Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy
Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy
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DOI：
10.1111/cas.14245
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发表时间：
2019-12-24
期刊：
影响因子：
5.7
通讯作者：
Maeda, Shin
中科院分区：
文献类型：
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作者：
Sugimori, Makoto;Sugimori, Kazuya;Maeda, Shin
根据癌症基因组序列，超过90%的胰腺导管腺癌（PDAC）病例具有活性KRAS突变。数字PCR（dPCR）能够准确检测和定量罕见突变。我们使用dPCR评估了接受化疗的晚期PDAC患者循环肿瘤DNA（ct-DNA）的动态。在47个配对的组织和ct-DNA样本中通过dPCR检测KRAS G12/13突变。21例患者在化疗期间每隔4至8周进行定量ct-DNA监测。使用组织DNA在这47例患者中的45例中检测到KRAS突变。在KRAS突变阴性病例中，下一代测序发现了KRAS Q61 K和NRAS Q61 R突变。使用ct-DNA在23/45例病例中检测到KRAS突变（肝或肺转移，18/19;突变等位基因频率[MAF]，0.1%-31.7%;腹膜转移，3/9 [0.1%]，局部晚期，2/17 [0.1%-0.2%]）。在ct-DNA监测中，MAF值的变化与疾病状态一致。在6例局部晚期病例中，KRAS突变与肝转移同时出现。在6例肝转移患者中，KRAS突变在疾病稳定或部分缓解期间消失，并在疾病进展时重新出现。KRAS突变在初始化疗后消失的患者的中位无进展生存期长于持续检测到突变的患者（248.5 vs 50天，P <0.001）。因此，ct-DNA监测能够持续评估疾病状态，并在化疗期间具有预后效用。
According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct-DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue- and ct-DNA samples. The 21 patients were subjected to quantitative ct-DNA monitoring at 4 to 8-week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation-negative cases, next-generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct-DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%-31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%-0.2%]). In the ct-DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression-free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P < .001). Therefore, ct-DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.