Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
Mol Cancer Ther. 2020 Jul;19(7):1486-1496. doi: 10.1158/1535-7163.MCT-19-1060. Epub 2020 May 5.
Treatment response assessment for patients with advanced solid tumors is complex and existing methods require greater precision. Current guidelines rely on imaging, which has known limitations, including the time required to show a deterministic change in target lesions. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to assess response or resistance to treatment early in the treatment course. Ninety-six patients with advanced cancer were prospectively enrolled (91 analyzed and 5 excluded), and blood was collected before and after initiation of a new, systemic treatment. Plasma cell-free DNA libraries were prepared for either WG or WG bisulfite sequencing. Longitudinal changes in the fraction of ctDNA were quantified to retrospectively identify molecular progression (MP) or major molecular response (MMR). Study endpoints were concordance with first follow-up imaging (FFUI) and stratification of progression-free survival (PFS) and overall survival (OS). Patients with MP ( = 13) had significantly shorter PFS (median 62 days vs. 310 days) and OS (255 days vs. not reached). Sensitivity for MP to identify clinical progression was 54% and specificity was 100%. MP calls were from samples taken a median of 28 days into treatment and 39 days before FFUI. Patients with MMR ( = 27) had significantly longer PFS and OS compared with those with neither call ( = 51). These results demonstrated that ctDNA changes early after treatment initiation inform response to treatment and correlate with long-term clinical outcomes. Once validated, molecular response assessment can enable early treatment change minimizing side effects and costs associated with additional cycles of ineffective treatment.
治疗反应评估对于晚期实体瘤患者较为复杂，且现有的方法需要更高的精准度。目前的指南依赖于影像学，其存在着一些已知的局限性，包括显示目标病变确定性变化所需的时间。全基因组（WG）循环肿瘤 DNA（ctDNA）的连续变化被用于在治疗过程的早期评估对治疗的反应或耐药性。96 名晚期癌症患者被前瞻性纳入（91 例分析，5 例排除），在开始新的全身性治疗之前和之后采集血液。为 WG 或 WG 亚硫酸氢盐测序制备无细胞血浆 DNA 文库。定量分析 ctDNA 分数的纵向变化，以回顾性识别分子进展（MP）或主要分子反应（MMR）。研究终点与首次随访成像（FFUI）一致，并对无进展生存期（PFS）和总生存期（OS）进行分层。有 MP（=13）的患者 PFS（中位数 62 天 vs. 310 天）和 OS（255 天 vs. 未达到）显著更短。MP 对识别临床进展的敏感性为 54%，特异性为 100%。MP 检测来自治疗开始后中位数 28 天和 FFUI 前 39 天的样本。有 MMR（=27）的患者与既没有 MP 也没有 MMR （=51）的患者相比，PFS 和 OS 显著更长。这些结果表明，治疗开始后早期的 ctDNA 变化可以提示对治疗的反应，并与长期临床结局相关。一旦得到验证，分子反应评估可以实现早期治疗改变，从而最小化与无效治疗周期相关的副作用和成本。
