小细胞肺癌中的多重定量蛋白质组学：DLL3分布的阶段关联性和胸苷磷酸化酶的独立预后信号
Multiplexed quantitative proteomics in small-cell lung cancer: stage-linked DLL3 distribution and an independent prognostic signal of thymidine phosphorylase.
作者
作者单位
- Department of Hospital Pathology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
- Division of Medical Oncology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea.
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
- Department of Thoracic and Cardiovascular Surgery, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
- Department of Radiology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
摘要
中文
Delta样配体3（DLL3）双特异性T细胞衔接器tarlatamab的监管批准已将DLL3定位为小细胞肺癌（SCLC）中临床可操作的靶点，但在真实世界SCLC队列中，DLL3是否与其他治疗相关蛋白一起独立具有预后意义仍未知。我们使用基于标准化质谱的绝对定量来解决这一问题。我们将选择反应监测质谱（SRM-MS）应用于2005-2015年间接受一线铂类/依托泊苷治疗的100例SCLC患者的存档福尔马林固定石蜡包埋肿瘤组织，以绝对摩尔单位定量了九种治疗相关蛋白（DLL3、ASCL1、EZH2、SLFN11、TYMP、MGMT、CD56、TUBB3、TOPO1）。分析了与肿瘤分期、铂类敏感性状态和总生存期（OS）的关联。SRM-MS在所有100个肿瘤中均获得了可解释的测量结果。DLL3与分期紧密相关，在76%的广泛期肿瘤中检测到，而局限期仅为29%（受试者工作特征曲线下面积0.78；P<0.001）。四分类DLL3/ASCL1模型对OS进行了分层（P=0.004）；然而，按分期分层分析显示，该信号仅限于局限期疾病，且主要由一个小的DLL3-/ASCL1-亚组（n=9，中位OS 25.8个月）驱动。在多变量Cox回归中，可检测的TYMP成为较短OS的独立预测因子。多重SRM-MS在临床适用于常规存档的FFPE SCLC组织，并提供一个定量框架，可能有助于解决SCLC中生物标志物指导的患者选择的未满足临床需求，特别是在DLL3定向治疗时代。
English
The regulatory approval of the delta-like ligand 3 (DLL3)-directed bispecific T-cell engager tarlatamab has positioned DLL3 as a clinically actionable target in small-cell lung cancer (SCLC), yet whether DLL3 is independently prognostic alongside other therapy-relevant proteins in real-world SCLC cohorts remains unknown. We addressed this using standardized mass spectrometry-based absolute quantitation. We applied selected reaction monitoring-mass spectrometry (SRM-MS) to archival formalin-fixed paraffin-embedded tumor tissue from 100 patients with SCLC treated with first-line platinum/etoposide (2005-2015), quantifying nine therapy-relevant proteins (DLL3, ASCL1, EZH2, SLFN11, TYMP, MGMT, CD56, TUBB3, TOPO1) in absolute molar units. Associations with tumor stage, platinum-sensitivity status, and overall survival (OS) were analyzed. SRM-MS yielded interpretable measurements in all 100 tumors. DLL3 was tightly stage-linked, detected in 76% of extensive-stage versus 29% of limited-stage tumors (area under the receiver operating characteristic curve 0.78; P<0.001). A four-class DLL3/ASCL1 model stratified OS (P=0.004); however, stage-stratified analyses showed that this signal was confined to limited-stage disease and largely driven by a small DLL3-/ASCL1- subgroup (n=9, median OS 25.8 months). In multivariable Cox regression, detectable TYMP emerged as an independent predictor of shorter OS. Multiplexed SRM-MS is clinically applicable to routinely archived FFPE SCLC tissue and provides a quantitative framework that may help address the unmet clinical need for biomarker-guided patient selection in SCLC, particularly in the era of DLL3-directed therapy.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q2
- 影响因子
- 3.4
- 新锐分区
- 3区