Ghidini Michele, Hahne Jens Claus, Senti Chiara, Heide Timon, Proszek Paula Z, Shaikh Ridwan, Carter Paul, Hubank Mike, Trevisani Francesco, Garrone Ornella, Cappelletti Maria Rosa, Generali Daniele, Cattaneo Monica, Gnocchi Nicoletta, Donati Gianvito, Gobbi Angela, Grizzi Giulia, Lampis Andrea, Elghadi Raghad, Tanzi Giulia, Tomasello Gianluca, Ratti Margherita, Pinato David J, Fassan Matteo, Vlachogiannis Georgios, Sottoriva Andrea, Cortellini Alessio, Passalacqua Rodolfo, Valeri Nicola
Division of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.
Clin Cancer Res. 2025 Feb 17;31(4):707-718. doi: 10.1158/1078-0432.CCR-24-0924.
We tested whether circulating tumor DNA (ctDNA) changes may be used to assess early response and clinical outcomes in patients with metastatic colorectal cancer (mCRC) undergoing first-line systemic anticancer therapy (SACT).
Eight hundred sixty-two plasma samples were collected 4-weekly from baseline (BL) until disease progression in patients with mCRC receiving first-line SACT. ctDNA was tested using tissue-agnostic next-generation sequencing panels. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the three variants with the highest allele frequency in BL ctDNA.
Eighty-three paired samples from 75 patients were available for analysis. Twelve pairs (14.4%) showed no variants in either BL or Mo1. In the remaining 71 comparisons (65 patients), 37 (52.1%) showed ctDNA normalization at Mo1. Patients who cleared ctDNA had significantly longer overall (45.6 months) and progression-free survival (13.9 months) compared with nonnormalized patients [overall survival = 22.6 months (log-rank P = 0.01) and progression-free survival = 10.7 months (log-rank P = 0.036), respectively]. In addition, a higher response rate was observed in patients with ctDNA clearance (72.9%) compared with nonnormalized cases (38.2%). Longitudinal sequencing of at least four time points in patients with a progression-free survival of >10 months showed emerging variants in 47.8% of cases; in all these patients, the trajectory of these new "outlier" variants seemed in stark contrast with the clinical-radiological course of disease and the trend in other mutations.
ctDNA clearance represents an early indicator of benefit from SACT in patients with mCRC; serial tracking of multiple variants is warranted to improve specificity and avoid misleading information due to the emergence of mutations of unknown clinical significance.
我们测试了循环肿瘤DNA（ctDNA）的变化是否可用于评估接受一线全身抗癌治疗（SACT）的转移性结直肠癌（mCRC）患者的早期反应和临床结局。
在接受一线SACT的mCRC患者中，从基线（BL）开始每4周收集一次血浆样本，直至疾病进展，共收集了862份血浆样本。使用不依赖组织的下一代测序平台检测ctDNA。ctDNA正常化定义为治疗1个月（第1个月）后，在BL ctDNA中具有最高等位基因频率的三个变体的清除率≥99%。
来自75名患者的83对配对样本可用于分析。12对（14.4%）在BL或第1个月均未显示变体。在其余71次比较（65名患者）中，37对（52.1%）在第1个月显示ctDNA正常化。与未正常化的患者相比，清除ctDNA的患者总生存期（45.6个月）和无进展生存期（13.9个月）显著更长[总生存期分别为22.6个月（对数秩检验P = 0.01）和无进展生存期为10.7个月（对数秩检验P = 0.036）]。此外，与未正常化的病例（38.2%）相比，ctDNA清除的患者观察到更高的缓解率（72.9%）。对无进展生存期>10个月的患者至少四个时间点进行纵向测序显示，47.8%的病例出现新变体；在所有这些患者中，这些新的“异常”变体的轨迹似乎与疾病的临床放射学进程和其他突变趋势形成鲜明对比。
ctDNA清除是mCRC患者从SACT中获益的早期指标；有必要对多个变体进行连续跟踪，以提高特异性并避免因出现临床意义不明的突变而产生误导性信息。
