ctDNA Detection with Low-Pass Whole-Genome Bisulfite Sequencing in RAS Wild-Type Metastatic Colorectal Cancer: An Exploratory Objective of the VALENTINO Trial.

experimental_design

We leveraged METER, a novel, highly reproducible, computational workflow that infers ctDNA presence and fraction from low-pass whole-genome bisulfite sequencing to investigate baseline and 8-week ctDNA dynamics in patients with RAS wild-type mCRC undergoing first-line treatment with panitumumab/FOLFOX in the VALENTINO randomized phase II trial. IchorCNA was used to provide a benchmark for METER.

我们利用METER，这是一种新颖、高度可重复的计算工作流程，它通过低通量全基因组双硫仑测序推断ctDNA的存在和比例，调查了在VALENTINO随机II期试验中接受帕尼单抗/FOLFOX一线治疗的RAS野生型mCRC患者的基线和8周ctDNA动态。使用IchorCNA为METER提供基准。

Results

A total of 154 patients were evaluable.

共有154名患者可进行评估。

Baseline ctDNA was detected in 72.7% of patients and was associated with significantly higher risk of progression [1.65, 95% confidence interval(CI), 1.13-2.42; P = 0.010] and death (HR: 2.24; 95% CI, 1.37-3.66; P < 0.001).

基线时在72.7%的患者中检测到循环肿瘤DNA（ctDNA），这与疾病进展的显著高风险相关[风险比1.65，95%置信区间（CI），1.13-2.42；P = 0.010]以及与死亡的显著高风险相关（风险比2.24；95% CI, 1.37-3.66；P < 0.001）。

CtDNA clearance at 8 weeks was observed in 80.2% of patients with baseline detectable ctDNA; persistence of ctDNA was associated with significantly higher risk of progression (2.70, 95% CI, 1.63-4.49; P < 0.001) and death (HR: 3.37; 95% CI, 2-5.69; P < 0.001).

在基线时ctDNA可检测的患者中，8周时观察到80.2%的患者ctDNA清除；ctDNA的持续存在与疾病进展的显著较高风险相关（风险比2.70，95%置信区间1.63-4.49；P < 0.001）以及死亡风险（风险比3.37；95%置信区间2-5.69；P < 0.001）。

CtDNA clearance was associated with a more profound depth of response (median -48.4% vs. -41.2%; P = 0.023) but not with a higher frequency of early tumor shrinkage (72% vs. 73.7%; P = 1).

ctDNA清除与更深层次的反应深度相关（中位数-48.4% vs. -41.2%；P = 0.023），但与早期肿瘤缩小的频率无关（72% vs. 73.7%；P = 1）。

METER expanded the number of ctDNA-positive patients relative to copy-number alteration- and variant allele frequency-based methods.

METER 相对于基于拷贝数变异和变异等位基因频率的方法，扩大了循环肿瘤 DNA（ctDNA）阳性患者的数量。

Conclusions

CtDNA detection and quantification with METER is a promising tool for cost-effective treatment monitoring in mCRC and can complement radiologic assessment of response dynamics.

使用 METER 进行循环肿瘤 DNA（ctDNA）的检测和定量是转移性结直肠癌（mCRC）成本效益治疗监测的一个有前景的工具，并且可以补充对治疗反应动态的放射学评估。