Department of Colorectal Surgery, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama, 241-8515, Japan.
Department of Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.
J Cancer Res Clin Oncol. 2024 May 28;150(5):281. doi: 10.1007/s00432-024-05805-3.
In metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of the RAS gene and its clinical significance.
This was a retrospective, single-center study that included 82 patients with tissue RAS-mutant (RAS-MT) mCRC who underwent circulating tumor DNA (ctDNA) RAS monitoring between January, 2013-April, 2023. Patients were analyzed for the rate of change over time to acquired RAS mutation loss (aRAS-ML) and clinicopathological factors. The prognostic relevance of mutation loss was assessed.
aRAS-ML was detected in 33 (40.2%) patients, 32 of whom had a mutation loss in the first ctDNA RAS assay. Patients with a RAS mutation detected in the first assay had a median time of 8 months until the second ctDNA RAS assay, with 4.5% cases newly converted to aRAS-ML; no new conversions were detected at the third assay. The aRAS-ML group exhibited more single-organ metastases in the target organ during ctDNA measurement (aRAS-ML: 84.8% vs. RAS-MT: 59.2%, p = 0.02). Of the 33 patients with aRAS-ML, seven (21.2%) received anti-epidermal growth factor receptor (EGFR) therapy, with a median progression-free survival of 8 months. Multivariate analysis revealed that persistent ctDNA RAS mutation was an independent prognostic factor for overall survival (hazard ratio: 2.7, 95% confidence interval: 1.1-6.3, p = 0.02).
The rate of ctDNA mutation loss in patients with RAS-MT mCRC decreases over time. Therefore, using a ctDNA RAS assay early in treatment will assist in challenging the use of EGFR regimens.
在转移性结直肠癌（mCRC）中，RAS 基因突变丢失可能发生在标准治疗方案期间。本研究旨在探讨 RAS 基因的时间动态变化及其临床意义。
这是一项回顾性、单中心研究，纳入了 2013 年 1 月至 2023 年 4 月期间接受循环肿瘤 DNA（ctDNA）RAS 监测的 82 例组织 RAS 突变阳性（RAS-MT）mCRC 患者。分析患者获得性 RAS 基因突变丢失（aRAS-ML）的时间变化率以及临床病理因素。评估突变丢失的预后相关性。
33 例（40.2%）患者检测到 aRAS-ML，其中 32 例在首次 ctDNA RAS 分析中发生突变丢失。首次检测到 RAS 突变的患者中位时间为 8 个月后进行第二次 ctDNA RAS 检测，4.5%的病例新转为 aRAS-ML；第三次检测未发现新的转换。aRAS-ML 组在 ctDNA 测量期间目标器官的单器官转移更多（aRAS-ML：84.8%比 RAS-MT：59.2%，p=0.02）。33 例 aRAS-ML 患者中，7 例（21.2%）接受抗表皮生长因子受体（EGFR）治疗，中位无进展生存期为 8 个月。多变量分析显示，持续的 ctDNA RAS 突变是总生存期的独立预后因素（风险比：2.7，95%置信区间：1.1-6.3，p=0.02）。
RAS-MT mCRC 患者的 ctDNA 突变丢失率随时间逐渐降低。因此，在治疗早期使用 ctDNA RAS 检测将有助于挑战 EGFR 方案的应用。
