在接受西妥昔单抗作为一线治疗的 RAS 野生型 mCRC 患者中，出现 RAS 突变：一项非干预性、非对照的多中心研究。
The emergence of RAS mutations in patients with RAS wild-type mCRC receiving cetuximab as first-line treatment: a noninterventional, uncontrolled multicenter study.
机构信息
Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
出版信息
Br J Cancer. 2023 Oct;129(6):947-955. doi: 10.1038/s41416-023-02366-z. Epub 2023 Jul 24.
ABSRTACT
BACKGROUND: Patients treated with anti-epidermal growth factor receptor (anti-EGFR) will ultimately develop acquired resistance promoted by clonal selection, mainly the emergence of mutations in the MAPK pathway (mostly RAS mutations). Baseline assessment of RAS mutations in the blood of patients correlates well with RAS tumour tissue testing and is currently an alternative option in routine clinical practice to guide first-line therapy. The aim of this study was the prevalence of acquired genomic alterations detected in the auxiliary tool of ctDNA testing and investigated the role of RAS ctDNA status for detecting tumour response and predicting benefit to anti-EGFR therapy.
METHODS
Only patients with concordant wild-type formalin-fixed, paraffin-embedded (FFPE) tumour tissue and baseline ctDNA RAS wild-type were included. RAS mutations in plasma were evaluated using MassARRAY platform. Blood samples were collected at baseline, every 3 months during first-line treatment, and at disease progression. The primary endpoint was the detection rate of RAS mutations during cetuximab treatment. The correlation between response and survival outcomes and the emergence of circulating RAS mutations was also analysed.
RESULTS
The detection rate of RAS mutations during treatment was 9.3% (10/108). RAS mutations detection occurred a median of 3 months prior to radiologic documentation. The subgroup of patients with RAS mutations exhibited significantly inferior progression-free survival and overall survival (P = 0.002 and 0.027, respectively) but the baseline characteristics, response rates, disease control rates, and metastatectomy were not significant (all P > 0.05).
CONCLUSIONS
We demonstrated that RAS ctDNA status might be a valuable biomarker for detecting early tumour response and predicting benefit to anti-EGFR therapy.
CLINICAL TRIAL REGISTRATION
NCT03401957 (January 17, 2018).
摘要
背景：接受抗表皮生长因子受体（anti-EGFR）治疗的患者最终会因克隆选择而产生获得性耐药，主要是 MAPK 通路（主要是 RAS 突变）的突变出现。患者血液中 RAS 突变的基线评估与 RAS 肿瘤组织检测具有良好的相关性，目前是指导一线治疗的常规临床实践中的替代选择。本研究的目的是检测辅助 ctDNA 检测中发现的获得性基因组改变的流行率，并研究 RAS ctDNA 状态在检测肿瘤反应和预测抗 EGFR 治疗获益中的作用。
方法
仅纳入基线时 ctDNA RAS 野生型与福尔马林固定石蜡包埋（FFPE）肿瘤组织一致的患者。使用 MassARRAY 平台评估血浆中的 RAS 突变。在一线治疗期间每 3 个月和疾病进展时采集基线血液样本。主要终点是在西妥昔单抗治疗期间检测到 RAS 突变的检出率。还分析了反应和生存结果与循环 RAS 突变的相关性。
结果
在治疗期间检测到 RAS 突变的检出率为 9.3%（10/108）。RAS 突变的检测发生在影像学记录前中位数 3 个月。具有 RAS 突变的患者亚组的无进展生存期和总生存期明显较差（分别为 P = 0.002 和 0.027），但基线特征、反应率、疾病控制率和转移切除术无显著差异（均 P > 0.05）。
结论
我们证明 RAS ctDNA 状态可能是一种有价值的生物标志物，可用于检测早期肿瘤反应和预测抗 EGFR 治疗的获益。
临床试验注册
NCT03401957（2018 年 1 月 17 日）。
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