Background Serial analysis of circulating tumor DNA (ctDNA) levels is a promising tool for both relapse prediction in the curative setting, as well as predicting clinical benefit from systemic treatment in metastasic colorectal cancer (mCRC). Most data in this context are derived from treatment naive patients. Objective To predict progressive disease (PD) as early as possible through monitoring of changes in ctDNA levels during systemic treatment in pretreated patients with mCRC. Design A prospective, single-center, observational study. Methods Patients treated beyond first-line were prospectively included between February 2020 and September 2021. Blood for ctDNA detection was taken before every treatment cycle from start of treatment until first restaging by CT-scan. ctDNA was detected by mutation- (mut-ctDNA) and methylation-specific ddPCR. Receiver Operating Characteristic (ROC)-analysis was used to describe sensitivity and specificity for prediction of PD at restaging for all time points. Results A total of 42 patients were included who all carried a mutation in tumor tissue. Detection rate of mut-ctDNA was 88.1% and 74.4% for meth-ctDNA. Absolute ctDNA levels before treatment were prognostic in terms of overall survival. Levels of ctDNA were significantly higher in patients with PD at restaging. Median time from start of treatment to restaging was 93 days (95% CI 88.8-96). After a median of 19 days of treatment (95% CI 16.1-20.2), a decline of either mutation- or methylation-specific ctDNA levels of ⩽58% predicted PD at restaging with a sensitivity/specificity of 92.9/85.7% and 85.7/100%, respectively. Median time to restaging was 66 days (95% CI 56.8-75.2). There was no significant increase of sensitivity/specificity at later time points of ctDNA measurements. Conclusion Monitoring early changes of ctDNA levels either by mut- or meth-ctDNA allows for early prediction of PD in pretreated patients with mCRC. This has the potential to complement RECIST-based treatment assessment with the aim to switch potentially insufficient treatments as early as possible, which is of particular interest in higher treatment lines.

中文翻译：

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通过对预处理的转移性结直肠癌中 ctDNA 动态进行突变或甲基化特异性检测来预测疗效。

背景 循环肿瘤 DNA (ctDNA) 水平的系列分析是一种很有前途的工具，可用于预测治疗环境中的复发，以及预测转移性结直肠癌 (mCRC) 全身治疗的临床获益。这方面的大多数数据都来自于未接受过治疗的患者。目的 通过监测已接受治疗的 mCRC 患者全身治疗期间 ctDNA 水平的变化，尽早预测进展性疾病 (PD)。设计一项前瞻性、单中心、观察性研究。方法 前瞻性纳入 2020 年 2 月至 2021 年 9 月期间接受过一线治疗的患者。从治疗开始到第一次通过 CT 扫描重新分期，每个治疗周期前均采集血液进行 ctDNA 检测。通过突变 (mut-ctDNA) 和甲基化特异性 ddPCR 检测 ctDNA。受试者操作特征 (ROC) 分析用于描述所有时间点重新分期时 PD 预测的敏感性和特异性。结果共纳入42例肿瘤组织均携带突变的患者。mut-ctDNA 的检出率为 88.1%，meth-ctDNA 的检出率为 74.4%。治疗前的绝对 ctDNA 水平可预测总生存期。PD 患者在再分期时的 ctDNA 水平显着较高。从治疗开始到重新分期的中位时间为 93 天 (95% CI 88.8-96)。平均治疗 19 天后（95% CI 16.1-20.2），突变或甲基化特异性 ctDNA 水平下降 ⩽58% 预测再分期时的 PD，敏感性/特异性为 92.9/85.7% 和 85.7/分别为 100%。重新分期的中位时间为 66 天 (95% CI 56.8-75.2)。在 ctDNA 测量的后期时间点，灵敏度/特异性没有显着增加。结论 通过 mut-ctDNA 或 meth-ctDNA 监测 ctDNA 水平的早期变化，可以早期预测接受过治疗的 mCRC 患者的 PD。这有可能补充基于 RECIST 的治疗评估，旨在尽早改变可能不足的治疗方法，这对于较高的治疗线尤其重要。