Xiong Liwen, Cui Shaohua, Ding Jingyan, Sun Yun, Zhang Longfu, Zhao Yizhuo, Gu Aiqin, Chu Tianqing, Wang Huimin, Zhong Hua, Ye Xin, Gu Yi, Zhang Xin, Hu Min, Jiang Liyan
Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
IMed Asia, AstraZeneca, Shanghai, China.
Oncotarget. 2017 Jul 10;8(38):63846-63856. doi: 10.18632/oncotarget.19139. eCollection 2017 Sep 8.
Genomic profiling using plasma cell-free DNA (cfDNA) represents a non-invasive alternative to tumor re-biopsy, which is challenging in clinical practice. The feasibility of dynamically monitoring epidermal growth factor receptor (EGFR) mutation status using serial plasma samples from non-small cell lung cancer (NSCLC) patients treated by tyrosine kinase inhibitors (TKIs) and its application in tracking clinical response and detection of resistance were investigated.
Forty-five NSCLC patients with EGFR mutation-positive pre-TKI plasma and at least two post-TKI plasma collections were recruited to this study. EGFR mutations including L858R, exon 19 deletion (19-del) and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples.
We observed a significant reduction in plasma EGFR mutation abundance during the first two-month of TKI treatment. Acquiring of secondary T790M gatekeeper mutation or completed "loss" of EGFR mutations represented two major categories of resistance profiles. Moreover, we demonstrated that levels of plasma EGFR mutations highly correlated with changes of tumor diameter as determined by radiographic imaging, or development of new lesions. In a subset of patients, we further showed that reappearance of EGFR mutations could be detected in plasma up to 5 months ahead of progressive disease (PD), suggesting an early detection of drug resistance.
Our findings suggest that genomic analysis using plasma cfDNA may offer an effective approach to monitor clinical response and emergence of resistance.
利用血浆游离DNA（cfDNA）进行基因组分析是肿瘤再次活检的一种非侵入性替代方法，而肿瘤再次活检在临床实践中具有挑战性。本研究探讨了使用酪氨酸激酶抑制剂（TKIs）治疗的非小细胞肺癌（NSCLC）患者的系列血浆样本动态监测表皮生长因子受体（EGFR）突变状态的可行性及其在跟踪临床反应和耐药性检测中的应用。
本研究招募了45例NSCLC患者，这些患者在接受TKI治疗前血浆EGFR突变呈阳性，且至少有两次TKI治疗后的血浆样本。使用液滴数字PCR（ddPCR）对纵向采集的血浆样本中的EGFR突变（包括L858R、外显子19缺失[19-del]和T790M）进行分析。
我们观察到在TKI治疗的前两个月血浆EGFR突变丰度显著降低。获得继发性T790M守门人突变或EGFR突变完全“消失”是两种主要的耐药模式。此外，我们证明血浆EGFR突变水平与影像学确定的肿瘤直径变化或新病灶的出现高度相关。在一部分患者中，我们进一步表明，在疾病进展（PD）前长达5个月的血浆中可检测到EGFR突变的重新出现，这表明可早期检测到耐药性。
我们的研究结果表明，利用血浆cfDNA进行基因组分析可能为监测临床反应和耐药性的出现提供一种有效的方法。
