Ohio State University School of Medicine, Columbus.
Tempus AI Inc, Chicago, Illinois.
JAMA Netw Open. 2024 Nov 4;7(11):e2442970. doi: 10.1001/jamanetworkopen.2024.42970.
The National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer suggest that RNA next-generation sequencing (NGS) may improve the detection of fusions and splicing variants compared with DNA-NGS alone. However, there is limited adoption of RNA-NGS in routine oncology clinical care today.
To analyze clinical evidence from a diverse cohort of patients with advanced lung adenocarcinoma and compare the detection of NCCN-recommended actionable structural variants (aSVs; fusions and splicing variants) via concurrent DNA and RNA-NGS vs DNA-NGS alone.
DESIGN, SETTING, AND PARTICIPANTS: This multisite, retrospective cohort study examined patients sequenced between February 2021 and October 2023 within the deidentified, Tempus multimodal database, consisting of linked molecular and clinical data. Participants included patients with advanced lung adenocarcinoma and sufficient tissue sample quantities for both RNA-NGS and DNA-NGS testing.
Received results from RNA-NGS and DNA-NGS solid-tissue profiling assays.
Detection rates of NCCN guideline-based structural variants (ALK, ROS1, RET and NTRK1/2/3 fusions, as well as MET exon 14 skipping splicing alterations) found uniquely by RNA-NGS.
In the evaluable cohort of 5570 patients, median (IQR) age was 67.8 (61.3-75.4) years, and 2989 patients (53.7%) were female. The prevalence of actionable structural variants detected by either RNA-NGS or DNA-NGS was 8.8% (n = 491), with 86.7% (n = 426) of these detected by DNA-NGS. Concurrent RNA-NGS and DNA-NGS identified 15.3% more patients harboring aSVs compared with DNA-NGS alone (491 vs 426 patients, respectively), including 14.3% more patients harboring actionable fusions (376 vs 329 patients) and 18.6% more patients harboring MET exon 14 skipping alterations (115 vs 97 patients). There was no significant association between the assay used for aSV detection and aSV-targeted therapeutic adoption or clinical outcome. Emerging structural variants (eSVs) were found to have a combined prevalence to be 0.7%, with only 47.5% of eSVs detected by DNA-NGS.
In this cohort study, the detection of structural variants via concurrent RNA-NGS and DNA-NGS was higher across multiple NCCN-guideline recommended biomarkers compared with DNA-NGS alone, suggesting that RNA-NGS should be routinely implemented in the care of patients with advanced NSCLC.
美国国家综合癌症网络 (NCCN) 非小细胞肺癌指南建议，与单独的 DNA-NGS 相比，RNA 下一代测序 (NGS) 可能提高融合和剪接变异的检测率。然而，目前 RNA-NGS 在常规肿瘤临床护理中的应用仍然有限。
分析来自晚期肺腺癌患者的多样化队列的临床证据，并比较通过同时进行 DNA 和 RNA-NGS 与单独进行 DNA-NGS 检测，对 NCCN 推荐的治疗性结构变异（融合和剪接变异）的检测。
设计、地点和参与者：这项多地点、回顾性队列研究分析了 2021 年 2 月至 2023 年 10 月期间在 Tempus 多模式数据库中进行的、经去识别处理的、包含链接分子和临床数据的患者的二代测序数据。参与者包括有足够的 RNA-NGS 和 DNA-NGS 测试组织样本量的晚期肺腺癌患者。
接受了 RNA-NGS 和 DNA-NGS 固体组织分析检测的结果。
通过 RNA-NGS 单独检测到的 NCCN 指南基于结构变异（ALK、ROS1、RET 和 NTRK1/2/3 融合，以及 MET 外显子 14 跳跃剪接改变）的检测率。
在可评估的 5570 例患者队列中，中位（IQR）年龄为 67.8（61.3-75.4）岁，2989 例患者（53.7%）为女性。通过 RNA-NGS 或 DNA-NGS 检测到的治疗性结构变异的患病率为 8.8%（n=491），其中 86.7%（n=426）通过 DNA-NGS 检测到。与单独进行 DNA-NGS 相比，同时进行 RNA-NGS 和 DNA-NGS 检测到更多患有 aSV 的患者（分别为 491 例和 426 例），包括 14.3%的患者患有可治疗的融合（376 例与 329 例）和 18.6%的患者患有 MET 外显子 14 跳跃改变（115 例与 97 例）。用于 aSV 检测的检测方法与 aSV 靶向治疗的采用或临床结果之间没有显著关联。新兴结构变异 (eSVs) 的总检出率为 0.7%，仅 47.5%的 eSVs 通过 DNA-NGS 检测到。
在这项队列研究中，与单独进行 DNA-NGS 相比，通过同时进行 RNA-NGS 和 DNA-NGS 检测到的结构变异在多个 NCCN 指南推荐的生物标志物中均有所增加，这表明 RNA-NGS 应常规应用于晚期 NSCLC 患者的治疗。
