Table_1_Genomic alterations associated with pseudoprogression and hyperprogressive disease during anti-PD1 treatment for advanced non-small-cell lung cancer.docx

IntroductionThis study aimed to elucidate the relationship between dynamic genomic mutation alteration and pseudoprogression (PsPD)/hyperprogressive disease (HPD) in immunotherapy-treated advanced non-small-cell lung cancer (NSCLC), to provide clinical evidence for identifying and distinguishing between PsPD and HPD.
MethodPatients with advanced NSCLC who were treated with anti-PD1 were enrolled. Whole blood was collected at baseline and post image progression. Serum was separated and sequenced using 425-panel next-generation sequencing analysis (NGS).
ResultsNGS revealed that not only single gene mutations were associated with PsPD/HPD before treatment, dynamic monitoring of the whole-blood genome mutation spectrum also varied greatly. Mutational burden, allele frequency%, and relative circulating tumor DNA abundance indicated that the fold change after image progression was much higher in the HPD group.
DiscussionThe gene mutation profiles of PsPD and HPD not only differed before treatment, but higher genome mutation spectrum post image progression indicated true disease progression in patients with HPD. This suggests that dynamic whole-genome mutation profile monitoring as NGS can distinguish PsPD from HPD more effectively than single gene detection, providing a novel method for guiding clinical immune treatment.

引言：本研究旨在明确接受免疫治疗的晚期非小细胞肺癌（non-small-cell lung cancer, NSCLC）患者中，动态基因组突变特征与假性进展（pseudoprogression, PsPD）/超进展疾病（hyperprogressive disease, HPD）之间的关联，为临床识别与区分PsPD和HPD提供循证依据。
方法：纳入接受抗PD-1治疗的晚期非小细胞肺癌患者。分别于基线期及影像学证实疾病进展后采集全血样本，分离血清后采用425基因面板下一代测序（next-generation sequencing, NGS）技术完成测序分析。
结果：下一代测序结果显示，治疗前不仅单基因突变与PsPD/HPD存在相关性，全血基因组突变谱的动态监测特征也存在显著差异。突变负荷、等位基因频率（%）及相对循环肿瘤DNA（circulating tumor DNA）丰度均提示，影像学进展后HPD组的倍数变化水平显著更高。
讨论：PsPD与HPD患者的基因突变谱在治疗前即存在差异，且影像学进展后更高的基因组突变谱水平提示HPD患者为真性疾病进展。这表明，相较于单基因检测，采用下一代测序开展的动态全基因组突变谱监测可更高效地鉴别PsPD与HPD，为指导临床免疫治疗提供了全新的检测思路与方法。