ctDNA检测Adagrasib治疗NSCLC中的多克隆KRAS耐药
ctDNA Detection of Polyclonal KRAS Resistance in Adagrasib-Treated NSCLC.
作者
作者单位
- Laboratoire de Biologie des Tumeurs Solides, CHU Montpellier, Université de Montpellier, Montpellier, France.
- Institut du Cancer de Montpellier (ICM), Montpellier, France.
摘要
中文
循环肿瘤DNA（ctDNA）监测可能比传统影像学更早检测到KRASG12C抑制剂的耐药。然而，在KRASG12C抑制剂的具体背景下，分子、影像学和临床进展之间的时间关系仍未得到充分描述。一名66岁女性，携带KRASG12C/STK11/KEAP1突变肺腺癌，在化疗免疫治疗进展后接受二线adagrasib治疗。通过微滴式数字PCR和靶向二代测序进行连续ctDNA监测。基线KRASG12C ctDNA（6205.3拷贝/mL）在7周后降至3.2拷贝/mL，表明初始缓解。然而，ctDNA水平在第4个月升至21.1拷贝/mL，第6个月升至315.2拷贝/mL。同时进行的NGS显示出现了三种新的KRAS突变（G12D、G13D、Q61H），证实多克隆耐药。值得注意的是，在此期间CT和MRI影像按照RECIST标准保持稳定。显著临床恶化（需长期住院）发生在ctDNA初次升高后约8周。患者在检测到耐药突变后2个月死亡。在本病例中，NGS ctDNA在影像学长期稳定期间检测到除原始G12C外的三种获得性KRAS耐药突变，展示了adagrasib压力下的多克隆进化。这些发现提示纵向液体活检监测可能为KRASG12C突变NSCLC提供早期耐药检测。
English
Circulating tumor DNA (ctDNA) monitoring may detect resistance to KRASG12C inhibitors earlier than conventional imaging. However, in the specific context of KRASG12C inhibitors, the temporal relationship between molecular, radiologic, and clinical progression remains poorly characterized. A 66-year-old woman with KRASG12C/STK11/KEAP1-mutant lung adenocarcinoma received second-line adagrasib after progression on chemo-immunotherapy. Serial ctDNA monitoring by droplet digital PCR and targeted next-generation sequencing was performed. Baseline KRASG12C ctDNA (6205.3 copies/mL) declined to 3.2 copies/mL after 7 weeks, indicating initial response. However, ctDNA levels rose to 21.1 copies/mL at month 4 and 315.2 copies/mL at month 6. Concurrent NGS revealed three emergent KRAS mutations (G12D, G13D, Q61H), confirming polyclonal resistance. Notably, CT and MRI imaging remained stable by RECIST criteria throughout this period. Significant clinical deterioration, requiring prolonged hospitalization, occurred approximately 8 weeks after initial ctDNA rise. The patient died 2 months after detection of resistance mutations. In this case, NGS ctDNA detected three acquired KRAS resistance mutations in addition to the original G12C, during a prolonged period of radiographic stability, illustrating polyclonal evolution under adagrasib pressure. These findings suggest that longitudinal liquid biopsy monitoring may provide early detection of resistance in KRASG12C-mutant NSCLC.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q2
- 影响因子
- 2.6
- 新锐分区
- 4区