Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study
Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study
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DOI：
10.1093/annonc/mdx212
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发表时间：
2017-08-01
影响因子：
50.5
通讯作者：
Bidard, F. -C.
中科院分区：
文献类型：
--
作者：
Cabel, L.;Riva, F.;Bidard, F. -C.
背景资料：最近的临床结果支持使用新的免疫检查点阻断剂（ICB），如抗PD-1（例如纳武单抗和派姆单抗）和抗PD-L1抗体。由于肿瘤免疫浸润，治疗期间ICB疗效的放射学评价具有挑战性。治疗过程中循环肿瘤DNA（ctDNA）水平的变化可能是一个很有前途的工具，非常准确的监测治疗效果，但数据缺乏与ICB.Patients和方法：这项前瞻性的试点研究进行了非小细胞肺癌，葡萄膜黑色素瘤，或微卫星不稳定的结直肠癌治疗的nivolumab或pembrolizumab单药治疗的患者在居里研究所。根据突变类型，在基线和8周后（w8）通过双向焦磷酸解活化聚合、液滴数字PCR或下一代测序评估ctDNA水平。结果：15例患者中10例在基线时检测到ctDNA。在第8周，观察到ctDNA水平的同步变化与肿瘤大小之间存在显著相关性（r = 0.86; P = 0.002）。在w8时ctDNA水平变得不可检测的患者呈现对治疗的显著且持久的应答。第8周的ctDNA检测也是无进展生存期的重要预后因素（风险比= 10.2; 95%置信区间2.5-41，P < 0.001）和总生存期（风险比= 15; 95%置信区间2.5-94.9，P = 0.004）。这项原理验证研究首次证明了定量ctDNA监测是评估抗PD-1药物治疗患者肿瘤反应的有价值工具。
Background: Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.Patients and methods: This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.Results: ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5-94.9, P = 0.004).Conclusion: This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.