049）与较低的脑转移发生率相关。值得注意的是，基线RB1突变患者接受巩固PCI后，脑转移风险未降低，20个月时的发生概率为34.7%，40个月时为62.6%。本研究提供了LS-SCLC患者有无脑转移的遗传特征的宝贵见解，有助于制定个性化治疗策略。识别与脑转移发生及时间相关的风险因素，有助于在标准治疗方案（dCRT加PCI）中优化临床决策。

Abstract

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.