Data from: Application of circulating tumor DNA as a non-invasive tool for monitoring the progression of colorectal cancer

Background: Liquid biopsy has been proposed to be a promising noninvasive tool to obtain information on tumor progression. Through a clinical observation of a case series of 6 consecutive patients, we aim to determine the value of circulating tumor DNA (ctDNA) for monitoring the tumor burden during the treatment of colorectal cancer (CRC).
Materials and methods: We used capture sequencing of 545 genes to identify somatic alternations in primary tumor tissues of the six CRC patients who underwent radical surgery and in 23 plasma samples collected at serial time points. We compared the mutation patterns and variant allele frequencies (VAFs) between the matched tissue and the plasma samples and evaluated the potential advantage of using ctDNA as a better tumor load indicator to detect disease relapse over carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9 and imaging studies.
Results: We identified low-frequency mutations with a mean VAF of 0.88% (corresponding to a mean tumor burden of 0.20ng/mL) in the preoperative plasmas of four patients with locally advanced CRC and a subset of mutations shared by their primary tumors. The tumor loads appeared a sudden decrease upon surgery or other adjuvant treatments and then generally maintained at low levels (0.092ng/mL) until disease recurred. ctDNA increased by 13-fold when disease relapsed in one patient while the CEA and CA 19-9 levels remained normal. In this patient, all six somatic mutations identified in the preoperative plasma were detected in the recrudescent plasma again, with five mutations showing allele fraction increase.
Conclusions: We described a multi-time-point profile of ctDNA of CRC patients during the course of comprehensive treatment and observed a correlation of ctDNA level with the clinically evaluated tumor progression. This demonstrated a new strategy by analyzing the heterogeneous ctDNA to evaluate and monitor the tumor burden in the treatment and follow-up of CRC patients, with potentially better potency than conventional biomarkers.

背景：液体活检（Liquid biopsy）已被证实是一种极具应用前景的非侵入性检测手段，可用于获取肿瘤进展相关信息。本研究通过对6例连续入组的结直肠癌患者开展病例系列临床观察，旨在明确循环肿瘤DNA（circulating tumor DNA, ctDNA）在结直肠癌（colorectal cancer, CRC）治疗过程中用于监测肿瘤负荷的临床价值。
材料与方法：本研究纳入6例接受根治性手术的结直肠癌患者，对其原发肿瘤组织以及多个时间点采集的23份血浆样本，采用545基因捕获测序技术检测体细胞变异。研究对比了匹配的组织样本与血浆样本的突变谱及变异等位基因频率（variant allele frequencies, VAFs），并评估了相较于癌胚抗原（carcinoembryonic antigen, CEA）、糖类抗原（cancer antigen, CA）19-9以及影像学检查，ctDNA作为更优的肿瘤负荷指标以检测疾病复发的潜在优势。
结果：本研究在4例局部进展期结直肠癌患者的术前血浆中，检测到平均变异等位基因频率为0.88%（对应平均肿瘤负荷为0.20ng/mL）的低频突变，且其中部分突变与患者原发肿瘤所携带的突变重合。患者的肿瘤负荷在接受手术或其他辅助治疗后出现显著下降，随后通常维持在较低水平（0.092ng/mL），直至疾病复发。1例患者疾病复发时，ctDNA水平升高13倍，而癌胚抗原与糖类抗原19-9水平仍处于正常参考范围内。该患者术前血浆中检出的全部6个体细胞突变，在复发后的血浆样本中均再次被检出，其中5个突变的等位基因频率出现升高。
结论：本研究描绘了结直肠癌患者在综合治疗全程中多个时间点的ctDNA动态变化谱，并观察到ctDNA水平与临床评估的肿瘤进展具有显著相关性。本研究提出了一种全新的策略：通过分析异质性ctDNA来评估和监测结直肠癌患者治疗及随访过程中的肿瘤负荷，其检测效能可能优于传统肿瘤标志物。