Quantitative Cell-Free DNA, KRAS, and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan
Quantitative Cell-Free DNA, KRAS, and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan
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DOI：
10.1158/1078-0432.ccr-11-0564
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发表时间：
2012-02-15
影响因子：
11.5
通讯作者：
Jakobsen, Anders
中科院分区：
文献类型：
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作者：
Spindler, Karen-Lise Garm;Pallisgaard, Niels;Jakobsen, Anders
目的：本研究调查了与西妥昔单抗和伊立替康三线治疗相关的转移性结直肠癌（mCRC）患者血浆中循环无细胞DNA（cfDNA）的水平以及cfDNA与血浆中肿瘤特异性突变的定量关系。入选标准为经组织病理学证实的化疗耐药mCRC，适当的东部肿瘤协作组体能状态，和器官功能。治疗包括伊立替康以350 mg/m2给药3周，每周给予250 mg/m2西妥昔单抗，直至疾病进展或出现不可接受的毒性。采用定量PCR方法检测基线时血浆中cfDNA等位基因、KRAS和BRAF突变等位基因的数量。只有3名患者BRAF突变呈阳性。在肿瘤中检测到的大多数KRAS突变也存在于血浆中[41例中的32例（78%）]。血浆cfDNA和血浆突变型KRAS水平（pmKRAS）强相关（r = 0.85，P < 10（-4））。在具有低cfDNA的患者中，疾病控制率为77%（75%四分位数（P = 0.009））。pmKRAS水平高于75%的患者疾病控制率为0%，而pmKRAS水平较低的患者疾病控制率为42%（P = 0.048）。考克斯分析证实了cfDNA和pmKRAS两者的预后重要性。高水平是一个穷人outcome.Conclusions的明确指标：KRAS分析在血浆中是一个可行的替代组织分析。cfDNA和pmKRAS的定量水平是强相关的，并且具有临床应用的前景。临床癌症研究; 18（4）; 1177-85。（C）2012年AACR。
Purpose: The present study investigated the levels of circulating cell-free DNA (cfDNA) in plasma from patients with metastatic colorectal cancer (mCRC) in relation to third-line treatment with cetuximab and irinotecan and the quantitative relationship of cfDNA with tumor-specific mutations in plasma.Experimental Design: Inclusion criteria were histopathologically verified chemotherapy-resistant mCRC, adequate Eastern Cooperative Oncology Group performance status, and organ function. Treatment consisted of irinotecan being administered at 350 mg/m(2) for 3 weeks and weekly administration of 250mg/m(2) cetuximab until progression or unacceptable toxicity. Aquantitative PCR method was developed to assess the number of cfDNA alleles and KRAS and BRAF mutation alleles in plasma at baseline.Results: The study included 108 patients. Only three patients were positive for BRAF mutations. The majority of KRAS mutations detected in tumors were also found in the plasma [32 of 41 (78%)]. Plasma cfDNA and plasma mutant KRAS levels (pmKRAS) were strongly correlated (r = 0.85, P < 10(-4)). The disease control rate was 77% in patients with low cfDNA (75% quartile (P = 0.009)]. Patients with pmKRAS levels higher than 75% had a disease control rate of 0% compared with 42% in patients with lower pmKRAS (P = 0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pmKRAS. High levels were clear indicators of a poor outcome.Conclusions: KRAS analysis in plasma is a viable alternative to tissue analysis. Quantitative levels of cfDNA and pmKRAS are strongly correlated and hold promise of clinical application. Clin Cancer Res; 18(4); 1177-85. (C)2012 AACR.