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Abstract：
OBJECTIVE: To evaluate the prognostic significance of detectable circulating cell-free DNA (cfDNA) BRAF V600E/K mutations in patients with advanced melanoma enrolled in a clinical trial without BRAF-targeted therapy.
METHODS: BRAF V600E/K mutation status was determined on archived tissue and pretreatment stored plasma from 149 patients with unresectable stage IV melanoma who were enrolled between May 5, 2010 and May 2, 2014 in the North Central Cancer Treatment Group/Alliance N0879 randomized phase 2 clinical trial. Results were reported as presence or absence of cfDNA BRAF V600E/K detection of assay vs tissue. Progression-free survival (PFS) and overall survival (OS) were assessed for patients with and without detectable BRAF mutation.
RESULTS: In total, 63 of 149 (42.3%) patients had BRAF V600E/K results for tissue and blood, and 20 of 63 (31.7%) patients had tissue-diagnosed mutant BRAF. Of these, 11 of 20 (55.0%) patients had detectable plasma cfDNA BRAF. Among patients with tissue-mutant BRAF V600E/K, PFS and OS were shorter for those with corresponding cfDNA mutations (PFS, 5.8 vs 12.0 months; P=.051; OS, 9.2 vs 27.1 months; P=.054). Our assay demonstrated sensitivity of 55% (95% CI, 0.322 to 0.768), specificity of 97.7% (95% CI, 0.932 to 1.000), positive predictive value of 91.7% (95% CI, 0.760 to 1.000), and negative predictive value of 82.4% (95% CI, 0.719 to 0.928).
CONCLUSIONS: In advanced melanoma, detectable cfDNA BRAF V600E/K mutation is present in about half the patients with stage IV with BRAF-mutant melanoma tumor tissue and appears to confer a poorer prognosis when detectable. Given the poorer prognosis, cfDNA can be used to risk-stratify patients with metastatic melanoma in practice or clinical trials.Trial Registration: clinicaltrials.gov Identifier: NCT00976573.
METHODS: BRAF V600E/K mutation status was determined on archived tissue and pretreatment stored plasma from 149 patients with unresectable stage IV melanoma who were enrolled between May 5, 2010 and May 2, 2014 in the North Central Cancer Treatment Group/Alliance N0879 randomized phase 2 clinical trial. Results were reported as presence or absence of cfDNA BRAF V600E/K detection of assay vs tissue. Progression-free survival (PFS) and overall survival (OS) were assessed for patients with and without detectable BRAF mutation.
RESULTS: In total, 63 of 149 (42.3%) patients had BRAF V600E/K results for tissue and blood, and 20 of 63 (31.7%) patients had tissue-diagnosed mutant BRAF. Of these, 11 of 20 (55.0%) patients had detectable plasma cfDNA BRAF. Among patients with tissue-mutant BRAF V600E/K, PFS and OS were shorter for those with corresponding cfDNA mutations (PFS, 5.8 vs 12.0 months; P=.051; OS, 9.2 vs 27.1 months; P=.054). Our assay demonstrated sensitivity of 55% (95% CI, 0.322 to 0.768), specificity of 97.7% (95% CI, 0.932 to 1.000), positive predictive value of 91.7% (95% CI, 0.760 to 1.000), and negative predictive value of 82.4% (95% CI, 0.719 to 0.928).
CONCLUSIONS: In advanced melanoma, detectable cfDNA BRAF V600E/K mutation is present in about half the patients with stage IV with BRAF-mutant melanoma tumor tissue and appears to confer a poorer prognosis when detectable. Given the poorer prognosis, cfDNA can be used to risk-stratify patients with metastatic melanoma in practice or clinical trials.Trial Registration: clinicaltrials.gov Identifier: NCT00976573.
摘要：
目的：评估可检测到的循环无细胞DNA(cfDNA)BRAFV600E/K突变对参与一项无BRAF靶向治疗临床试验的晚期黑色素瘤患者的预后意义。
方法：在2010年5月5日至2014年5月2日在北中心癌症治疗组/AllianceN0879随机2期临床试验中纳入的149例不可切除的IV期黑色素瘤患者的存档组织和治疗储存血浆中确定BRAFV600E/K突变状态。结果被报道为测定与组织的cfDNABRAFV600E/K检测的存在或不存在。评估有和没有BRAF突变的患者的无进展生存期（PFS）和总生存期（OS）。
结果：总计，149例患者中有63例（42.3%）的组织和血液有BRAFV600E/K结果，63例患者中有20例（31.7％）患有组织诊断的突变型BRAF。其中,20名患者中有11名(55.0%)具有可检测的血浆cfDNABRAF。在组织突变的BRAFV600E/K患者中，具有相应cfDNA突变的患者的PFS和OS较短(PFS，5.8个月vs12.0个月；P=.051；OS，9.2对27.1个月；P=.054）。我们的分析显示灵敏度为55%(95%CI，0.322至0.768)，特异性为97.7%（95%CI，0.932至1.000），阳性预测值为91.7%（95%CI，0.760至1.000），阴性预测值为82.4%(95%CI，0.719~0.928)。
结论：在晚期黑色素瘤中，可检测的cfDNABRAFV600E/K突变存在于约一半的具有BRAF突变型黑色素瘤肿瘤组织的IV期患者中,当可检测到时,其预后似乎较差.鉴于预后较差，cfDNA可用于在实践中或临床试验中转移性黑色素瘤患者的风险分层。试用注册：clinicaltrials.gov标识符：NCT00976573。
方法：在2010年5月5日至2014年5月2日在北中心癌症治疗组/AllianceN0879随机2期临床试验中纳入的149例不可切除的IV期黑色素瘤患者的存档组织和治疗储存血浆中确定BRAFV600E/K突变状态。结果被报道为测定与组织的cfDNABRAFV600E/K检测的存在或不存在。评估有和没有BRAF突变的患者的无进展生存期（PFS）和总生存期（OS）。
结果：总计，149例患者中有63例（42.3%）的组织和血液有BRAFV600E/K结果，63例患者中有20例（31.7％）患有组织诊断的突变型BRAF。其中,20名患者中有11名(55.0%)具有可检测的血浆cfDNABRAF。在组织突变的BRAFV600E/K患者中，具有相应cfDNA突变的患者的PFS和OS较短(PFS，5.8个月vs12.0个月；P=.051；OS，9.2对27.1个月；P=.054）。我们的分析显示灵敏度为55%(95%CI，0.322至0.768)，特异性为97.7%（95%CI，0.932至1.000），阳性预测值为91.7%（95%CI，0.760至1.000），阴性预测值为82.4%(95%CI，0.719~0.928)。
结论：在晚期黑色素瘤中，可检测的cfDNABRAFV600E/K突变存在于约一半的具有BRAF突变型黑色素瘤肿瘤组织的IV期患者中,当可检测到时,其预后似乎较差.鉴于预后较差，cfDNA可用于在实践中或临床试验中转移性黑色素瘤患者的风险分层。试用注册：clinicaltrials.gov标识符：NCT00976573。
