Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia.
JAMA Oncol. 2019 Feb 1;5(2):173-180. doi: 10.1001/jamaoncol.2018.4305.
The clinical implications of adding plasma-based circulating tumor DNA next-generation sequencing (NGS) to tissue NGS for targetable mutation detection in non-small cell lung cancer (NSCLC) have not been formally assessed.
To determine whether plasma NGS testing was associated with improved mutation detection and enhanced delivery of personalized therapy in a real-world clinical setting.
DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study enrolled 323 patients with metastatic NSCLC who had plasma testing ordered as part of routine clinical management. Plasma NGS was performed using a 73-gene commercial platform. Patients were enrolled at the Hospital of the University of Pennsylvania from April 1, 2016, through January 2, 2018. The database was locked for follow-up and analyses on January 2, 2018, with a median follow-up of 7 months (range, 1-21 months).
The number of patients with targetable alterations detected with plasma and tissue NGS; the association between the allele fractions (AFs) of mutations detected in tissue and plasma; and the association of response rate with the plasma AF of the targeted mutations.
Among the 323 patients with NSCLC (60.1% female; median age, 65 years [range, 33-93 years]), therapeutically targetable mutations were detected in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF for 113 (35.0%) overall. Ninety-four patients (29.1%) had plasma testing only at the discretion of the treating physician or patient preference. Among the 94 patients with plasma testing alone, 31 (33.0%) had a therapeutically targetable mutation detected, thus obviating the need for an invasive biopsy. Among the remaining 229 patients who had concurrent plasma and tissue NGS or were unable to have tissue NGS, a therapeutically targetable mutation was detected in tissue alone for 47 patients (20.5%), whereas the addition of plasma testing increased this number to 82 (35.8%). Thirty-six of 42 patients (85.7%) who received a targeted therapy based on the plasma result achieved a complete or a partial response or stable disease. The plasma-based targeted mutation AF had no correlation with depth of Response Evaluation Criteria in Solid Tumors response (r = -0.121; P = .45).
Integration of plasma NGS testing into the routine management of stage IV NSCLC demonstrates a marked increase of the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy.
在非小细胞肺癌（NSCLC）中，将基于血浆的循环肿瘤 DNA 下一代测序（NGS）添加到组织 NGS 以检测靶向突变的临床意义尚未得到正式评估。
确定在真实临床环境中，血浆 NGS 检测是否与提高突变检测和增强个性化治疗的提供有关。
设计、地点和参与者：这项前瞻性队列研究纳入了 323 名转移性 NSCLC 患者，他们的血浆检测是作为常规临床管理的一部分而进行的。使用 73 基因商业平台进行血浆 NGS。患者于 2016 年 4 月 1 日至 2018 年 1 月 2 日在宾夕法尼亚大学医院入组。数据库于 2018 年 1 月 2 日锁定以进行随访和分析，中位随访时间为 7 个月（范围，1-21 个月）。
用血浆和组织 NGS 检测到的具有靶向性改变的患者数量；组织和血浆中检测到的突变等位基因分数（AFs）之间的关联；以及反应率与靶向突变的血浆 AF 的关联。
在 323 名 NSCLC 患者中（60.1%为女性；中位年龄为 65 岁[范围，33-93 岁]），总体上有 113 例（35.0%）患者的 EGFR、ALK、MET、BRCA1、ROS1、RET、ERBB2 或 BRAF 存在可治疗的靶基因突变。94 名患者（29.1%）仅根据治疗医生的判断或患者的意愿进行血浆检测。在单独进行血浆检测的 94 名患者中，31 名（33.0%）检测到具有治疗意义的靶基因突变，从而避免了进行有创活检。在其余 229 名同时进行血浆和组织 NGS 检测或无法进行组织 NGS 检测的患者中，47 名（20.5%）患者仅在组织中检测到具有治疗意义的靶基因突变，而增加血浆检测则将这一数字增加到 82 名（35.8%）。基于血浆结果接受靶向治疗的 42 名患者中的 36 名（85.7%）实现了完全或部分缓解或疾病稳定。基于血浆的靶向突变 AF 与实体瘤反应评价标准（RECIST）的缓解深度无相关性（r=−0.121；P=0.45）。
将血浆 NGS 检测纳入 IV 期 NSCLC 的常规管理中，显示出对治疗性靶基因突变的检测有显著增加，并提高了分子指导治疗的提供。
