Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer
Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer
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DOI：
10.1093/annonc/mdv177
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发表时间：
2015-08-01
影响因子：
50.5
通讯作者：
Gibbs, P.
中科院分区：
文献类型：
--
作者：
Tie, J.;Kinde, I.;Gibbs, P.
背景：转移性结直肠癌（mCRC）治疗反应的早期指标可用于优化治疗。我们探讨了循环肿瘤DNA（ctDNA）水平的早期变化作为一个标记的therapeutic efficacy.Patients和方法：这项前瞻性研究涉及53例接受标准一线化疗的结直肠癌患者。在治疗前、治疗后3天和第2周期前收集的血浆中评估ctDNA和CEA两者。在基线和8-10周时进行计算机断层扫描（CT），并使用RECIST v1.1标准进行集中评估。使用mCRC中频繁突变的15个基因的组对肿瘤进行测序，以鉴定用于ctDNA分析的候选突变。对于每个患者，选择一个肿瘤突变，使用称为Safe-SeqS.Results的数字基因组测定来评估血浆样品中ctDNA的存在和水平：在52例（98.1%）肿瘤中鉴定了ctDNA分析的候选突变。这些患者特异性候选组织突变在来自这52名患者中的48名患者的血浆的无细胞DNA中是可检测的（一致性92.3%）。在第2周期前观察到ctDNA水平显著降低（中位数5.7倍; P < 0.001），这与8-10周时的CT反应相关（比值比= 5.25，ctDNA降低10倍; P = 0.016）。ctDNA前体2的显著降低（>= 10倍）与较小的降低与无进展生存期增加的趋势相关（中位数14.7与8.1个月; HR = 1.87; P = 0.266）。一线化疗期间ctDNA的早期变化可预测后期放射学反应。
Background: Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy.Patients and methods: This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8-10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS.Results: Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8-10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (>= 10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266).Conclusions: ctDNA is detectable in a high proportion of treatment naive mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.