Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2023 Jan 17;29(2):410-421. doi: 10.1158/1078-0432.CCR-22-1134.
We sought to determine whether sequencing analysis of circulating cell-free DNA (cfDNA) in patients with prospectively accrued endometrial cancer captures the mutational repertoire of the primary lesion and allows for disease monitoring.
Peripheral blood was prospectively collected from 44 newly diagnosed patients with endometrial cancer over a 24-month period (i.e., baseline, postsurgery, every 6 months after). DNA from the primary endometrial cancers was subjected to targeted next-generation sequencing (NGS) of 468 cancer-related genes, and cfDNA to a high-depth NGS assay of 129 genes with molecular barcoding. Sequencing data were analyzed using validated bioinformatics methods.
cfDNA levels correlated with surgical stage in endometrial cancers, with higher levels of cfDNA being present in advanced-stage disease. Mutations in cfDNA at baseline were detected preoperatively in 8 of 36 (22%) patients with sequencing data, all of whom were diagnosed with advanced-stage disease, high tumor volume, and/or aggressive histologic type. Of the 38 somatic mutations identified in the primary tumors also present in the cfDNA assay, 35 (92%) and 38 (100%) were detected at baseline and follow-up, respectively. In 6 patients with recurrent disease, changes in circulating tumor DNA (ctDNA) fraction/variant allele fractions in cfDNA during follow-up closely mirrored disease progression and therapy response, with a lead time over clinically detected recurrence in two cases. The presence of ctDNA at baseline (P < 0.001) or postsurgery (P = 0.014) was significantly associated with reduced progression-free survival.
cfDNA sequencing analysis in patients with endometrial cancer at diagnosis has prognostic value, and serial postsurgery cfDNA analysis enables disease and treatment response monitoring. See related commentary by Grant et al., p. 305.
我们旨在确定对前瞻性采集的患有子宫内膜癌患者的循环游离 DNA（cfDNA）进行测序分析是否能够捕获原发性病变的突变谱，并允许进行疾病监测。
在 24 个月的时间内（即基线、手术后、手术后每 6 个月），前瞻性地从 44 例新诊断为子宫内膜癌的患者中采集外周血。将原发性子宫内膜癌的 DNA 进行靶向下一代测序（NGS），对 129 个基因进行高深度 NGS 检测，其中包括分子条形码。使用经过验证的生物信息学方法分析测序数据。
cfDNA 水平与子宫内膜癌的手术分期相关，晚期疾病中存在更高水平的 cfDNA。在具有测序数据的 36 例患者中，有 8 例（22%）在基线时检测到 cfDNA 中的突变，所有这些患者均被诊断为晚期疾病、高肿瘤体积和/或侵袭性组织学类型。在原发性肿瘤中发现的 38 个体细胞突变中，有 35 个（92%）和 38 个（100%）分别在基线和随访时被检测到。在 6 例复发疾病患者中，cfDNA 中循环肿瘤 DNA（ctDNA）分数/变异等位基因分数的变化在随访期间与疾病进展和治疗反应密切相关，在 2 例中，其提前时间超过了临床检测到的复发时间。基线（P < 0.001）或手术后（P = 0.014）存在 ctDNA 与无进展生存期缩短显著相关。
在诊断时对子宫内膜癌患者进行 cfDNA 测序分析具有预后价值，并且连续进行手术后 cfDNA 分析可实现疾病和治疗反应监测。见 Grant 等人的相关评论，第 305 页。
