PO.CL01.11 · 临床研究
动态血浆KRAS和EGFR ctDNA谱分析可识别转移性肺癌的治疗反应和新生耐药
Dynamic plasma KRAS and EGFR ctDNA profiling identifies treatment response and nascent resistance in metastatic lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景:液体活检能够实现微创的肿瘤基因组评估。我们评估了转移性肺癌中KRAS和EGFR的连续循环肿瘤DNA(ctDNA)监测,以表征突变动态、将变化与临床事件相关联,并评估血浆检测用于早期耐药检测的价值。
目的:描述全身治疗期间纵向的KRAS和EGFR血浆模式,并将ctDNA动力学与治疗变更和结局相关联。
方法:前瞻性入组35例转移性肺癌患者(31.4%为女性;中位年龄70岁,IQR 41-84)。在基线时采集血浆,并对其中20例患者在第4、8、12和24周及此后直至疾病进展或死亡时采集血浆。使用Idylla平台的靶向ctDNA检测评估KRAS和EGFR状态。
结果:KRAS和EGFR的组织-血浆一致性为一般至中等(Cohen's kappa分别为0.35和0.43)。连续监测显示患者间存在显著异质性以及突变等位基因分数的动态变化。两例患者在第4周出现早期KRAS升高;其中一例死亡,另一例进展至二线治疗并在第8周出现第二个KRAS密码子12突变(G12R与基线G12C并存),与克隆多样化一致。另一例患者显示KRAS检测呈波动性——基线和第8周存在,但第4周和第12周缺失——提示与治疗排程相关的短暂克隆抑制和再扩增。一例患者的EGFR水平随治疗变化:基线和第4周较高,在换用Amivantamab后于第8周清除,随后在因毒性停药后于第12周再次出现。仅一例患者(8.3%)观察到EGFR突变;其他患者在整个随访期间均保持EGFR野生型。
结论:纵向血浆KRAS和EGFR检测捕捉到不断演变的突变格局,可预示疾病进展并反映治疗效应,包括继发克隆的出现和突变分数的短暂抑制。连续ctDNA谱分析是组织基因分型用于早期耐药检测和治疗指导的一种实用辅助手段。需要更大规模的队列来量化预测性能,并将ctDNA动力学整合入临床决策算法中。
查看英文原文 English abstract
Background: Liquid biopsy enables minimally invasive tumor genomic assessment. We evaluated serial circulating tumor DNA (ctDNA) monitoring for KRAS and EGFR in metastatic lung cancer to characterize mutational dynamics, correlate changes with clinical events, and assess plasma testing for early resistance detection.
Aims: Describe longitudinal KRAS and EGFR plasma patterns during systemic therapy and relate ctDNA kinetics to treatment changes and outcomes.
Methods: Thirty-five metastatic lung cancer patients were prospectively enrolled (31.4% female; median age 70, IQR 41-84). Plasma was collected at baseline and, for 20 patients, at weeks 4, 8, 12 and 24 and thereafter until progression or death. KRAS and EGFR status was assessed with targeted ctDNA assays using the Idylla platform.
Results: Tissue-plasma concordance was fair to moderate for KRAS and EGFR (Cohen's kappa 0.35 and 0.43). Serial monitoring showed marked interpatient heterogeneity and dynamic shifts in mutant allele fractions. Two patients had early KRAS increases at week 4; one died and the other progressed to second-line therapy and developed a second KRAS codon 12 mutation (G12R alongside baseline G12C) at week 8, consistent with clonal diversification. Another patient showed oscillating KRAS detection-present at baseline and week 8 but absent at weeks 4 and 12-suggesting transient clonal suppression and re-expansion related to treatment scheduling. One patient's EGFR levels tracked therapy: high at baseline and week 4, cleared at week 8 after switching to Amivantamab, then reappeared at week 12 after treatment discontinuation for toxicity. EGFR mutations were observed in one patient only (8.3%); others remained EGFR wild type throughout follow-up.
Conclusions: Longitudinal plasma KRAS and EGFR testing captured evolving mutational landscapes that anticipated progression and reflected treatment effects, including emergence of secondary clones and transient suppression of mutant fractions. Serial ctDNA profiling is a pragmatic adjunct to tissue genotyping for early resistance detection and therapeutic guidance. Larger cohorts are needed to quantify predictive performance and integrate ctDNA kinetics into clinical decision algorithms.
利益披露 Disclosure
V. Buzzi, None..
G. Berti, None..
M. Santillo, None..
A. Belli, None..
G. Favarato, None..
M. Iannopollo, None..
E. Rosi, None..
F. Lavorini, None..
S. Tomassetti, None..
A. Arcangeli, None..
E. Lastraioli, None.