Background/Objectives: In metastatic colorectal cancer (mCRC), liquid biopsy has enabled the identification of “neo-RAS-Wild-Type (WT)”, a transient phase characterized by the disappearance of RAS mutations, with significant clinical implications for re-sensitization to EGFR blockade. This study aimed to prospectively track the kinetics of neo-RAS-WT in circulating tumor DNA (ctDNA) among RAS-mutant mCRC patients receiving first-line and subsequent systemic therapies.Methods: A total of 380 serial blood samples from 35 patients were analyzed. Each patient provided a median of 10 ctDNA samples at three-month intervals during first-line and subsequent therapies. The patients were categorized into three groups: neo-RAS-WT, non-shedding, and persistent mutant.Results: During first-line treatment, 68% of patients transitioned to RAS-WT. Of these, 17% were neo-RAS-WT, while the majority were classified as non-shedding. In the second-line setting, the percentage of neo-RAS-WT increased to 34%, which dropped to 8.5% during the third-line setting. The duration of the neo-RAS-WT window was significantly longer in neo-RAS-WT patients compared to non-shedding patients (p= 0.037). Patients who achieved RAS-WT status had improved progression-free survival (PFS) compared to those with persistent mutant, with significant differences observed across all treatment lines: first-line (p= 0.004), second-line (p< 0.0001), and third-line (p= 0.001). Multivariate analysis revealed that the duration of the RAS-WT window correlated with extended first-line PFS (HR: 0.78; 95% CI: 0.69–0.89;p< 0.0001), second-line PFS (HR: 0.66; 95% CI: 0.52–0.84;p= 0.001), and overall survival (OS) (HR: 0.82; 95% CI: 0.72–0.95;p= 0.006).Conclusions: While the neo-RAS-WT window is transient in non-shedding, it is durable in neo-RAS-WT patients, persisting until disease progression. These findings highlight the potential utility of ctDNA testing in refining treatment strategies for RAS-mutant mCR.
背景/目的：在转移性结直肠癌（mCRC）中，液体活检技术能够识别“新RAS野生型（WT）”，即RAS突变暂时消失的阶段，这对重新启用EGFR阻断治疗具有重要临床意义。本研究旨在前瞻性追踪接受一线及后续系统治疗的RAS突变mCRC患者循环肿瘤DNA（ctDNA）中新RAS-WT的动态变化。 方法：共分析35例患者的380份连续血液样本。每例患者在一线及后续治疗期间每三个月采集一次ctDNA样本，中位样本数为10份。患者被分为三组：新RAS-WT组、非脱落组和持续突变组。 结果：一线治疗期间，68%的患者转为RAS-WT状态。其中17%为新RAS-WT患者，大多数被归类为非脱落组。在二线治疗中，新RAS-WT比例上升至34%，而在三线治疗中降至8.5%。新RAS-WT患者的RAS-WT窗口期持续时间显著长于非脱落组患者（p=0.037）。与持续突变组相比，达到RAS-WT状态的患者无进展生存期（PFS）显著改善，各治疗线均观察到显著差异：一线（p=0.004）、二线（p<0.0001）和三线（p=0.001）。多变量分析显示，RAS-WT窗口期持续时间与延长的一线PFS（HR：0.78；95% CI：0.69–0.89；p<0.0001）、二线PFS（HR：0.66；95% CI：0.52–0.84；p=0.001）和总生存期（OS）（HR：0.82；95% CI：0.72–0.95；p=0.006）相关。 结论：虽然新RAS-WT窗口期在非脱落组中是短暂的，但在新RAS-WT患者中具有持久性，可持续至疾病进展。这些发现凸显了ctDNA检测在优化RAS突变mCRC治疗策略中的潜在应用价值。
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