Purpose: we tested whether ctDNA changes may be used to assess early response and clinical outcome in metastatic colorectal cancer (mCRC) patients undergoing front-line systemic anti-cancer therapy (SACT). Experimental Design: 862 plasma samples were collected 4-weekly from baseline (BL) until disease progression in mCRC patients receiving front line SACT. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the 3 variants with the highest allele frequency in BL ctDNA. Results: 83 paired samples from 75 patients were available for analysis. 12 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 that cleared ctDNA had significantly longer overall (45.6 months) and progression-free survival (13.9 months) compared to non-normalized patients [OS= 22.6 months (Log-rank p = 0.01) and PFS= 10.7 months (Log-rank p = 0.036) respectively]. In addition, higher response rate was observed in patients with ctDNA clearance (72.9%) compared to non-normalized cases (38.2%). Longitudinal sequencing of at least four timepoints in pts with a PFS>10 months showed emerging variants in 47.8% of cases; in all these patients the trajectory of these new “outlier” variants appeared in stark contrast with the clinical-radiological course of disease and the trend in other mutations. Conclusions: ctDNA clearance represents an early indicator of benefit from SACT in mCRC patients; serial tracking of multiple variants is warranted to improve specificity and to avoid misleading information due to the emergence of mutations of unknown clinical significance.

中文翻译：

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一线化疗转移性结直肠癌患者的循环肿瘤 DNA 动力学和临床结局


目的：我们测试了 ctDNA 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果。实验设计： 在接受一线 SACT 的 mCRC 患者中，从基线 （BL） 至疾病进展，每周 4 周收集 862 份血浆样本。ctDNA 正常化定义为治疗 1 个月后 （Mo1） 在 BL ctDNA 中等位基因频率最高的 3 个变体中清除率为 ≥99%。结果： 来自 75 例患者的 83 个配对样本可用于分析。12 对 （14.4%） 显示 BL 或 Mo1 均无变异。在其余 71 项比较 （65 名患者） 中，37 项 （52.1%） 显示 ctDNA 在 Mo1 处正常化。与未正常化的患者相比，清除 ctDNA 的患者的总生存期 （45.6 个月） 和无进展生存期 （13.9 个月） 显著更长 [OS= 22.6 个月 （Log-rank p = 0.01） 和 PFS = 10.7 个月 （Log-rank p = 0.036）]。此外，与未正常化的病例 （38.2%） 相比，在 ctDNA 清除患者 （72.9%） 中观察到更高的反应率。PFS>10 个月 pts 中至少 4 个时间点的纵向测序显示 47.8% 的病例出现变异;在所有这些患者中，这些新的“异常值”变异的轨迹与疾病的临床放射学病程和其他突变的趋势形成鲜明对比。结论：ctDNA 清除率是 mCRC 患者 SACT 获益的早期指标;有必要对多个变异进行连续跟踪，以提高特异性并避免由于出现临床意义未知的突变而产生误导性信息。