在转移性结直肠癌 (mCRC) 中，RAS 突变会导致对抗表皮生长因子受体抗体产生耐药性。目前尚不清楚 RAS 突变是否会变得无法克隆检测。CO.26 是一项 II 期临床试验，评估了 durvalumab tremelimumab 在经过大量预处理的 mCRC 中的作用。使用循环肿瘤 DNA (ctDNA) 测序在基线、第 8 周和进展时跟踪随时间推移的 RAS 突变状态。在存档肿瘤组织中存在 KRAS/NRAS 突变的 95 名患者中，6.3% (6/95) 的 RAS 检测不到在 CO.26 研究的基线或第 8 周收集的 ctDNA 突变。其中，67% (4/6) 的消失是暂时的，随着疾病进展，相同的突变会重新出现。在三个病例中，无法证明其他先前存在的 CRC 相关树干突变同时持续存在，这表明 ctDNA 的肿瘤脱落率较低，从而使真正的克隆回复为 RAS 野生型 (WT) 的发生率可能低至 3.2%（3 /95）。与持续 RAS 突变的患者 (75%) 相比，neo-RAS-WT 组中在试验基线时出现超过 4 个病变的患者较少 (33%)，P = 0.046。 RAS 消失突变患者与持续性 RAS 突变患者之间，癌症诊断时发生同步转移 (33% vs 63%；P = .15) 或试验基线时发生肝转移 (50% vs 68.5%；P = .17) 的可能性没有显着差异。 IV 期诊断的总生存率（风险比，0.77 [95% CI，0.35 至 1.72]；P = .52）在 RAS 消失突变患者与持续存在突变患者之间没有显着差异。 RAS 突变的消失与原发肿瘤侧面 (P = .41)、档案 BRAF/MEK/ERK 突变状态 (P = .16/1.00/.09) 或基线 ctDNA HER2 扩增 (P = 1.00) 无关我们在 CO.26 试验中发现 neo-RAS-WT 现象的患病率为 3.2%-6.3%。然而，67% 的明显病例是短暂的，随后会再次出现。

In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable.CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00).We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.