Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary.
Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary.
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DOI：
10.1158/0008-5472.can-17-0628
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发表时间：
2017-08-15
期刊：
影响因子：
11.2
通讯作者：
Kurzrock R
中科院分区：
文献类型：
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作者：
Kato S;Krishnamurthy N;Banks KC;De P;Williams K;Williams C;Leyland-Jones B;Lippman SM;Lanman RB;Kurzrock R
原发性不明癌 (CUP) 是一种罕见且难以治疗的恶性肿瘤，通过识别可操作的驱动突变可能会改善其治疗。我们使用循环肿瘤 DNA (ctDNA) 的靶向临床级下一代测序 (NGS) 检测了 442 名 CUP 患者的 54-70 个基因。总体而言，80% 的患者表现出 ctDNA 改变； 66%，≥ 1 个特征性改变，排除意义不明的变异。 TP53 相关基因最常被改变 (37.8%)，其次是参与 MAPK 通路 (31.2%)、PI3K 信号传导 (18.1%) 和细胞周期机制 (10.4%) 的基因。在 87.9% 的 CUP 病例中观察到不同的基因组图谱，其中 99.7% 表现出潜在的可靶向改变。介绍了一位在治疗期间 ctDNA 含量动态变化的患者和一位因错配修复基因异常而接受基于检查点抑制剂的治疗方案的反应者。我们的结果表明，ctDNA 评估在 CUP 中是可行的，并且大多数患者具有独特的体细胞特征，具有药理学上可行的改变，证明在下一代临床试验中纳入非侵入性液体活检是合理的。
Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated interrogated 54–70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66%, ≥ 1 characterized alteration(s) excluding variants of unknown significance. TP53-associated genes were most commonly altered (37.8%) followed by genes involved in the MAPK pathway (31.2%), PI3K signaling (18.1%) and the cell cycle machinery (10.4%). Distinct genomic profiles were observed in 87.9% of CUP cases with 99.7% exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of non-invasive liquid biopsies in next-generation clinical trials.