循环无细胞 DNA 中激活型 EGFR 突变的数量是监测奥希替尼反应的标志物。

The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response.

机构信息

Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

出版信息

Br J Cancer. 2018 Nov;119(10):1252-1258. doi: 10.1038/s41416-018-0238-z. Epub 2018 Nov 6.

BACKGROUND

Circulating cell-free DNA (cfDNA) may help understand the molecular response to pharmacologic treatment and provide information on dynamics of clonal heterogeneity. Therefore, this study evaluated the correlation between treatment outcome and activating EGFR mutations (act-EGFR) and T790M in cfDNA in patients with advanced NSCLC given osimertinib.

METHODS

Thirty-four NSCLC patients resistant to first/second-generation EGFR-TKIs, positive for both act-EGFR and T790M in cfDNA at the time of progression were enrolled in this study. Plasma samples were obtained at osimertinib baseline and after 3 months of therapy; cfDNA was analyzed by droplet digital PCR and results were expressed as mutant allele frequency (MAF).

RESULTS

At baseline, act-EGFR MAF was significantly higher than T790M (p < 0.0001). act-EGFR MAF and T790M/act-EGFR MAF ratio were significantly correlated with disease response (p = 0.02). Cut-off values of act-EGFR MAF and T790M/act-EGFR ratio of 2.6% and 0.22 were found, respectively. The PFS of patients with act-EGFR MAF of > 2.6% and < 2.6%, were 10 months vs. not reached, respectively (p = 0.03), whereas patients with T790M/act-EGFR ≤ 0.22 had poorer PFS than patients with a value of > 0.22 (6 months vs. not reached, respectively, p = 0.01).

CONCLUSION

act-EGFR MAF and T790M/act-EGFR MAF ratio are potential markers of outcome in patients treated with osimertinib.

背景

循环游离 DNA（cfDNA）可帮助了解药物治疗的分子反应，并提供有关克隆异质性动态的信息。因此，本研究评估了奥希替尼治疗的晚期 NSCLC 患者中 cfDNA 中治疗反应与激活的 EGFR 突变（act-EGFR）和 T790M 之间的相关性。

方法

本研究纳入了 34 名对第一代/第二代 EGFR-TKI 耐药、进展时 cfDNA 中同时存在 act-EGFR 和 T790M 的 NSCLC 患者。在奥希替尼基线和治疗 3 个月时采集血浆样本；通过液滴数字 PCR 分析 cfDNA，并以突变等位基因频率（MAF）表示结果。

结果

基线时，act-EGFR MAF 明显高于 T790M（p<0.0001）。act-EGFR MAF 和 T790M/act-EGFR MAF 比值与疾病反应显著相关（p=0.02）。分别发现 act-EGFR MAF 和 T790M/act-EGFR MAF 比值的截断值为 2.6%和 0.22。act-EGFR MAF>2.6%和<2.6%的患者的 PFS 分别为 10 个月和未达到，分别（p=0.03），而 T790M/act-EGFR≤0.22 的患者的 PFS 比 T790M/act-EGFR>0.22 的患者差（6 个月与未达到，分别，p=0.01）。