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Correlation of BRAF mutation status in circulating-free DNA and tumor and association with clinical outcome across four BRAFi and MEKi clinical trials

机译:四个BRAFi和MEKi临床试验中无循环DNA和肿瘤中BRAF突变状态的相关性以及与临床结果的关联

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摘要

Purpose: Tumor-derived circulating cell–free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome. Experimental Design: Patients with BRAF V600 mutation–positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined. Results: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K–positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation–positive cfDNA in plasma had higher response rates to dabrafenib and trametinib. Conclusions: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation–positive tumors. The lack of circulating, BRAF mutation–positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome.
机译:目的:源自肿瘤的循环无细胞DNA(cfDNA)是潜在的替代来源,可从中获得肿瘤突变状态。分析了来自BRAF抑制剂(BRAFi)达布拉非尼或MEK抑制剂(MEKi)曲美替尼的四项临床研究的cfDNA数据,以确定cfDNA中的BRAF突变状态与肿瘤组织之间的关联,以及BRAF cfDNA突变状态与基线因子和临床结果。实验设计:在使用基于PCR的测定法对肿瘤中的BRAF状况进行中央确认后,将每项研究纳入具有BRAF V600突变阳性黑色素瘤的患者。确定了基线时从患者血浆中cfDNA中的BRAF突变状态,共836例入组患者中的732例(88%)。结果:分别有76%和81%的BRAF V600E / V600K阳性肿瘤患者在cfDNA中检测到BRAF突变。与具有可检测的cfDNA BRAF突变的患者相比,在四项研究中的每项研究中,cfDNA的BRAF突变均为阴性的患者的无进展生存期(PFS)和总体生存期更长。在四项研究中的三项中,对基线因素进行多变量调整后,BRAF突变cfDNA的存在是PFS的独立预后因素。血浆中BRAF突变阳性cfDNA阴性的患者对dabrafenib和曲美替尼的应答率更高。结论:cfDNA中的BRAF突变可在超过75%的患有BRAF突变阳性肿瘤的晚期黑色素瘤患者中检测到。对于转移性黑色素瘤患者,缺乏循环的,BRAF突变阳性cfDNA具有临床意义,并且可能是疾病预后更好的预后指标。

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