Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA.
Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA.
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DOI：
10.1158/1078-0432.ccr-17-1341
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发表时间：
2018-04-15
期刊：
影响因子：
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通讯作者：
Patel AA
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文献类型：
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作者：
Goldberg SB;Narayan A;Kole AJ;Decker RH;Teysir J;Carriero NJ;Lee A;Nemati R;Nath SK;Mane SM;Deng Y;Sukumar N;Zelterman D;Boffa DJ;Politi K;Gettinger SN;Wilson LD;Herbst RS;Patel AA
决定继续或暂停免疫检查点抑制剂的治疗通常是由系列成像上看到的肿瘤动力学指导的。然而，免疫治疗反应具有独一无二的挑战性，因为肿瘤通常缓慢缩小，或者由于炎症而出现一过性增大。我们假设，通过量化循环肿瘤DNA(CtDNA)水平的变化来实时监测肿瘤细胞死亡可以早期评估免疫治疗的效果。我们比较了28例接受免疫检查点抑制剂治疗的转移性非小细胞肺癌患者中，ctDNA水平的纵向变化与放射学肿瘤大小的变化以及与生存结果的关系。通过使用多基因下一代测序分析确定血浆中与癌症相关的体细胞突变的等位基因比例来量化ctDNA。我们将ctDNA反应定义为突变等位基因比例较基线下降50%，并进行第二次验证性测量。观察到ctDNA反应和放射学反应之间有很强的一致性(Cohen‘s kappa，0.753)。在这两类患者中，通过ctDNA获得初步反应的中位时间为24.5天，而通过成像获得初始反应的中位时间为72.5天。CtDNA应答者的治疗时间明显长于无应答者(中位数为205.5天，无应答者为69天；P<；0.001)。CtDNA应答与较好的无进展生存率(风险比为0.29；95%可信区间为0.09~0.89；P=0.03)和较好的总体生存率(风险比为0.17；95%可信区间为0.05~0.62；P=0.007)相关。CtDNA水平的下降是治疗效果的早期标志，并预测接受免疫检查点抑制剂治疗的非小细胞肺癌患者的生存时间延长。
Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real-time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy. We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 metastatic non-small cell lung cancer patients receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multi-gene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement. Strong agreement was observed between ctDNA response and radiographic response (Cohen’s kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA vs. 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders vs. non-responders (median 205.5 vs. 69 days; P<0.001). A ctDNA response was associated with superior progression-free survival (hazard ratio [HR], 0.29; 95% CI, 0.09–0.89; P=0.03), and superior overall survival (HR, 0.17; 95% CI, 0.05–0.62; P=0.007). A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for non-small cell lung cancer.